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David A Kalmbach,1 Philip Cheng,1 Roopina Sangha,2 Louise M O’Brien,3 Leslie M Swanson,4 Laura Palagini,5 Luisa F Bazan,6 Thomas Roth,1 Christopher L Drake1 1Thomas Roth Sleep Disorders and Research Center, Henry Ford Health System, Novi, MI, USA; 2Department of Obstetrics and Gynecology, Henry Ford Health System, Detroit, MI, USA; 3Departments of Obstetrics &Gynecology and Neurology, University of Michigan, Ann Arbor, MI, USA; 4Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI, USA; 5Departments of Neuroscience and Psychiatry, University of Pisa, Pisa, Italy; 6Division of Sleep Medicine, Henry Ford Health System, Detroit, MI, USACorrespondence: David A KalmbachThomas Roth Sleep Disorders & Research Center, Henry Ford Health System, Novi, MI, USATel +1248 325 3938Email dkalmba1@hfhs.orgObjective: To characterize sleep habits and parameters among women in mid-to-late pregnancy and to identify disparities associated with poverty, race, and obesity.Design: Cross-sectional.Setting: Large multi-site health system in Metro Detroit.Participants: A total of 267 pregnant women (27.3% non-Hispanic black; gestational age: 27.99±1.20 weeks) completed online surveys on sleep quality, insomnia symptoms, sleep aid use, signs/symptoms of sleep-disordered breathing, and sociodemographics. Body mass index (BMI) and patient insurance were derived from medical records.Results: As high as 76.2% of the women reported global sleep disturbance, 30.6% endorsed snoring, 24.3% sleep

David A Kalmbach,1 Sheryl A Kingsberg,2 Thomas Roth,1 Philip Cheng,1 Cynthia Fellman-Couture,1 Christopher L Drake11Division of Sleep Medicine, Thomas Roth Sleep Disorders & Research Center, Henry Ford Health System, Detroit, MI, USA; 2Departments of Reproductive Biology and Psychiatry, Case Western Reserve University, Cleveland, OH, USACorrespondence: Christopher L Drake 39450 W 12 Mile Road, Novi, MI 48377, USATel +1 248 344 6672Fax +1 248 344 8084Email cdrake1@hfhs.orgObjective: Menopause triggers changes in sexual function and many women develop sexual problems. Insomnia is common in postmenopausal women, and disturbed sleep has been linked to poor sexual health. Thus, postmenopausal women with insomnia may be especially vulnerable to developing sexual difficulties. This study estimated rates of sexual distress in postmenopausal women with chronic insomnia and explored associations between various facets of sexual health, insomnia symptoms, and insomnia-related stress dysregulation.Design: Cross-sectional.Setting: Large multi-site health system in the US.Participants: 150 postmenopausal women diagnosed with DSM-5 chronic insomnia disorder (56.44±5.64 years) completed measures of sexual distress, sexual function, hot flashes, insomnia symptoms, depression, and stress dysregulation in the forms of cognitive-emotional arousal (worry, rumination), sleep reactivity, and somatic hyperarousal.Results: Nearly half of the sample endorsed clinically significant sexual distress (46.9%). Insomnia symptoms were largely associated with poor sexual arousal, orgasmic dysfunction, sexual distress, and sexual dissatisfaction. Insomnia-related stress dysregulation was similarly associated with these facets of sexual health but was also linked to problems with low desire and greater vaginal pain during sex. Hot flashes and depression were negatively associated with sexual health.Conclusion: Postmenopausal women with chronic insomnia endorse high rates of sexual distress. Although compromised sexual function appears directly related to poor sleep itself, our data suggest that stress dysregulation may play vital role in sexual problems endorsed by postmenopausal insomniacs, particularly regarding low desire and vaginal pain. Prospective research is needed to characterize the evolution of these co-occurring symptoms.Keywords: menopause, sexual function, sexual distress, sleep, worry, rumination

David A Kalmbach,1 Andrea S Cuamatzi-Castelan,1 Christine V Tonnu,1 Kieulinh Michelle Tran,1 Jason R Anderson,2 Thomas Roth,1 Christopher L Drake1 1Thomas Roth Sleep Disorders and Research Center, Henry Ford Health System, Detroit, MI, USA; 2Department of Psychological Sciences, Kent State University, Kent, OH, USA Abstract: Hyperarousal is a key component in all modern etiological models of insomnia disorder. Overall patterns in the literature suggest that over-active neurobiological and psychological systems contribute to difficulty sleeping. Even so, mixed results regarding the specific mechanisms linking hyperarousal to sleep disturbance limit current etiological conceptualizations. Similar basal arousal profiles between individuals with high vs low risk for insomnia in the absence of stress exposure suggest that dysregulated stress “response” rather than general hyperarousal may be a more pertinent marker of risk. In this report, we discuss evidence for hyperarousal in insomnia and explore the role of sleep reactivity. A trait characteristic, sleep reactivity is the degree to which stress disrupts sleep, manifesting as difficulty falling and staying asleep. Premorbid sleep reactivity has been shown to identify individuals at risk for future insomnia disorder, such as highly reactive sleepers (whose sleep systems are sensitive to stress) who are at elevated disease risk. Research points to genetics, family history of insomnia, gender, and environmental stress as factors that influence sleep reactivity. Importantly, stress-related cognitive–emotional reactivity (e.g., rumination, worry) may exploit the vulnerability of a highly reactive sleep system. We propose that sleep reactivity and cognitive–emotional reactivity may share a bidirectional relationship, conferring an insalubrious environment for sleep in response to stress. Future research on sleep reactivity is needed to identify its neurobiology, characterize its relationship with cognitive–emotional reactivity, and explore the potential clinical utility of sleep reactivity in treatment planning. Keywords: insomnia, hyperarousal, stress, sleep reactivity

