Cardiovascular risk in adults with Delayed Sleep Phase Syndrome (DSPS) and Attention-Deficit/Hyperactivity Disorder (ADHD).

TRIAL REGISTRATION: FASE, https://www.trialregister.nl/, #NTR3831.

Delayed Mid-Sleep Time Associated With Weight Gain While Controlling for Eating Behaviors and Attention Deficit Hyperactivity Disorder Symptoms During the COVID-19 Pandemic.

OBJECTIVE: Society's sleep-wake cycle and eating behaviors have altered and are considered the psychological outcomes of the coronavirus disease-2019 (COVID-19) pandemic. Our aim was to examine the relationship between sleep-wake rhythms, eating behaviors (dieting, oral control, and bulimic behaviors), and attention deficit hyperactivity disorder (ADHD) symptoms with weight gain during the COVID-19 pandemic. METHODS: The participants were 578 female university students divided into three groups based on weight change during COVID-19 who lost weight, whose weight did not change (nWC), and who gained weight (WG). The participants' information about weight change in the last year and responses to the Pittsburg Sleep Quality Index, Eating Attitudes Test, Adult ADHD Severity Rating Scale, and Wender Utah Rating Scale were collected via an online survey from January 8, 2021 to January 11, 2021. RESULTS: The sleep-wake phase was more delayed in WGs than in the other two groups. The bulimic behavior score was higher and the oral control behavior score was lower in the WG group than in the nWC group. A hierarchical regression analysis model, in which weight change scores were dependent variables, showed that mid-sleep time in second step (ß=4.71, t=2.18, p=0.03), and oral control (ß=-0.11, t=-3.24, p=0.001)/bulimic behaviors (ß=0.20, t=3.20, p=0.001) in third step were associated with weight change after controlling for both current and childhood ADHD symptoms. CONCLUSION: Chronotherapeutic approaches that regulate sleep-wake rhythm may facilitate weight control of individuals during stressful periods, such as the COVID-19 outbreak.

Melatonin Treatment for Pediatric Patients with Insomnia: Is There a Place for It?

Sleep is a vital physiological function that is impaired in ranges from 10% in the typically developing pediatric population to over 80% in populations of children with neurodevelopmental disorders and/or psychiatric comorbidities. Pediatric insomnia disorder is an increasing public health concern given its negative impact on synaptic plasticity involved in learning and memory consolidation but also on mood regulation, hormonal development and growth, and its significant impact on quality of life of the child, the adolescent and the family. While first-line treatment of pediatric insomnia should include parental education on sleep as well as sleep hygiene measures and behavioural treatment approaches, pharmacological interventions may be necessary if these strategies fail. Melatonin treatment has been increasingly used off-label in pediatric insomnia, given its benign safety profile. This article aims to identify the possible role of melatonin treatment for pediatric insomnia, considering its physiological role in sleep regulation and the differential effects of immediate release (IR) versus prolonged release (PR) melatonin. For the physician dealing with pediatric insomnia, it is particularly important to be able to distinguish treatment rationales implying different dosages and times of treatment intake. Finally, we discuss the benefit-risk ratio for melatonin treatment in different pediatric populations, ranging from the general pediatric population to children with different types of neurodevelopmental disorders, such as autism spectrum disorder or ADHD.

Mood phenotypes in rodent models with circadian disturbances.

Many physiological functions with approximately 24-h rhythmicity (circadian rhythms) are generated by an internal time-measuring system of the circadian clock. While sleep/wake cycles, feeding patterns, and body temperature are the most widely known physiological functions under the regulation of the circadian clock, physiological regulation by the circadian clock extends to higher brain functions. Accumulating evidence suggests strong associations between the circadian clock and mood disorders such as depression, but the underlying mechanisms of the functional relationship between them are obscure. This review overviews rodent models with disrupted circadian rhythms on depression-related responses. The animal models with circadian disturbances (by clock gene mutations and artifactual interventions) will help understand the causal link between the circadian clock and depression.

Attention-Deficit/Hyperactivity Disorder and Delayed Sleep Phase Syndrome in Adults: A Randomized Clinical Trial on the Effects of Chronotherapy on Sleep.

