Managing non-24-hour sleep-wake rhythm disorder with ramelteon in a 12-year-old girl with Pierre Robin sequence and developmental delay: a case report.

The author recently observed a case involving a 12-year-old sighted girl who exhibited symptoms typical of non-24-hour sleep-wake rhythm disorder (N24SWD). This disorder, more commonly found in blind individuals, presents a unique challenge when diagnosed in those with vision. Several interventions can be attempted, ranging from behavioral adjustments to light therapy. Although melatonin has been noted for its effectiveness in realigning the patient's sleep-wake cycle, the use of ramelteon, a melatonin receptor agonist, has seldom been reported in managing N24SWD. However, this case illuminates the potential of ramelteon as another therapeutic option for sighted individuals with N24SWD. Further study is suggested to determine the potential of ramelteon in managing this disorder among sighted individuals of varying age groups. CITATION: Huang C-H. Managing non-24-hour sleep-wake rhythm disorder with ramelteon in a 12-year-old girl with Pierre Robin sequence and developmental delay: a case report. J Clin Sleep Med. 2024;20(6):995-997.

Continuous positive airway pressure as an accurate marker for non-24-hour sleep-wake rhythm disorder.

Non-24-h sleep-wake rhythm disorder is quite rare in sighted patients and frequently associated with psychiatric disorders. We report the case of a 46-year-old man with autism spectrum disorder (ASD) and agoraphobia who had been referred for a suspicion of obstructive sleep apnea syndrome (OSAS). Polysomnography and arterial blood gas confirmed moderate OSAS associated with hypoventilation. Continuous positive airway pressure (CPAP) was started on fixed mode with excellent results. At follow-up, his CPAP report data revealed an irregular sleep-wake rhythm with a progressive offset of sleep schedule and wake time delayed from 1 h from day to day. Melatonin (or agonist) is efficacious and safe for long-term treatment in ASD and circadian rhythm sleep-wake disorder (CRSWD) with light therapy and wakefulness promoting medication. This case underlines the importance to sensitise psychiatrists to sleep and CRSWD, and also that CPAP data offer a possible objective alternative to sleep diary.

Melatonin supplementation for the treatment of infantile spasms: protocol for a randomised placebo-controlled triple-blind trial.

INTRODUCTION: Infantile spasms (IS) is a type of severe epileptic encephalopathy that occurs in infancy and early childhood. IS is characterised clinically by epileptic spasms, often accompanied by sleep disorder and abnormal circadian rhythm. The endogenous circadian rhythm disorder, in turn, can make spasms worse. Melatonin has also been found to have anticonvulsant and neuroprotective properties by adjusting the circadian rhythm. However, there are lack of relevant studies on controlling IS by using melatonin. This study aims to analyse the therapeutic effect of melatonin supplementation for the treatment of IS. METHODS AND ANALYSIS: This is a triple-blinded (trial participant, outcome assessor and the data analyst), prospective, randomised controlled trial to be conducted in the Department of Paediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China from November 2020. Patients (n=70) aged 3 months to 2 years with IS will be recruited in this study after receiving written consent from their parents or guardians. Patients will be randomly divided into two equal groups and treated with a combination of adrenocorticotropic hormone, magnesium sulfate and either melatonin or placebo. Clinical data from the patients in the two groups before and after the treatment will be collected and compared. The primary outcome will be assessed 2 weeks later by seizure diaries and reported as the average reduced rate of spasms frequency. Secondary outcomes include the response rate (the rate of spasms-free), electroencephalogram hypsarrhythmia assessment and the psychomotor development assessment (Denver Developmental Screening Test). Sleep quality and safety will also be assessed. ETHICS AND DISSEMINATION: The protocol for this study was approved by the Ethics Committee of Chinese PLA General Hospital (reference number S2020-337-01) and was reported according to the Standard Protocol Items: Recommendations for Interventional Trials statement. Findings of this research will be disseminated through national and international meetings, conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2000036208.

Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol.

