Objective adherence to dental device versus positive airway pressure treatment in adults with obstructive sleep apnea.

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 disorders, depression and anxiety are associated with adverse safety outcomes in healthcare workers: A prospective cohort study.

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 6 months 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.

Predictors of sleepiness in obstructive sleep apnoea at baseline and after 6†months of continuous positive airway pressure therapy.

We evaluated factors associated with subjective and objective sleepiness at baseline and after 6 months of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA).We analysed data from the Apnoea Positive Pressure Long-term Efficacy Study (APPLES), a prospective 6-month multicentre randomised controlled trial with 1105 subjects with OSA, 558 of who were randomised to active CPAP. Epworth sleepiness scale (ESS) scores and the mean sleep latency (MSL) on the maintenance of wakefulness test at baseline and after 6 months of CPAP therapy were recorded.Excessive sleepiness (ESS score >10) was present in 543 (49.1%) participants. Younger age, presence of depression and higher apnoea-hypopnoea index were all associated with higher ESS scores and lower MSL. Randomisation to the CPAP group was associated with lower odds of sleepiness at 6 months. The prevalence of sleepiness was significantly lower in those using CPAP >4 h·night-1versus using CPAP ≤4 h·night-1 Among those with good CPAP adherence, those with ESS >10 at baseline had significantly higher odds (OR 8.2, p<0.001) of persistent subjective sleepiness.Lower average nightly CPAP use and presence of sleepiness at baseline were independently associated with excessive subjective and objective sleepiness after 6 months of CPAP therapy.

Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials.

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).

The critical role of sleep spindles in hippocampal-dependent memory: a pharmacology study.

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.

An approach for determining the reliability of manual and digital scoring of sleep stages.

STUDY OBJECTIVES: Inter-scorer variability in sleep staging is largely due to equivocal epochs that contain features of more than one stage. We propose an approach that recognizes the existence of equivocal epochs and evaluates scorers accordingly. METHODS: Epoch-by-epoch staging was performed on 70 polysomnograms by six qualified technologists and by a digital system (Michele Sleep Scoring [MSS]). Probability that epochs assigned the same stage by only two of the six technologists (minority score) resulted from random occurrence of two errors was calculated and found to be <5%, thereby indicating that the stage assigned is an acceptable variant for the epoch. Acceptable stages were identified in each epoch as stages assigned by at least two technologists. Percent agreement between each technologist and the other five technologists, acting as judges, was determined. Agreement was considered to exist if the stage assigned by the tested scorer was one of the acceptable stages for the epoch. Stage assigned by MSS was likewise considered in agreement if included in the acceptable stages made by the technologists. RESULTS: Agreement of technologists tested against five qualified judges increased from 80.8% (range 70.5%-86.4% among technologists) when using the majority rule, to 96.1 (89.8%-98.5%) by the proposed approach. Agreement between unedited MSS and same judges was 90.0% and increased to 92.1% after brief editing. CONCLUSIONS: Accounting for equivocal epochs provides a more accurate estimate of a scorer's (human or digital) competence in scoring sleep stages and reduces inter-scorer disagreements. The proposed approach can be implemented in sleep-scoring training and accreditation programs.

Strategies for de-identification and anonymization of electronic health record data for use in multicenter research studies.

BACKGROUND: De-identification and anonymization are strategies that are used to remove patient identifiers in electronic health record data. The use of these strategies in multicenter research studies is paramount in importance, given the need to share electronic health record data across multiple environments and institutions while safeguarding patient privacy. METHODS: Systematic literature search using keywords of de-identify, deidentify, de-identification, deidentification, anonymize, anonymization, data scrubbing, and text scrubbing. Search was conducted up to June 30, 2011 and involved 6 different common literature databases. A total of 1798 prospective citations were identified, and 94 full-text articles met the criteria for review and the corresponding articles were obtained. Search results were supplemented by review of 26 additional full-text articles; a total of 120 full-text articles were reviewed. RESULTS: A final sample of 45 articles met inclusion criteria for review and discussion. Articles were grouped into text, images, and biological sample categories. For text-based strategies, the approaches were segregated into heuristic, lexical, and pattern-based systems versus statistical learning-based systems. For images, approaches that de-identified photographic facial images and magnetic resonance image data were described. For biological samples, approaches that managed the identifiers linked with these samples were discussed, particularly with respect to meeting the anonymization requirements needed for Institutional Review Board exemption under the Common Rule. CONCLUSIONS: Current de-identification strategies have their limitations, and statistical learning-based systems have distinct advantages over other approaches for the de-identification of free text. True anonymization is challenging, and further work is needed in the areas of de-identification of datasets and protection of genetic information.

