The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial.

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

Length polymorphism in the Period 3 gene is associated with sleepiness and maladaptive circadian phase in night-shift workers.

The objective of the current study was to determine if night-shift workers carrying the five-repeat variant of the Period 3 gene show elevated levels of nocturnal sleepiness and earlier circadian phase compared with homozygotes for the four-repeat allele. Twenty-four permanent night-shift workers were randomly selected from a larger study. Participants took part in an observational laboratory protocol including an overnight multiple sleep latency test and half-hourly saliva collection for calculation of dim-light melatonin onset. Period 3(-/5) shift workers had significantly lower multiple sleep latency test during overnight work hours compared with Period 3(4/4) workers (3.52 ± 23.44 min versus 10.39 ± 6.41 min, P = 0.003). We observed no significant difference in sleepiness during early morning hours following acute sleep deprivation. Long-allele carriers indicated significantly higher sleepiness on the Epworth Sleepiness Scale administered at 17:00 hours (12.08 ± 2.55 versus 8.00 ± 1.94, P < 0.001). We observed a significantly earlier melatonin onset in Period 3(-/5) individuals compared with Period 3(4/4) shift workers (20:44 ± 6:37 versus 02:46 ± 4:58, P = 0.021). Regression analysis suggests that Period 3 genotype independently predicts sleepiness even after controlling for variations in circadian phase, but we were unable to link Period 3 to circadian phase when controlling for sleepiness. Period 3(-/5) shift workers showed both subjective and objective sleepiness in the pathological range, while their Period 3(4/4) counterparts showed sleepiness within normal limits. Period 3(-/5) night workers also show a mean circadian phase 6 h earlier (i.e. less adapted) than Period 3(4/4) workers. Because Period 3(-/5) workers have maladaptive circadian phase as well as pathological levels of sleepiness, they may be at greater risk for occupational and automotive accidents. We interpret these findings as a call for future research on the role of Period 3 in sleepiness and circadian phase, especially as they relate to night work.

Is a blunted cortisol response to stress a premorbid risk for insomnia?

STUDY OBJECTIVES: Vulnerability to stress-related sleep disturbances (sleep reactivity) is an established heritable risk factor for insomnia disorder with unclear biological underpinnings. Preliminary research points to a blunted cortisol response to stress as a biological predisposition to familial risk for insomnia, but the role of cortisol response in sleep reactivity is unknown. Therefore, the current studies examined whether sleep reactivity is associated with a blunted cortisol response to two laboratory stressors among participants without insomnia. METHODS: Two community samples of adults with no lifetime history of insomnia completed the Trier Social Stress Test (N = 35) or the Cold Pressor Task (N = 34). Participants were grouped by insomnia-risk using sleep reactivity scores from the Ford Insomnia Response to Stress Test (FIRST). Physiological responses were measured via markers of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol) and autonomic nervous system (ANS; heart rate, mean arterial pressure, and salivary alpha amylase). RESULTS: Participants with high insomnia-risk (FIRST score > 18) exhibited blunted cortisol responses to both stressors. There were no group differences in ANS responses across stressors. CONCLUSIONS: Insomnia-risk as indicated by sleep reactivity is associated with blunted cortisol responses to psychosocial and physical laboratory stressors among premorbid adults without insomnia disorder. This study replicates previous research and supports a blunted cortisol response to stress as a biomarker for insomnia vulnerability that may be detected using the FIRST. Prospective research is needed to elucidate whether a blunted cortisol response to stress is one mechanism by which sleep reactive individuals may be at risk of developing insomnia.

Familial Risk for Insomnia Is Associated With Abnormal Cortisol Response to Stress.

Objectives: Abnormalities in the stress system have been implicated in insomnia. However, studies examining physiological stress regulation in insomnia have not consistently detected differences in the hypothalamic-pituitary-adrenal (HPA)-axis response to stress. One explanation may be that deficits in the stress system are associated specifically with a biological vulnerability to insomnia rather than the phenotypic expression of insomnia. To examine stress response as a function of vulnerability to insomnia, this study tested response to the Trier Social Stress Test in a sample of healthy sleepers with varying familial risks for insomnia. Methods: Thirty-five healthy individuals with and without familial risk for insomnia were recruited to complete a laboratory stressor. Participants with one or both biological parents with insomnia were categorized as positive for familial risk, whereas those without biological parents with insomnia were categorized as negative for familial risk. Participants completed the Trier Social Stress Test in the laboratory, and psychological and physiological (autonomic and HPA-axis) responses were compared. Results: Despite self-reported increases in anxiety, those positive for familial risk exhibited a blunted cortisol response relative to those without familial risk for insomnia. Individuals with blunted cortisol also reported heightened reactivity to personal life stressors, including increased sleep disturbances, elevated cognitive intrusions, and more behavioral avoidance. Conclusions: Findings from this study provide initial evidence that abnormal stress regulation may be a biological predisposing factor conferred via familial risk for insomnia. This deficit may also predict negative consequences over time, including insomnia and the associated psychiatric comorbidities.