Delayed sleep phase syndrome (DSPS) is the most common sleep disturbance in adults with attention-deficit/hyperactivity disorder (ADHD). We previously showed that chronotherapy with melatonin effectively advanced the dim-light melatonin onset (DLMO), a biomarker for the internal circadian rhythm, by 1.5 h and reduced ADHD symptoms by 14%. Melatonin combined with bright light therapy (BLT) advanced the DLMO by 2 h, but did not affect ADHD symptoms. This article explores whether sleep times advanced along with DLMO, leading to longer sleep duration and better sleep in general, which might explain the working mechanism behind the reduction in ADHD symptoms after treatment with melatonin. This article presents exploratory secondary analysis on objective and self-reported sleep characteristics from a three-armed double-blind randomized placebo-controlled clinical trial (RCT), which included 49 adults (18-55 years) with ADHD and DSPS. Participants were randomized to receive sleep education and 3 weeks of (1) 0.5 mg/day placebo, (2) 0.5 mg/day melatonin, or (3) 0.5 mg/day melatonin plus 30 min of bright light therapy (BLT) between 0700 and 0800 h. Sleep was assessed at baseline, directly after treatment, and 2 weeks after the end of treatment. Objective measures were obtained by actigraphy, self-reported measures by various sleep questionnaires and a sleep diary. Melatonin with or without BLT did not advance sleep times, improve sleep in general, or strengthen wake-activity rhythms. So even though the DLMO had advanced, sleep timing did not follow. Adding extensive behavioral coaching to chronotherapy is necessary for advancing sleep times along with DLMO and to further alleviate ADHD symptoms.

Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review.

Delayed sleep-wake phase disorder (DSWPD) is a common circadian sleep-wake phase disorders brings serious social impairment of the patients. Melatonin is the main medication option; however, it has not been approved in some countries, and over-the-counter melatonin is under poor quality control. The melatonin receptor agonist ramelteon might be a potential treatment option, but there are few reports regarding its use in DSWPD patients. Existing pharmacological and chronobiological studies suggest that an ultra-low dose of ramelteon in the early night is beneficial for DSWPD. Here, we present our clinical experience together with a pharmacological review and discussion. Twenty-three DSWPD patients, of whom 18 patients had a treatment history of a normal dose of ramelteon, were prescribed low-dose ramelteon (median: 0.571 mg, 1/14 of a tablet) to be taken in the early night (mean: 18:10). After the treatment, the mean sleep schedule was significantly advanced, and clinical symptoms were improved. CITATION: Shimura A, Kanno T, Inoue T. Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. J Clin Sleep Med. 2022;18(12):2861-2865.

From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach.

We present ten insights that can be gained from computational models based on molecular mechanisms for the mammalian circadian clock. These insights range from the conditions in which circadian rhythms occur spontaneously to their entrainment by the light-dark (LD) cycle and to clock-related disorders of the sleep-wake cycle. Endogenous oscillations originate spontaneously from transcription-translation feedback loops involving clock proteins such as PER, CRY, CLOCK and BMAL1. Circadian oscillations occur in a parameter domain bounded by critical values. Outside this domain the circadian network ceases to oscillate and evolves to a stable steady state. This conclusion bears on the nature of arrhythmic behavior of the circadian clock, which may not necessarily be due to mutations in clock genes. Entrainment by the LD cycle occurs in a certain range of parameter values, with a phase that depends on the endogenous period of the circadian clock. A decrease in PER phosphorylation is accompanied by a decrease in endogenous period and a phase advance of the clock; this situation accounts for the familial, advanced sleep phase syndrome (FASPS). The mirror delayed sleep phase syndrome (DSPS) can be accounted for, similarly, by an increase in PER phosphorylation and a rise in autonomous period. Failure of entrainment by the LD cycle in the model corresponds to the non-24 h sleep-wake cycle syndrome, in which the phase of the circadian clock drifts in the course of time. Quasi-periodic oscillations that develop in these conditions sometimes correspond to long-period patterns in which the circadian clock is nearly entrained for long bouts of time before its phase rapidly drifts until a new regime of quasi-entrainment is re-established. In regard to jet lag, the computational approach accounts for the two modes of re-entrainment observed after an advance or delay which correspond, respectively, to an eastward or westward flight: the clock adjusts in a direction similar (orthodromic) or opposite (antidromic) to that of the shift in the LD cycle. Computational modeling predicts that in the vicinity of the switch between orthodromic and antidromic re-entrainment the circadian clock may take a very long time to resynchronize with the LD cycle. Repetitive perturbations of the circadian clock due, for example, to chronic jet lag -a situation somewhat reminiscent of shift work- may lead to quasi-periodic or chaotic oscillations. The latter irregular oscillations can sometimes be observed in normal LD cycles, raising the question of their possible relevance to fragmented sleep patterns observed in narcolepsy. The latter condition, however, appears to originate from disorders in the orexin neural circuit, which promotes wakefulness, rather than from an irregular operation of the circadian clock.