Pharmacokinetic profile of SKP-1041, a modified release formulation of zaleplon.

OBJECTIVES: Two investigations aimed to define the pharmacokinetic profile of a modified-release preparation of zaleplon (SKP-1041). METHODS: Protocol SOM001 was a 5-way crossover, double-blind, randomized trial comparing three novel modified-release formulations of zaleplon 15 mg (SKP-1041A, SKP-1041B, SKP-1041C) to placebo and immediate-release zaleplon 10 mg. Protocol SOM002 was a randomized, crossover, open-label trial to compare the pharmacokinetics of SKP-1041B after day and night administration. In SOM001, study drug was administered at 9:00 a.m. (fasted); blood samples were obtained beginning 1 h predose through 12 h postdose. In study SOM002, study drug was administered at 9:00 a.m. or 10:30 p.m.; blood samples were obtained beginning 1 h predose through 12 h postdose. Subjects were 19 (SOM001) and 23 (SOM002) healthy adults between ages 20-46. RESULTS: Dose-normalized total AUCs for modified-release preparations A, B, C and immediate-release zaleplon were not significantly different; peak plasma concentrations were similar for A and B, and both were significantly higher than C. Time to peak plasma concentration for A, B, and C were 4-5 h compared to 1.5 h for immediate-release zaleplon; mean terminal phase half-life was in the range 1-2 h for A, B and immediate-release zaleplon. No significant differences were noted between day and night administration in the SOM002 study. CONCLUSIONS: Zaleplon, 15 mg, in a novel, modified-release formulation (SKP-1041) had a time to peak plasma concentrations at 4-5 h postdose compared to 1.5 h for immediate-release zaleplon, 10 mg. The pharmacokinetic profile suggests this formulation may be useful for treating middle-of-the-night awakening.

Alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by gaboxadol and zolpidem.

OBJECTIVE: to evaluate cyclic alternating pattern (CAP) in a phase advance model of transient insomnia and the effects of gaboxadol and zolpidem. DESIGN: a randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h. SETTING: 6 sleep research laboratories in US PARTICIPANTS: 55 healthy subjects (18-57 y) INTERVENTIONS: Gaboxadol 15 mg (GBX), zolpidem 10 mg (ZOL), and placebo (PBO). MEASUREMENTS: routine polysomnographic (PSG) measures, CAP, spectral power density, and self-reported sleep measures RESULTS: The phase advance model of transient insomnia produced significant changes in CAP parameters. Both GBX and ZOL significantly and differentially modified CAP parameters in the direction of more stable sleep. GBX brought the CAP rate in stage 1 sleep and slow wave sleep (SWS) closer to baseline levels but did not significantly change the CAP rate in stage 2. ZOL reduced the CAP rate in stage 2 to near baseline levels, whereas the CAP rate in stage 1 and SWS was reduced substantially below baseline levels. The CAP parameter A1 index (associated with SWS and sleep continuity) showed the highest correlation with self-reported sleep quality, higher than any traditional PSG, spectral, or other self-reported measures. CONCLUSION: disruptions in CAP produced by phase advanced sleep were significantly and differentially modulated by gaboxadol and zolpidem. The relative independence of CAP parameters from other electrophysiological measures of sleep, their high sensitivity to sleep disruption, and their strong association with subjective sleep quality suggest that CAP variables may serve as valuable endpoints in future insomnia research.

Reliability and validity of the brief insomnia questionnaire in the America insomnia survey.