CITATION: Circadian rhythm sleep-wake disorders result from the lack of synchronization between endogenous circadian rhythms and daily environmental or behavioral cycles. Current treatment of circadian rhythm sleep-wake disorders relies on strengthening normal zeitgebers, or temporal cues, through the combination of strict behavioral modification, controlled light exposure, and supplemental melatonin or melatonin receptor agonists. These therapies can be difficult to maintain and are supported with only limited clinical outcome data. The effectiveness of exogenous melatonin, in particular, may be reduced by the patient's continued production of endogenous melatonin with a temporal pattern that is not conducive to the desired sleep schedule. Here we describe the case of a single, sighted patient with a circadian rhythm sleep-wake disorder who benefited from the combined use of a beta blocker to suppress endogenous melatonin secretion along with the timed administration of exogenous melatonin. We suggest that the positive results obtained justify further study of this mechanism-guided approach. CITATION: Gehrman PR, Anafi RC. Treatment of a patient with a circadian sleep-wake disorder using a combination of melatonin and metoprolol. J Clin Sleep Med. 2021;17(10):2121-2124.

Characterization of pharmaco-EEG fingerprint and sleep-wake profiles of Lavandula angustifolia Mill. essential oil inhalation and diazepam administration in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lavandula angustifolia Mill. Essential oil (Lavender EO) has a long history of medicinal use and is particularly claimed to possess anxiolytic and sedative properties. Lavender EO aromatherapy has been used to reduce distress and improve insomnia naturally. Increasing evidence appeared to show similarities between the effects of lavender EO and the anxiolytic drugs, benzodiazepines. However, its effects on sleep-wake and electrical brain patterns in comparison to that of the standard anxiolytic, diazepam, remained to be explored. AIM OF THE STUDY: The aim of this work was to investigate electroencephalography (EEG) profiles and sleep-pattern elicited by lavender EO inhalation compared to that of diazepam, a standard anxiolytic drug in in vivo rat model. MATERIALS AND METHODS: Adult male Wistar rats were anesthetized for electrode implantation on the frontal and parietal skulls. EEG signals were recorded for 180 min following intraperitoneal injection of diazepam (10 mg/kg) or during continuous inhalation of lavender EO (200 µL) or distilled water (control). Fast Fourier transform was used for the analyses of EEG power spectra and sleep-wake parameters. RESULTS: During a 30-60 min period, diazepam and lavender EO significantly increased frontal powers of 0.78-45.31 and 7.03-18.36 Hz, respectively. Both treatments also increased parietal powers with lower magnitudes of significant change. Significant increases in some frequency ranges remained until a 60-90 min period. Sleep-wake analyses also revealed that diazepam significantly reduced time spent in wake, increased time spent in non-rapid eye movement (NREM), increased episode duration of NREM, decreased numbers of wake episode and decreased rapid eye movement (REM) sleep latency. On the other hand, lavender EO only significantly decreased wake episodes and latency to REM sleep. Lavender EO inhalation reduced numbers of wake episode but maintain normal time spent in wake, NREM and REM sleeps. CONCLUSIONS: These findings might suggest beneficial and distinct anxiolytic-like effects of lavender EO for sleep enhancing purposes.

Effect of Suvorexant vs Placebo on Total Daytime Sleep Hours in Shift Workers: A Randomized Clinical Trial.

Importance: Many shift workers have difficulty sleeping during the daytime owing to an inappropriately timed circadian drive for wakefulness. Objective: To determine whether a dual hypocretin receptor antagonist would enable shift workers to have more daytime sleep. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial included 2 weeks of baseline data and 3 weeks of intervention data, from March 2016 to December 2018. Individuals were recruited through poster advertisements in the broader San Francisco Bay area in California. From an initial voluntary recruitment cohort of 38 shift workers, 19 individuals with self-reported difficulty sleeping during the daytime following night work shift were included. Data were analyzed from Janaury to March 2019. Interventions: 1 week of 10 mg suvorexant or placebo, titrated upward to 20 mg suvorexant or placebo for 2 additional weeks. Main Outcomes and Measures: Objective (ie, actigraphy) and subjective (ie, sleep logs) measures of sleep. Results: Among 19 participants who completed the study (mean [SD] age, 37.7 [11.1] years; 13 [68%] men), 8 participants (42%) were assigned to the suvorexant group and 11 participants (58%) were assigned to the placebo group. Compared with individuals in the placebo group, individuals in the suvorexant group increased their objective total sleep time by a mean (SE) of 1.04 (0.53) hours (P = .05) at the end of 1 week of 10-mg doses and by 2.16 (0.75) hours (P = .004) by the end of the 2 weeks of 20-mg doses. Subjective sleep was similarly improved as, compared with the placebo group, individuals in the suvorexant group increased their subjective total sleep time by a mean (SE) of 2.08 (0.47) hours (P < .001) at the end of 1 week of 10-mg doses and by 2.97 (0.56) hours (P < .001) by the end of the 2 weeks of 20-mg doses. Physician ratings of daytime sleep aligned with these measures, as there was no change in the placebo group and a much improved change in the suvorexant group. No adverse events were reported in the suvorexant group. Conclusions and Relevance: This pilot study found that the use of a dual hypocretin receptor antagonist in shift workers under real-world conditions resulted in more than 2 extra hours of daytime sleep per episode. Future research should confirm this pilot finding in a larger sample size and examine whether, over the long term, use of this medication has a concomitant improvement in medical and psychiatric health as well as workplace performance and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02491788.