Marith van Schrojenstein Lantman,1 Marlou Mackus,1 Thomas Roth,2 Joris C Verster1,3,4 1Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Utrecht University, Utrecht, The Netherlands; 2Sleep Disorders and Research Center, Henry Ford Health System, Detroit, Michigan, USA; 3Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands; 4Centre for Human Psychopharmacology, Swinburne University, Melbourne VIC, Australia Introduction: An evening of alcohol consumption often occurs at the expense of sleep time. The aim of this study was to determine the relationship between total sleep time and the duration and severity of the alcohol hangover.Methods: A survey was conducted among Dutch University students to collect data on their latest alcohol hangover. Data on alcohol consumption, total sleep time, hangover severity, and duration were collected. Alcohol consumption and hangover severity and duration were compared for participants who (a) slept 7 hours.Results: Data from N=578 students (40.1% men and 59.9% women) were included in the statistical analyses. Significant correlations were found between total sleep time and alcohol consumption (r=0.117, p=0.005), hangover severity (r= –0.178, p=0.0001) and hangover duration (r=0.168, p=0.0001). In contrast, total alcohol consumption did not correlate significantly with overall hangover severity or duration. Those who slept longer than 7 hours consumed significantly more alcohol (p=0.016) and reported extended hangover duration (p=0.004). However, they also reported significantly less severe hangovers (p=0.001) than students who slept

Thomas Roth,1 Tali Nir,2 Nava Zisapel2,3 1Henry Ford Sleep Disorders Center, Detroit, MI, USA; 2Neurim Pharmaceuticals Ltd, Tel Aviv, Israel; 3Department of Neurobiology Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Introduction: Melatonin, secreted by the pineal gland during the night phase, is a regulator of the biological clock and sleep tendency. Totally blind subjects frequently report severe, periodic sleep problems, with 50%–75% of cases displaying non-24-hour sleep–wake disorder (N24HSWD) due to inability to synchronize with the environmental day–night cycle. Melatonin immediate-release preparations are reportedly effective in N24HSWD. Here, we studied the efficacy and safety of prolonged-release melatonin (PRM), a registered drug for insomnia, for sleep disorders in totally blind subjects living in normal social environments. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit >20 minutes whether significant or not) to allow early decision-making on further drug development in this indication. Trial registration: ClinicalTrials.gov registry – NCT00972075. Methods: In a randomized, double-blind, placebo-controlled proof-of-principle study, 13 totally blind subjects had 2 weeks' placebo run-in, 6 weeks' randomized (1:1) PRM (Circadin®) or placebo nightly, and 2 weeks' placebo run-out. Outcome measures included daily voice recorded sleep diary, Clinical Global Impression of Change (CGIC), WHO-Five Well-being Index (WHO-5), and safety. Results: Mean nightly sleep duration improved by 43 minutes in the PRM and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: -14.4 to 69 minutes; P=0.18; effect size: 0.82) meeting the primary endpoint. Mean sleep latency decreased by 29 minutes with PRM over placebo (P=0.13; effect size: 0.92) and nap duration decreased in the PRM but not placebo group. The variability in sleep onset/offset and latency tended to decrease during PRM but not placebo treatment. The potentially beneficial effects of PRM persisted during the 2 weeks of discontinuation period, consistent with clock stabilizing effects. PRM was well-tolerated, adverse events were of mild or moderate severity and similar between PRM and placebo. Conclusion: Nightly use of PRM may potentially improve patient-reported sleep difficulties in totally blind individuals trying to adhere to normal social lifestyle. A larger study powered to demonstrate a statistically significant effect is warranted. Keywords: biological clock, non-24-hour sleep–wake disorder, sleep, melatonin

Joris C Verster¹, Thomas Roth²¹Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Utrecht University, Utrecht, The Netherlands; ²Sleep Disorders and Research Center, Henry Ford Health System, Detroit, MI, USAAbstract: This review discusses the methodology of the standardized on-the-road driving test and standard operation procedures to conduct the test and analyze the data. The on-the-road driving test has proven to be a sensitive and reliable method to examine driving ability after administration of central nervous system (CNS) drugs. The test is performed on a public highway in normal traffic. Subjects are instructed to drive with a steady lateral position and constant speed. Its primary parameter, the standard deviation of lateral position (SDLP), ie, an index of 'weaving', is a stable measure of driving performance with high test–retest reliability. SDLP differences from placebo are dose-dependent, and do not depend on the subject's baseline driving skills (placebo SDLP). It is important that standard operation procedures are applied to conduct the test and analyze the data in order to allow comparisons between studies from different sites.Keywords: driving test, SDLP, methodology, on-the-road, highway

Michael J Thorpy,1 Thomas Roth2,31Sleep-Wake Disorders Center, Montefiore Medical Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, NY, USA; 2University of Michigan School of Medicine, Ann Arbor, 3Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan, USAAbstract: While some systems classify medications according to therapeutic class, others are based on the mechanism of action of the drugs. The two main classifications of medications used to treat patients in the United States are those of the United States Pharmacopeia and US Food and Drug Administration, and they vary in their organization of the medication categories. Here we propose a taxonomy for medications used to treat sleep and circadian rhythm disorders based on symptoms and disorders.Keywords: circadian, sleep, taxonomy, classification, diagnosis