Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial.

STUDY OBJECTIVES: Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. METHODS: Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). RESULTS: ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. CONCLUSIONS: The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

Validation of sleep measurement in a multisensor consumer grade wearable device in healthy young adults.

STUDY OBJECTIVES: Our objective was to examine the ability of a consumer-grade wearable device (Basis B1) with accelerometer and heart rate technology to assess sleep patterns compared with polysomnography (PSG) and research-grade actigraphy in healthy adults. METHODS: Eighteen adults underwent consecutive nights of sleep monitoring using Basis B1, actigraphy, and PSG; 40 nights were used in analyses. Discrepancies in gross sleep parameters and epoch-by-epoch agreements in sleep/wake classification were assessed. RESULTS: Basis B1 accuracy was 54.20 ± 8.20%, sensitivity was 98.90 ± 2.70%, and specificity was 8.10 ± 15.00%. Accuracy, sensitivity, and specificity for distinguishing between the different sleep stages were 60-72%, 48-62%, and 57-86%, respectively. Pearson correlations demonstrated strong associations between Basis B1 and PSG estimates of sleep onset latency and total sleep time; moderate associations for sleep efficiency, duration of light sleep, and duration of rapid eye movement sleep; and a weak association for duration of deep sleep. Basis B1 significantly overestimates total sleep time, sleep efficiency, and duration of light sleep and significantly underestimates wake after sleep onset and duration of deep sleep. CONCLUSIONS: Basis B1 demonstrated utility for estimates of gross sleep parameters and performed similarly to actigraphy for estimates of total sleep time. Basis B1 specificity was poor, and Basis B1 is not useful for the assessment of wake. Basis B1 accuracy for sleep stages was better than chance but is not a suitable replacement for PSG assessment. Despite low cost, ease of use, and attractiveness for patients, consumer devices are not yet accurate or reliable enough to guide treatment decision making in clinical settings.

Sleepless Night and Day, the Plight of Progressive Supranuclear Palsy.

Objectives: To elucidate the unique sleep and waking characteristics in progressive supranuclear palsy (PSP), a neurodegenerative disease associated with motor deficits and dementia that largely affects the brainstem and thalamic regions. Methods: A total of 20 PSP and 16 healthy older adult controls participated in this study. The participants underwent an overnight polysomnography and multiple sleep latency test (MSLT) the following day. Prior to the MSLT last trial, they were asked to complete the Stanford Sleepiness Scale. Data were assessed for measures of latency to sleep onset, sleep duration, waking, and sleep staging during the night. Mean sleep latency, a measure of daytime sleepiness, sleep onset rapid eye movement (REM) periods, and microsleeps were studied with the MSLT. Spectral analysis of wake electroencephalogram (EEG) was performed for 30-second periods at the start of each MSLT trial. Results: PSP took significantly longer time to fall asleep (p < .001), slept less during the night (p ≤ .001), and had more wake after sleep onset than controls (p ≤ .001). PSP had less N2 sleep (p < .05) and N3 sleep (p < .05), and REM sleep (p < .001) than controls. During the MSLT, PSP took significantly longer to fall asleep (p < .001), did not have microsleeps when they remained awake throughout the assessment periods, but were subjectively sleepier than controls (p < .05). Gamma power was increased during wake EEG in PSP (p < .01). Conclusions: Sleep/waking regulation and REM sleep regulation are disrupted in PSP, leading to profound sleep deprivation without recuperation. Our findings suggest a diminished homeostatic sleep drive in PSP. This hyperaroused state is unique and is a severely disabling feature of PSP.

Rest-activity rhythm disruption in progressive supranuclear palsy.