STUDY OBJECTIVES: to evaluate the reliability and validity of the Brief Insomnia Questionnaire (BIQ), a fully structured questionnaire developed to diagnose insomnia according to hierarchy-free Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR), International Classification of Diseases-10 (ICD-10), and research diagnostic criteria/International Classification of Sleep Disorders-2 (RDC/ICSD-2) general criteria without organic exclusions in the America Insomnia Survey (AIS). DESIGN: probability subsamples of AIS respondents, oversampling BIQ positives, completed short-term test-retest interviews (n = 59) or clinical reappraisal interviews (n = 203) to assess BIQ reliability and validity. SETTING: the AIS is a large (n = 10,094) epidemiologic survey of the prevalence and correlates of insomnia. PARTICIPANTS: adult subscribers to a national managed healthcare plan. INTERVENTION: None MEASUREMENTS AND RESULTS: BIQ test-retest correlations were 0.47-0.94 for nature of the sleep problems (initiation, maintenance, nonrestorative sleep [NRS]), 0.72-0.95 for problem frequency, 0.66-0.88 for daytime impairment/distress, and 0.62 for duration of sleep. Good individual-level concordance was found between BIQ diagnoses and diagnoses based on expert interviews for meeting hierarchy-free inclusion criteria for diagnoses in any of the diagnostic systems, with area under the receiver operating characteristic curve (AUC, a measure of classification accuracy insensitive to disorder prevalence) of 0.86 for dichotomous classifications. The AUC increased to 0.94 when symptom-level data were added to generate continuous predicted-probability of diagnosis measures. The AUC was lower for dichotomous classifications based on RDC/ICSD-2 (0.68) and ICD-10 (0.70) than for DSM-IV-TR (0.83) criteria but increased consistently when symptom-level data were added to generate continuous predicted-probability measures of RDC/ICSD-2, ICD-10, and DSM-IV-TR diagnoses (0.92-0.95). CONCLUSIONS: these results show that the BIQ generates accurate estimates of the prevalence and correlates of hierarchy-free insomnia in the America Insomnia Survey.

Enhancing slow wave sleep with sodium oxybate reduces the behavioral and physiological impact of sleep loss.

STUDY OBJECTIVES: To investigate whether enhancement of slow wave sleep (SWS) with sodium oxybate reduces the impact of sleep deprivation. DESIGN: Double-blind, parallel group, placebo-controlled design SETTING: Sleep research laboratory PARTICIPANTS: Fifty-eight healthy adults (28 placebo, 30 sodium oxybate), ages 18-50 years. INTERVENTIONS: A 5-day protocol included 2 screening/baseline nights and days, 2 sleep deprivation nights, each followed by a 3-h daytime (08:00-11:00) sleep opportunity and a recovery night. Sodium oxybate or placebo was administered prior to each daytime sleep period. Multiple sleep latency test (MSLT), psychomotor vigilance test (PVT), Karolinska Sleepiness Scale (KSS), and Profile of Mood States were administered during waking hours. MEASUREMENTS AND RESULTS: During daytime sleep, the sodium oxybate group had more SWS, more EEG spectral power in the 1-9 Hz range, and less REM. Mean MSLT latency was longer for the sodium oxybate group on the night following the first daytime sleep period and on the day following the second day sleep period. Median PVT reaction time was faster in the sodium oxybate group following the second day sleep period. The change from baseline in SWS was positively correlated with the change in MSLT and KSS. During recovery sleep the sodium oxybate group had less TST, SWS, REM, and slow wave activity (SWA) than the placebo group. CONCLUSIONS: Pharmacological enhancement of SWS with sodium oxybate resulted in a reduced response to sleep loss on measures of alertness and attention. In addition, SWS enhancement during sleep restriction appears to result in a reduced homeostatic response to sleep loss.

Subtypes of sleep disturbance: associations among symptoms, comorbidities, treatment, and medical costs.

Medical claims and survey data were used to evaluate patients with sleep disturbance lasting 1 year or more, and to identify subtypes of sleep disturbance using latent class analysis. Four subtypes were identified from the 1,374 patients. Subtypes differed on the number of sleep disturbance symptoms, presence of non-restorative sleep and comorbidities, degree of daytime impairment, and insomnia severity. The results from this study suggest that patient-reported symptoms of sleep disturbance, the frequency of symptoms, functional impairment, and comorbid conditions are important elements in distinguishing among groups of patients with varying degrees of sleep problems. These data provide evidence that the Insomnia Severity Index (ISI) varies accordingly with the frequency and resulting impairment of symptoms captured in the 4 clusters.

Comparing two measures of sleep depth/intensity.