Differential sleep, sleepiness, and neurophysiology in the insomnia phenotypes of shift work disorder.

STUDY OBJECTIVES: To characterize and compare insomnia symptoms within two common phenotypes of Shift Work Disorder. DESIGN: Observational laboratory and field study. SETTING: Hospital sleep center. PARTICIPANTS: 34 permanent night workers. Subjects were classified by Epworth Sleepiness Scale and Insomnia Severity Index into 3 subgroups: asymptomatic controls, alert insomniacs (AI), and sleepy insomniacs (SI). MEASUREMENTS: Sleep parameters were assessed by sleep diary. Circadian phase was evaluated by dim-light salivary melatonin onset (DLMO). Objective sleepiness was measured using the multiple sleep latency test (MSLT). Brain activity was measured using the N1 event-related potential (ERP). A tandem repeat in PER3 was genotyped from saliva DNA. RESULTS: (1) AI group showed normal MSLT scores but elevated N1 amplitudes indicating cortical hyperarousal. (2) SI group showed pathologically low MSLT scores but normal N1 amplitudes. (3) AI and SI groups were not significantly different from one another in circadian phase, while controls were significantly phase-delayed relative to both SWD groups. (4) AI showed significantly longer sleep latencies and lower sleep efficiency than controls during both nocturnal and diurnal sleep. SI significantly differed from controls in nocturnal sleep parameters, but differences during diurnal sleep periods were smaller and not statistically significant. (5) Genotype × phenotype χ² analysis showed significant differences in the PER3 VNTR: 9 of 10 shift workers reporting sleepiness in a post hoc genetic substudy were found to carry the long tandem repeat on PER3, while 4 of 14 shift workers without excessive sleepiness carried the long allele. CONCLUSIONS: Our results suggest that the sleepy insomnia phenotype is comprehensively explained by circadian misalignment, while the alert insomnia phenotype resembles an insomnia disorder precipitated by shift work.

Circadian phase, sleepiness, and light exposure assessment in night workers with and without shift work disorder.

Most night workers are unable to adjust their circadian rhythms to the atypical hours of sleep and wake. Between 10% and 30% of shiftworkers report symptoms of excessive sleepiness and/or insomnia consistent with a diagnosis of shift work disorder (SWD). Difficulties in attaining appropriate shifts in circadian phase, in response to night work, may explain why some individuals develop SWD. In the present study, it was hypothesized that disturbances of sleep and wakefulness in shiftworkers are related to the degree of mismatch between their endogenous circadian rhythms and the night-work schedule of sleep during the day and wake activities at night. Five asymptomatic night workers (ANWs) (3 females; [mean ± SD] age: 39.2 ± 12.5 yrs; mean yrs on shift = 9.3) and five night workers meeting diagnostic criteria (International Classification of Sleep Disorders [ICSD]-2) for SWD (3 females; age: 35.6 ± 8.6 yrs; mean years on shift = 8.4) participated. All participants were admitted to the sleep center at 16:00 h, where they stayed in a dim light (<10 lux) private room for the study period of 25 consecutive hours. Saliva samples for melatonin assessment were collected at 30-min intervals. Circadian phase was determined from circadian rhythms of salivary melatonin onset (dim light melatonin onset, DLMO) calculated for each individual melatonin profile. Objective sleepiness was assessed using the multiple sleep latency test (MSLT; 13 trials, 2-h intervals starting at 17:00 h). A Mann-Whitney U test was used for evaluation of differences between groups. The DLMO in ANW group was 04:42 ± 3.25 h, whereas in the SWD group it was 20:42 ± 2.21 h (z = 2.4; p < .05). Sleep did not differ between groups, except the SWD group showed an earlier bedtime on off days from work relative to that in ANW group. The MSLT corresponding to night work time (01:00-09:00 h) was significantly shorter (3.6 ± .90 min: [M ± SEM]) in the SWD group compared with that in ANW group (6.8 ± .93 min). DLMO was significantly correlated with insomnia severity (r = -.68; p < .03), indicating that the workers with more severe insomnia symptoms had an earlier timing of DLMO. Finally, SWD subjects were exposed to more morning light (between 05:00 and 11:00 h) as than ANW ones (798 vs. 180 lux [M ± SD], respectively z = -1.7; p < .05). These data provide evidence of an internal physiological delay of the circadian pacemaker in asymptomatic night-shift workers. In contrast, individuals with SWD maintain a circadian phase position similar to day workers, leading to a mismatch/conflict between their endogenous rhythms and their sleep-wake schedule.