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models.

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.

Circadian Rhythm Sleep-Wake Disorders.

The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options.

Health-related interventions among night shift workers: a critical review of the literature.

OBJECTIVES: Associations between shift work and chronic disease have been observed, but relatively little is known about how to mitigate these adverse health effects. This critical review aimed to (i) synthesize interventions that have been implemented among shift workers to reduce the chronic health effects of shift work and (ii) provide an overall evaluation of study quality. METHODS: MeSH terms and keywords were created and used to conduct a rigorous search of MEDLINE, CINAHL, and EMBASE for studies published on or before 13 August 2012. Study quality was assessed using a checklist adapted from Downs & Black. RESULTS: Of the 5053 articles retrieved, 44 met the inclusion and exclusion criteria. Over 2354 male and female rotating and permanent night shift workers were included, mostly from the manufacturing, healthcare, and public safety industries. Studies were grouped into four intervention types: (i) shift schedule; (ii) controlled light exposure; (iii) behavioral; and, (iv) pharmacological. Results generally support the benefits of fast-forward rotating shifts; simultaneous use of timed bright light and light-blocking glasses; and physical activity, healthy diet, and health promotion. Mixed results were observed for hypnotics. Study quality varied and numerous deficiencies were identified. CONCLUSIONS: Except for hypnotics, several types of interventions reviewed had positive overall effects on chronic disease outcomes. There was substantial heterogeneity among studies with respect to study sample, interventions, and outcomes. There is a need for further high-quality, workplace-based prevention research conducted among shift workers.

Tasimelteon: first global approval.

Tasimelteon (HETLIOZ™) is an orally bioavailable agonist of the melatonin MT1 and MT2 receptors that has been approved in the US for the treatment of non-24-hour sleep-wake disorder. It is the first US FDA-approved medication for this orphan indication. Melatonin is thought to play a role in governing the body's natural sleep-wake cycle through physiological processes regulated in the suprachiasmatic nucleus of the hypothalamus. The hormone is secreted by the pineal gland, with onset typically occurring when daylight begins to dim. In healthy, sighted individuals, the endogenous circadian period is a little over 24 hours, but is entrained to the 24-hour day through exposure to environmental cues, such as light and darkness. In the absence of these cues, synchronisation is lost and the circadian rhythm follows the intrinsic non-24-hour clock, resulting in disorders like non-24-hour sleep-wake disorder. Because the rhythm of endogenous melatonin is considered to be a measure of the human circadian phase, the carefully timed administration of melatonin analogues, such as tasimelteon, can potentially promote circadian readjustment. This article summarizes the milestones in the development of tasimelteon leading to this first approval for the treatment of non-24-hour sleep-wake disorder.

[Orexin: clinical and therapeutic implications]. / Orexina: implicaciones clínicas y terapéuticas.

INTRODUCTION. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. DEVELOPMENT. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. CONCLUSIONS. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction.