Narcolepsy type 2: A rare, yet existing entity.

Because of unspecific diagnostic criteria, there is much controversy around narcolepsy type 2, its existence and its frequency. With this retrospective and purely descriptive study, we aimed to compare the frequency of narcolepsy type 2 compared to the well-described narcolepsy type 1, in a large (n = 3,782) retrospective sample from a single tertiary sleep centre. After 2 weeks washout of sleep-wake active medication, all patients with excessive daytime sleepiness (n = 1,392) underwent 2 weeks actigraphy, polysomnography and multiple sleep latency test, and all diagnoses were made along current diagnostic criteria. Narcolepsy type 1 was diagnosed in 91 patients, and 191 patients without cataplexy had multiple sleep latency test (MSLT) results indicating narcolepsy. After exclusion of shift work syndrome (n = 19), suspected insufficient sleep syndrome (n = 128), delayed sleep phase syndrome (n = 4) and obstructive sleep apnea (n = 34), six patients were diagnosed with narcolepsy type 2, of whom two patients later developed narcolepsy type 1. Altogether, our observations suggest that narcolepsy type 2 exists, but its frequency may be much lower compared to narcolepsy type 1. In addition, they emphasize the importance of scrupulously excluding other potential causes of sleepiness, if possible, with 2-week actigraphy and polysomnography.

Treatment of severe morning sleep inertia with bedtime long-acting bupropion and/or long-acting methylphenidate in a series of 4 patients.

STUDY OBJECTIVES: To assess the benefit of bedtime long-acting bupropion and/or long-acting methylphenidate in the therapy of severe morning sleep inertia (SI), a chronic condition that has major adverse consequences on level of functioning and quality of life, and for which there is no recognized therapy. METHODS: Patients underwent clinical interviews and examinations and completed comprehensive questionnaires. They underwent overnight video-polysomnography and next-day multiple sleep latency testing (apart from 1 case with obstructive sleep apnea). Treatments are described in the case reports. RESULTS: Case 1, a 16-year-old girl who was very late to school every day from severe morning SI despite obstructive sleep apnea being fully controlled with continuous positive airway pressure therapy, responded to bedtime bupropion-extended release (xl) 150 mg, together with methylphenidate-sr (sustained release), 36 mg (along with 20 mg methylphenidate taken 1 hour before the alarm would go off). She woke up in a timely fashion and has started her classes on time, with benefit maintained at 6-month follow-up. Case 2, a 29-year-old female with idiopathic hypersomnia and major depression and associated severe morning SI while maintained on 20 mg twice-daily generic Adderall, responded immediately (first night) to bedtime bupropion-xl, 150 mg, with benefit maintained at the 4-month follow-up. Case 3, a 74-year-old man with idiopathic hypersomnia and major depression maintained on daily methylphenidate-sr and direct-release methylphenidate, along with 300 mg bupropion-xl, developed progressively severe morning SI that immediately responded to changing his bupropion-xl regimen to 150 mg nightly and 150 mg every morning, with benefit maintained at the 3-year follow-up. Case 4, a 60-year-old female with idiopathic hypersomnia and severe morning SI, was immediately intolerant to bedtime bupropion-xl, which was discontinued. CONCLUSIONS: Bedtime use of long-acting bupropion and/or long-acting methylphenidate can be effective in the therapy for severe morning SI and warrants further clinical use along with systematic research.

Effects of chronotherapy on circadian rhythm and ADHD symptoms in adults with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome: a randomized clinical trial.

The majority of adults with Attention-Deficit/Hyperactivity Disorder (ADHD) have a delayed circadian rhythm that is a characteristic of Delayed Sleep Phase Syndrome (DSPS). Treatment of DSPS may improve both the circadian rhythm and ADHD symptoms. In this three-armed randomized clinical trial, 51 adults (18-55 y) with ADHD and DSPS received sleep education and 3 weeks of (1) 0.5 mg/d placebo, (2) 0.5 mg/d melatonin, or (3) 0.5 mg/d melatonin plus 30 minutes of 10,000 lux bright light therapy (BLT) between 07:00 and 08:00 h. Placebo/melatonin conditions were double-blind. Treatment took place in the participants' naturalistic home settings. Dim-light melatonin onset (DLMO) was measured in saliva as marker of internal circadian rhythm. Melatonin or placebo administration followed individual schedules, starting 3 hours before the individual DLMO and weekly advancing by 1 h. DLMO and ADHD Rating Scale score were assessed at baseline, directly after 3-week treatment, and two weeks after the end of treatment. Results show that at baseline 77% had a DLMO after 21:00 h with an average DLMO at 23:43 h ± 1h46. Directly after treatment, melatonin had advanced DLMO by 1h28 (p = .001), and melatonin plus BLT by 1h58 (p < .001). Placebo did not affect DLMO. ADHD symptoms reduced by 14% (p = .038) directly after melatonin treatment. Placebo and melatonin plus BLT did not impact ADHD symptoms. Two weeks after end of treatment, ADHD symptoms and DLMO had returned to baseline levels. It can be concluded that low doses of melatonin advanced the circadian rhythm and reduced self-reported ADHD symptoms. Given the large number of adult ADHD patients with concurrent DSPS, treating delayed sleep with melatonin is an important component of effective ADHD treatment.

