Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used ...neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.
Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor ...adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited.
To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment.
This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo.
Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (
< 0.05), with dose-dependent effects observed at Week 1 maintained over the study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on Patient Global Impression of Change (key secondary endpoint;
< 0.05). Adverse events were reported in 47.9% of placebo- and 67.9% of solriamfetol-treated participants; five participants experienced serious adverse events (two 1.7% placebo, three 0.8% solriamfetol); none were deemed related to study drug. The most common adverse events with solriamfetol were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), anxiety (7.0%), and nasopharyngitis (5.1%).
Solriamfetol significantly increased wakefulness and reduced sleepiness in participants with obstructive sleep apnea and excessive sleepiness; most adverse events were mild or moderate in severity. Clinical trial registered with www.clinicaltrials.gov (NCT02348606) and www.eudract.ema.europa.eu (EudraCT 2014-005514-31).
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.
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).
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.
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.
Solriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA ...(37.5-150 mg/d).
Does solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use?
Participants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated.
At baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, -2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were -2.4 (95% CI, -4.2 to -0.5), -1.3 (95% CI, -3.1 to 0.5), -4.2 (95% CI, -5.7 to -2.7), and -4.7 (95% CI, -6.1 to -3.2) and among nonadherent participants were -0.7 (95% CI, -3.5 to 2.1), -2.6 (95% CI, -5.4 to 0.1), -5.0 (95% CI, -7.2 to -2.9), and -4.6 (95% CI, -7.0 to -2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol.
Solriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol.
ClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31.
To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).
The Apnea Positive Pressure Long-term Efficacy Study ...(APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.
Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function A/P), Buschke Selective Reminding Test-Sum Recall (learning and memory L/M), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function E/F)
The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.
CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.
Registered at clinicaltrials.gov. Identifier: NCT00051363.
Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.
Excessive daytime sleepiness (EDS) affects approximately half of patients with obstructive sleep apnea (OSA) and can persist in some despite normalization of breathing, oxygenation, and sleep quality ...with primary OSA therapy, such as continuous positive airway pressure (CPAP). EDS is often overlooked and under discussed in the primary care setting and in the follow-up of CPAP-treated patients due to difficult assessment of such a multi-dimensional symptom. This review aims to provide suggestions for procedures that can be implemented into routine clinical practice to identify, evaluate, and manage EDS in patients treated for OSA, including how to appropriately use various self-report and objective assessments along the clinical pathway and options for pharmacotherapy. In addition, examples of when it is appropriate to refer a patient to a sleep specialist for evaluation are discussed.
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 300 mg/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 7.0 min), 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 10.7 min), 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.
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•Solriamfetol treatment outcomes were analyzed according to depression history.•Depression history was prevalent in people with narcolepsy/obstructive sleep apnea.•Solriamfetol improved excessive daytime sleepiness regardless of depression history.•Concomitant antidepressant use did not affect response to solriamfetol.•Safety/tolerability was similar regardless of depression history/antidepressant use.
This post hoc analysis characterized the weekly incidence and overall duration of common early-onset, treatment-emergent adverse events (TEAEs) during solriamfetol treatment.
Participants ...(obstructive sleep apnea OSA, n = 474; narcolepsy, n = 236) were randomized to 12 weeks of placebo or solriamfetol 37.5 (OSA only), 75, 150, or 300 mg. For common early-onset TEAEs (those occurring in ≥ 5% of participants in any solriamfetol dose group and with a higher incidence than that observed in placebo-treated participants during week 1), the incidence of new occurrence or change in severity over time was calculated for each subsequent study week. Data were analyzed separately for each study and summarized by placebo and combined solriamfetol groups.
Common early-onset TEAEs (at doses ≤ 150 mg; ie, approved doses) included headache (OSA, 5.1%; narcolepsy, 8.5%), nausea (OSA, 2.5%; narcolepsy, 4.2%), decreased appetite (OSA, 4.2%; narcolepsy, 5.9%), as well as anxiety (2.1%), insomnia (1.3%), and feeling jittery (3.0%) in OSA and dry mouth (4.2%) in narcolepsy. Incidence of common early-onset TEAEs was highest at week 1 and decreased over time. In OSA at doses ≤ 150 mg, headache, nausea, and feeling jittery had median durations ≤ 8 days, whereas decreased appetite, anxiety, and insomnia had longer durations. In narcolepsy at doses ≤ 150 mg, headache and nausea had median durations ≤ 8 days, whereas decreased appetite and dry mouth had longer durations. Most TEAEs were mild to moderate in severity.
Common early-onset TEAEs with solriamfetol are limited in duration, with the majority subsiding during the first week of treatment.
Registry: ClinicalTrials.gov; Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in Narcolepsy; URL: https://clinicaltrials.gov/ct2/show/NCT02348593; Identifier: NCT02348593; and Name: Twelve-week Study of the Safety and Efficacy of JZP-110 in the Treatment of Excessive Sleepiness in OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348606; Identifier: NCT02348606.
Rosenberg R, Thorpy MJ, Dauvilliers Y, et al. Incidence and duration of common early-onset adverse events in randomized controlled trials of solriamfetol for treatment of excessive daytime sleepiness in obstructive sleep apnea and narcolepsy.
. 2022;18(1):235-244.
Purpose
Preliminary studies have shown a significant decrease in severity of obstructive sleep apnea (OSA) with the use of a combination of atomoxetine and oxybutynin, with patients having moderate ...pharyngeal collapsibility during sleep more likely to respond. This study evaluated the efficacy and safety of AD036 (atomoxetine 80 mg and oxybutynin 5 mg) in the treatment of OSA.
Methods
This trial was a phase 2, randomized, placebo-controlled crossover study comparing AD036, atomoxetine 80 mg alone, and placebo during three home sleep studies, each separated by about 1 week. The trial included patients with OSA and moderate pharyngeal collapsibility as defined by a higher proportion of hypopneas to apneas and mild oxygen desaturation.
Results
Of 62 patients who were randomized, 60 were included in
efficacy
analyses. The apnea–hypopnea index (AHI) from a median (interquartile range) of 14.2 (5.4 to 22.3) events/h on placebo to 6.2 (2.8 to 13.6) with AD036 and 4.8 (1.4 to 11.6) with atomoxetine alone (
p
< .0001). Both drugs also decreased the oxygen desaturation index (ODI) and the hypoxic burden (
p
< .0001). AD036, but not atomoxetine alone, reduced the respiratory arousal index and improved ventilation at the respiratory arousal threshold (greater
V
active
). There was a trend for total sleep time to be decreased more with atomoxetine alone than with AD036. The most common adverse event was insomnia (12% with AD036, 18% with atomoxetine).
Conclusion
AD036 significantly improved OSA severity in patients with moderate pharyngeal collapsibility. Atomoxetine may account for the majority of improvement in OSA severity, while the addition of oxybutynin may mitigate the disruptive effect of atomoxetine on sleep and further improve ventilation.
Trial registration
Clinical trial registered with
www.clinicaltrials.gov
(NCT04445688).
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