OBJECTIVE/BACKGROUND: The brainstem is among the first regions affected in progressive supranuclear palsy (PSP) and is part of the sleep/circadian regulation network. In two small studies, blood pressure and core body temperature circadian patterns were disrupted in PSP; however, it is unclear if circadian activity rhythms are also affected. Our objective was to perform circadian analyses of the rest-activity rhythms in PSP and determine the association with increasing disease severity. PATIENTS/METHODS: Individuals with a clinical PSP diagnosis (n = 17; nine men) and healthy older adults (n = 17; nine men) were selected for this study. Participants wore actigraphy wristbands and completed sleep diaries for up to 14 consecutive days. Data were analyzed to assess circadian activity strength (amplitude, mesor, f-ratio), phase (acrophase), and circadian stability (intradaily variability, interdaily stability, relative amplitude). Analyses controlled for sleep fragmentation, cognition, and self-reported depression. The association between disease severity using the PSP rating scale and circadian activity rhythm disruption was assessed. RESULTS: Individuals with PSP had significantly lower circadian activity mesor (p ≤ 0.001), amplitude (p ≤ 0.001), robustness (f-ratio, p <0.01), relative amplitude (p ≤ 0.001), and interdaily stability (p ≤ 0.01), with increased intradaily variability (p <0.05). CAR remained weaker in PSP after controlling for sleep fragmentation, and again when also controlling for cognitive impairment and depression. Weaker circadian activity (mesor, amplitude, f-ratio, and relative amplitude) was associated with increased disease severity. CONCLUSIONS: Circadian activity rhythms are disrupted in individuals with PSP as compared to controls, and worsen with disease severity. This is the first study of its kind to describe circadian activity rhythms in PSP.

Cognitive behavioral therapy for insomnia in posttraumatic stress disorder: a randomized controlled trial.

STUDY OBJECTIVES: Examine whether cognitive behavioral therapy for insomnia (CBT-I) improves sleep in posttraumatic stress disorder (PTSD) as well as nightmares, nonsleep PTSD symptoms, depression symptoms, and psychosocial functioning. DESIGN: RANDOMIZED CONTROLLED TRIAL WITH TWO ARMS: CBT-I and monitor-only waitlist control. SETTING: Department of Veterans Affairs (VA) Medical Center. PARTICIPANTS: Forty-five adults (31 females: [mean age 37 y (22-59 y)] with PTSD meeting research diagnostic criteria for insomnia, randomly assigned to CBT-I (n = 29; 22 females) or monitor-only waitlist control (n = 16; nine females). INTERVENTIONS: Eight-session weekly individual CBT-I delivered by a licensed clinical psychologist or a board-certified psychiatrist. MEASUREMENTS AND RESULTS: Measures included continuous monitoring of sleep with diary and actigraphy; prepolysomnography and postpolysomnography and Clinician-Administered PTSD Scale (CAPS); and pre, mid, and post self-report questionnaires, with follow-up of CBT-I participants 6 mo later. CBT-I was superior to the waitlist control condition in all sleep diary outcomes and in polysomnography-measured total sleep time. Compared to waitlist participants, CBT-I participants reported improved subjective sleep (41% full remission versus 0%), disruptive nocturnal behaviors (based on the Pittsburgh Sleep Quality Index-Addendum), and overall work and interpersonal functioning. These effects were maintained at 6-mo follow-up. Both CBT-I and waitlist control participants reported reductions in PTSD symptoms and CAPS-measured nightmares. CONCLUSIONS: Cognitive behavioral therapy for insomnia (CBT-I) improved sleep in individuals with posttraumatic stress disorder, with durable gains at 6 mo. Overall psychosocial functioning improved following CBT-I. The initial evidence regarding CBT-I and nightmares is promising but further research is needed. Results suggest that a comprehensive approach to treatment of posttraumatic stress disorder should include behavioral sleep medicine. CLINICAL TRIAL INFORMATION: TRIAL NAME: Cognitive Behavioral Treatment Of Insomnia In Posttraumatic Stress Disorder. URL: http://clinicaltrials.gov/ct2/show/NCT00881647. REGISTRATION NUMBER: NCT00881647.