STUDY OBJECTIVES: To compare delta spectral power (delta) and odds ratio product (ORP) as measures of sleep depth during sleep restriction with placebo or a drug that increases delta. METHODS: This is a secondary analysis of data from a study of 41 healthy participants randomized to receive placebo or gaboxadol 15 mg during sleep restriction. Participants underwent in-laboratory sleep studies on two baseline, four sleep restriction (5-h), and two recovery nights. Relation between delta or ORP and sleep depth was operationally defined as the degree of association of each metric to the probability of arousal or awakening occurring during the next 30 s (arousability). RESULTS: ORP values in wake, N1, N2, N3, and REM were significantly different. Delta differed between both N2 and N3 and other sleep stages but not between wake and N1 or N1 and REM. Epoch-by-epoch and individual correlations between ORP and delta power were modest or insignificant. The relation between ORP and arousability was linear across the entire ORP range. Delta also changed with arousability but only when delta values were less than 300 µV2. Receiver-operating-characteristic analysis found the ability to predict imminent arousal to be significantly greater with ORP than with log delta power for all experimental conditions. Changes in ORP, but not log delta, across the night correlated with next-day physiologic sleep tendency. CONCLUSIONS: Compared to delta power, ORP is more discriminating among sleep stages, more sensitive to sleep restriction, and more closely associated with arousability. This evidence supports ORP as a measure of sleep depth/intensity.

Nocturia and disturbed sleep in the elderly.

BACKGROUND: Nocturnal urination (nocturia) is such a commonplace occurrence in the lives of many older adults that it is frequently overlooked as a potential cause of sleep disturbance. METHODS: We examined the prevalence of nocturia and examined its role in self-reported insomnia and poor sleep quality in a survey of 1424 elderly individuals, ages 55-84. Data were derived from a 2003 National Sleep Foundation telephone poll conducted in a representative sample of the United States population who underwent a 20-min structured telephone interview. Nocturia was not a focus of the survey, but data collected relevant to this topic allowed examination of relevant associations with sleep. RESULTS: When inquired about in a checklist format, nocturia was listed as a self-perceived cause of nocturnal sleep "every night or almost every night" by 53% of the sample, which was over four times as frequently as the next most often cited cause of poor sleep, pain (12%). In multivariate logistic models, nocturia was an independent predictor both of self-reported insomnia (75% increased risk) and reduced sleep quality (71% increased risk), along with female gender and other medical and psychiatric conditions. CONCLUSIONS: Nocturia is a frequently overlooked cause of poor sleep in the elderly and may warrant targeted interventions.

Modafinil for excessive sleepiness associated with shift-work sleep disorder.

BACKGROUND: Patients with shift-work sleep disorder chronically have excessive sleepiness during night work and insomnia when attempting to sleep during the day. We evaluated the use of modafinil for treating sleepiness in patients with this disorder. METHODS: In a three-month, double-blind trial, we randomly assigned 209 patients with shift-work sleep disorder to receive either 200 mg of modafinil or placebo before the start of each shift. Assessments were performed with the use of the nighttime Multiple Sleep Latency Test, the Clinical Global Impression of Change, the Psychomotor Vigilance Test, diaries of patients, and daytime polysomnography. After randomization, we conducted monthly assessments. RESULTS: Treatment with modafinil, as compared with placebo, resulted in a modest improvement from baseline in mean (+/-SEM) nighttime sleep latency (the interval between the time a person attempts to fall asleep and the onset of sleep) (1.7+/-0.4 vs. 0.3+/-0.3 minutes, respectively; P=0.002), and more patients had improvement in their clinical symptoms (74 percent vs. 36 percent, respectively; P<0.001). Patients who were receiving modafinil also had a reduction in the frequency and duration of lapses of attention during nighttime testing of their performance on the Psychomotor Vigilance Test (change from baseline, a reduction in lapse frequency of 2.6 vs. an increase of 3.8, respectively; P<0.001), and proportionally fewer patients reported having had accidents or near accidents while commuting home (29 percent vs. 54 percent, respectively; P<0.001). Despite these benefits, patients treated with modafinil continued to have excessive sleepiness and impaired performance at night. Modafinil did not adversely affect daytime sleep as compared with placebo. Headache was the most common adverse event. CONCLUSIONS: Treatment with 200 mg of modafinil reduced the extreme sleepiness that we observed in patients with shift-work sleep disorder and resulted in a small but significant improvement in performance as compared with placebo. However, the residual sleepiness that was observed in the treated patients underscores the need for the development of interventions that are even more effective.