The impact of delayed sleep phase disorder on adolescents and their family.

INTRODUCTION: We investigated the impact of delayed sleep phase disorder (DSPD) on the daily lives of adolescents and their families. METHOD: In this qualitative study, six adolescents with DSPD, and six parents were given in-depth interviews. Using thematic analysis, we merged open codes into themes that reflected the impact of the disorder. RESULT: We identified five themes: (1) Impact on the adolescents' school and social life: describing the negative influence of DSPD on school performance and friendships. (2) Impact on the parents, feeling guilty and powerless: showing the consequences of many unsuccessful attempts to improve the situation, with a lack of understanding from their social support system. (3) Impact on the family, conflicts, and misunderstanding: describing the negative influence on other family members, family relationships, and home atmosphere. (4) Impact on the parents, being weary of everything: describing the effect on the parents' mood and social life. (5) Factors mediating the severity of impact, of which personal characteristics and school support seemed most important. Themes 2 to 4 were highly interrelated. CONCLUSIONS: Adolescent DSPD not only affects cognitive functioning and mental health but has a much broader impact, also affecting social life, family life, and parental well-being. This information provides new potential points of engagement for therapy, guidance, and support for these families. Greater awareness and recognition of the impact of DSPD is needed on the part of physicians as well as the general population, to increase support and reduce misunderstanding of these adolescents and their parents.

Sleep education in primary school prevents future school refusal behavior.

BACKGROUND: Sleep disorders, along with extreme difficulty in awakening, are one of the main causes of school refusal. The accumulation of chronic sleep deprivation accompanied by a late-night lifestyle is considered the basic inciting factor. METHODS: From 2007, we initiated a sleep education program (Min-Iku) in Fukui, Japan, with the aim of improving pupil lifestyle and preventing future school refusal. All grade 1-6 Miyake-primary school (M-PS) pupils participated in this program and gave their informed consent. The Min-Iku included (i) implementation of a "daily life rhythm survey" by recording the sleep-wake rhythm in a table for 14 days; (ii) evaluation of the sleep table according to the classifications A-D; (iii) interviews of stage D children and their guardians; (iv) lectures on the importance of daily life rhythms for parents and teachers; and (v) 45 min classwork for all participating pupils. RESULTS: In 2007, 10% of M-PS graduates developed school refusal behavior after entering Kaminaka junior high school (K-JHS). The incidence of school refusal, however, decreased each year after the implementation of the Min-Iku program and finally reached 0 by 2012. The sleep onset time of pupils improved each year, with the most common sleep time reaching 9:30 p.m. on both weekdays and holidays. With an earlier sleep time, the night-time sleep duration was significantly extended (P < 0.001 vs 2007 data). CONCLUSION: The Min-Iku program for primary school pupils successfully achieved a more routine night-time sleep pattern and a regular life rhythm, which prevented school refusal during the subsequent JHS years.

Is Idiopathic Hypersomnia a Circadian Rhythm Disorder?

PURPOSE OF REVIEW: The pathophysiology of idiopathic hypersomnia remains unclear, but some of its clinical features suggest the possibility of circadian dysfunction. This review will provide an overview of recent studies of circadian biology that have begun to elucidate the potential role of circadian rhythm dysfunction in idiopathic hypersomnia. RECENT FINDINGS: Clinically, people with idiopathic hypersomnia tend to have both a late chronotype and prominent sleep inertia or sleep drunkenness. Melatonin and cortisol profiles in people with IH confirm this tendency toward phase delay. More recently, it has been suggested that the night phase as defined by melatonin profile or period length as defined by BMA1 in dermal fibroblasts may also be prolonged in people with IH. Additionally, amplitude of melatonin rhythm and circadian gene expression, particularly BMAL1, PER1, and PER2, may be impaired in this disease. SUMMARY: Clinical features, melatonin profiles, and circadian gene expression all suggest abnormalities of the circadian system may be a contributor to the pathogenesis of IH.

Chronotype and Psychiatric Disorders.

PURPOSE OF REVIEW: Chronotype, reflecting interindividual differences in daily activity patterns and sleep-wake cycles, is intrinsically connected with well-being. Research indicates increased risk of many adverse mental health outcomes for evening-type individuals. Here, we provide an overview of the current evidence available on the relationship between chronotype and psychiatric disorders. RECENT FINDINGS: The association between eveningness and depression is well established cross-sectionally, with preliminary support from longitudinal studies. The mechanisms underlying this relationship warrant further research; deficient cognitive-emotional processes have recently been implicated. Eveningness is associated with unhealthy lifestyle habits, and the propensity of evening types to addiction has been recognized. Chronotype may also be implicated in disordered eating. SUMMARY: Eveningness is associated with depression-including seasonal affective disorder (SAD)-and substance dependence, while support for a relation with anxiety disorders and psychosis is lacking. In bipolar disorder, chronotype is linked to depression but not mania. Eveningness is also related to sleep disturbances and poor lifestyle habits, which may increase risk for psychiatric disorders.

Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation.

OBJECTIVES: Delayed sleep phase syndrome (DSPS) is a chronic dysfunction of circadian rhythm of the subject that impairs functioning in social, occupational, or other spheres. High rate of depression is found among DSPS patients. Aripiprazole (APZ), a second-generation antipsychotic, is effective in treatment of depression as well as schizophrenia. Recently, few case reports show the effectiveness of APZ in treating DSPS and non-24-hour sleep-wake rhythm disorder. Therefore, we tried to treat DSPS with depression using APZ. METHODS: Twelve subjects (including four women) aged 19-64 years were included. The subjects were prescribed initially 0.5-3 mg of APZ once a day with subsequent dose adjustments. RESULTS: Sleep onset, midpoint of sleep, and sleep offset were significantly advanced by 1.1, 1.8, and 2.5 hours, respectively. Unexpectedly, sleep duration became significantly shorter by 1.3 hours after treatment. Their depressive moods showed an unremarkable change. CONCLUSION: Low dose of APZ advanced the sleep rhythm and reduced nocturnal sleep time in the subjects with DSPS. Since it is not easy for physicians to treat prolonged sleep duration often associated with DSPS, this medication would become a new therapeutic option for these patients.

Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders.

Melatonin is a physiological hormone involved in sleep timing and is currently used exogenously in the treatment of primary and secondary sleep disorders with empirical evidence of efficacy, but very little evidence from randomised, controlled studies. The aim of this meta-analysis was to assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders. An electronic literature review search of MEDLINE (1950-present) Embase (1980- present), PsycINFO (1987- present), and Scopus (1990- present), along with a hand-searching of key journals was performed in July 2013 and then again in May 2015. This identified all studies that compared the effect of exogenous melatonin and placebo in patients with primary insomnia, delayed sleep phase syndrome, non 24-h sleep wake syndrome in people who are blind, and rapid eye movement-behaviour disorder. Meta-analyses were performed to determine the magnitude of effect in studies of melatonin in improving sleep. A total of 5030 studies were identified; of these citations, 12 were included for review based on the inclusion criteria of being: double or single-blind, randomised and controlled. Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia (p = 0.002), delayed sleep phase syndrome (p < 0.0001), and regulating the sleep-wake patterns in blind patients compared with placebo. These findings highlight the potential importance of melatonin in treating certain first degree sleep disorders. The development of large-scale, randomised, controlled trials is recommended to provide further evidence for therapeutic use of melatonin in a variety of sleep difficulties.

Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles.

People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness-eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.

The sleepy teenager - diagnostic challenges.

The sleepy teenager puts the doctor in a, often tricky, situation where it must be decided if we deal with normal physiology or if we should suspect pathological conditions. What medical investigations are proper to consider? What differential diagnoses should be considered in the first place? And what tools do we actually have? The symptoms and problems that usually are presented at the clinical visit can be both of medical and psychosocial character - and actually they are often a mixture of both. Subsequently, the challenge to investigate the sleepy teenager often includes the examination of a complex behavioral pattern. It is important to train and develop diagnostic skills and to realize that the physiological or pathological conditions that can cause the symptoms may have different explanations. Research in sleep disorders has shown different pathological mechanisms congruent with the variations in the clinical picture. There are probably also different patterns of involved neuronal circuits although common pathways may exist. The whole picture remains to be drawn in this interesting and challenging area.

Sex differences in circadian timing systems: implications for disease.

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamic-adrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.

Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles

People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness-eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.