Slow wave sleep enhancement with gaboxadol reduces daytime sleepiness during sleep restriction.

STUDY OBJECTIVES: To evaluate the impact of enhanced slow wave sleep (SWS) on behavioral, psychological, and physiological changes resulting from sleep restriction. DESIGN: A double-blind, parallel group, placebo-controlled design was used to compare gaboxadol (GBX) 15 mg, a SWS-enhancing drug, to placebo during 4 nights of sleep restriction (5 h/night). Behavioral, psychological, and physiological measures of the impact of sleep restriction were assessed in both groups at baseline, during sleep restriction and following recovery sleep. SETTING: Sleep research laboratory. PARTICIPANTS: Forty-one healthy adults; 9 males and 12 females (mean age: 32.0 +/- 9.9 y) in the placebo group and 10 males and 10 females (mean age: 31.9 +/- 10.2 y) in the GBX group. INTERVENTIONS: Both experimental groups underwent 4 nights of sleep restriction. Each group received either GBX 15 mg or placebo on all sleep restriction nights, and both groups received placebo on baseline and recovery nights. MEASUREMENTS AND RESULTS: Polysomnography documented a SWS-enhancing effect of GBX with no group difference in total sleep time during sleep restriction. The placebo group displayed the predicted deficits due to sleep restriction on the multiple sleep latency test (MSLT) and on introspective measures of sleepiness and fatigue. Compared to placebo, the GBX group showed significantly less physiological sleepiness on the MSLT and lower levels of introspective sleepiness and fatigue during sleep restriction. There were no differences between groups on the psychomotor vigilance task (PVT) and a cognitive test battery, but these measures were minimally affected by sleep restriction in this study. The correlation between change from baseline in MSLT on Day 6 and change from baseline in SWS on Night 6 was significant in the GBX group and in both group combined. CONCLUSIONS: The results of this study are consistent with the hypothesis that enhanced SWS, in this study produced by GBX, reduces physiological sleep tendency and introspective sleepiness and fatigue which typically result from sleep restriction.

Efficacy of the selective extrasynaptic GABA A agonist, gaboxadol, in a model of transient insomnia: a randomized, controlled clinical trial.

OBJECTIVE: The hypnotic efficacy of gaboxadol, a selective extrasynaptic GABA A agonist (SEGA), was evaluated in a phase-advance model of transient insomnia. METHODS: Healthy subjects (18-64 years) completed a randomized, double-blind, parallel group study in which the sleep period was advanced 4h from habitual sleep time. Polysomnographic (PSG) and self-reported sleep measures were used to compare gaboxadol 10mg (N =271) and 15 mg (N =274) versus placebo (N =277). RESULTS: In the placebo group, the phase-advance procedure disrupted sleep maintenance as measured by PSG wakefulness after sleep onset (WASO) and self-reported WASO (sWASO), and also, to a lesser extent, disrupted sleep onset as measured by PSG latency to persistent sleep (LPS) and self-reported time to sleep onset (sTSO). Both doses of gaboxadol decreased WASO and sWASO versus placebo (p

Reliability of the American Academy of Sleep Medicine Rules for Assessing Sleep Depth in Clinical Practice.

STUDY OBJECTIVES: The American Academy of Sleep Medicine has published manuals for scoring polysomnograms that recommend time spent in non-rapid eye movement sleep stages (stage N1, N2, and N3 sleep) be reported. Given the well-established large interrater variability in scoring stage N1 and N3 sleep, we determined the range of time in stage N1 and N3 sleep scored by a large number of technologists when compared to reasonably estimated true values. METHODS: Polysomnograms of 70 females were scored by 10 highly trained sleep technologists, two each from five different academic sleep laboratories. Range and confidence interval (CI = difference between the 5th and 95th percentiles) of the 10 times spent in stage N1 and N3 sleep assigned in each polysomnogram were determined. Average values of times spent in stage N1 and N3 sleep generated by the 10 technologists in each polysomnogram were considered representative of the true values for the individual polysomnogram. Accuracy of different technologists in estimating delta wave duration was determined by comparing their scores to digitally determined durations. RESULTS: The CI range of the ten N1 scores was 4 to 39 percent of total sleep time (% TST) in different polysomnograms (mean CI ± standard deviation = 11.1 ± 7.1 % TST). Corresponding range for N3 was 1 to 28 % TST (14.4 ± 6.1 % TST). For stage N1 and N3 sleep, very low or very high values were reported for virtually all polysomnograms by different technologists. Technologists varied widely in their assignment of stage N3 sleep, scoring that stage when the digitally determined time of delta waves ranged from 3 to 17 seconds. CONCLUSIONS: Manual scoring of non-rapid eye movement sleep stages is highly unreliable among highly trained, experienced technologists. Measures of sleep continuity and depth that are reliable and clinically relevant should be a focus of clinical research.

The direct and indirect costs of untreated insomnia in adults in the United States.

OBJECTIVES: To estimate the direct and indirect cost burden of untreated insomnia among younger adults (age 18-64), and to estimate the direct costs of untreated insomnia for elderly patients (age 65 and over). DESIGN: A retrospective, observational study comparing insomnia patients to matched samples without insomnia. SETTINGS: Self-insured, employer sponsored health insurance plans in the U.S. PATIENTS OR PARTICIPANTS: 138,820 younger adults and 75,558 elderly patients with insomnia, plus equal-sized, matched comparison groups. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: Direct costs included inpatient, outpatient, pharmacy, and emergency room costs for all diseases, for six months before an index date. The index date for insomnia patients was the date of diagnosis with or the onset of prescription treatment for insomnia, some-time during July 1, 1999-June 30, 2003. Non-insomnia patients were assigned the same index dates as the insomnia patients to whom they were matched. Indirect costs included costs related to absenteeism from work and the use of short-term disability programs. Propensity score matching was used to find insomnia and non-insomnia patients who had similar demographics, location, health plan type, comorbidities, and drug use patterns. Regression analyses controlled for factors that were different even after matching was completed. We found that average direct and indirect costs for younger adults with insomnia were about $1,253 greater than for patients without insomnia. Among the elderly, direct costs were about $1,143 greater for insomnia patients. CONCLUSIONS: Insomnia is associated with a significant economic burden for younger and older patients.

The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia.

STUDY OBJECTIVES: Evaluate the hypnotic efficacy of gaboxadol, a selective extrasynaptic GABAA agonist (SEGA), in a phase advance model of transient insomnia. DESIGN: A randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h. SETTING: Sleep research laboratories. PARTICIPANTS: 109 healthy subjects (18-58 y). INTERVENTIONS: Gaboxadol 5 mg, 10 mg, and 15 mg (GBX5, GBX10, GBX15) versus placebo (PBO). Zolpidem 10 mg (ZOL10) was used as an active reference. MEASUREMENTS: Polysomnographic (PSG) and self-reported (s) sleep measures RESULTS: Wakefulness after sleep onset (WASO) decreased (P < 0.05) and total sleep time (TST) increased (P < 0.001) in all treatments versus PBO. Latency to persistent sleep was shorter (P < 0.05) than PBO for all treatments except GBX5. GBX10 and GBX15 increased slow wave activity (SWA; 0.75-4.5 Hz, P < 0.001) and theta activity (4.75-7.75Hz; P < 0.001) and reduced sigma activity (12.25-15.0 Hz; significant for GBX15 only, P < 0.001) compared to PBO in NREM sleep EEG, in a dose-response manner. Zolpidem suppressed power density over a broad low frequency range including delta and theta frequencies (2.25-8.0 Hz, P < 0.05) and also enhanced sigma activity (P < 0.001). Self-reported sWASO and sTST improved for all treatments versus PBO (P < 0.05). Self-reported sleep latency was reduced following GBX10 (P < 0.05) and ZOL10 (P < 0.001). Neither drug treatment was associated with residual effects the morning after treatment. CONCLUSIONS: Gaboxadol and zolpidem improved objective and subjective efficacy measures in this model of transient insomnia. The gaboxadol-induced enhancement of SWA and theta activity and the reduction of sigma activity contrasts with zolpidem's effects on the spectral EEG. These differences may reflect the different mechanisms of action of the two drugs.