TITLE: Orexina: implicaciones clinicas y terapeuticas.Introduccion. Se ha descrito recientemente una nueva clase de neuropeptidos, las orexinas, tambien llamadas hipocretinas, producidos por un reducido grupo de neuronas hipotalamicas y cuyas acciones son mediadas por dos tipos de receptores, OX1R y OX2R. En concreto, las neuronas orexinergicas se han localizado en exclusiva en celulas de areas del hipotalamo lateral, dorsomedial y perifornical. A pesar de este origen anatomico tan localizado, las neuronas orexinergicas se proyectan ampliamente a numerosas regiones troncoencefalicas, corticales y limbicas. Desarrollo. Este patron difuso de distribucion de las fibras orexinergicas estaria indicando la intervencion de este sistema peptidico en una amplia variedad de funciones y, de hecho, se ha relacionado con los mecanismos que permiten la regulacion del ciclo sueño-vigilia, la ingesta de comida y de bebida y determinados aprendizajes como el aprendizaje de preferencias gustativas. Se ha sugerido tambien que la alteracion en el funcionamiento del sistema orexinergico explicaria la aparicion de determinados trastornos clinicos como la narcolepsia, la obesidad o la adiccion a drogas de abuso. Conclusiones. Nuevas investigaciones ayudaran a conocer el funcionamiento de las neuronas orexinergicas y la interaccion entre los sistemas que regulan la emocion, la homeostasis energetica y los mecanismos de recompensa con los sistemas que regulan el ciclo de sueño-vigilia. Se confia en que ese conocimiento permita desarrollar nuevos farmacos que, actuando sobre el sistema orexinergico, sean eficaces en el tratamiento de las alteraciones del sueño como el insomnio o la narcolepsia, de los trastornos de la alimentacion o de la drogadiccion.

Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders.

Treatment of circadian rhythm sleep disorders (CRSD) may include light therapy, chronotherapy and melatonin. Exogenous melatonin is increasingly being used in patients with insomnia or CRSD. Although pharmacopoeias and the European food safety authority (EFSA) recommend administering melatonin 1-2 h before desired bedtime, several studies have shown that melatonin is not always effective if administered according to that recommendation. Crucial for optimal treatment of CRSD, melatonin and other treatments should be administered at a time related to individual circadian timing (typically assessed using the dim light melatonin onset (DLMO)). If not administered according to the individual patient's circadian timing, melatonin and other treatments may not only be ineffective, they may even result in contrary effects. Endogenous melatonin levels can be measured reliably in saliva collected at the patient's home. A clinically reliably DLMO can be calculated using a fixed threshold. Diary and polysomnographic sleep-onset time do not reliably predict DLMO or circadian timing in patients with CRSD. Knowing the patient's individual circadian timing by assessing DLMO can improve diagnosis and treatment of CRSD with melatonin as well as other therapies such as light or chronotherapy, and optimizing treatment timing will shorten the time required to achieve results.

A randomized controlled trial with bright light and melatonin for the treatment of delayed sleep phase disorder: effects on subjective and objective sleepiness and cognitive function.

Delayed sleep phase disorder (DSPD) is a circadian rhythm sleep disorder. Patients with DSPD have problems initiating sleep if they go to bed at a conventional time, and they often have problems waking at desired times. If they rise early in the morning, they usually experience severe sleepiness during morning hours. In the present study, we investigated the short- and long-term effects on measures of subjective and objective sleepiness and cognitive function of bright light and melatonin treatment alongside gradually advanced rise times in adolescents and young adults. Four treatment conditions were used in the short-term intervention (2 weeks): dim light (placebo) + placebo capsule, bright light + placebo capsule, dim light (placebo) + melatonin capsule, and bright light + melatonin capsule. This was followed by a long-term intervention (3 months) including 2 conditions: no treatment and combined bright light + melatonin treatment. Effects of treatment on sleepiness and fatigue were the primary outcome measures, and effects on cognitive function were secondary outcome measures. On a gradual advancement of the rise time schedule, all treatment conditions (bright light, melatonin, combination, and placebo) were almost equally effective in improving subjective daytime sleepiness, fatigue, and cognitive function in the 2-week study. The 2-week intervention showed no effect on objective sleepiness. Long-term treatment increased some of the positive effects seen after 2 weeks. The combined bright light and melatonin treatment improved subjective daytime sleepiness, fatigue, and cognitive function in the 3-month study. The no-treatment group returned to baseline values on most variables. In conclusion, a gradual advancement of rise times seems to produce positive effects on subjective sleepiness, fatigue, and cognitive performance during short-term treatment of patients with DSPD. However, the benefits from gradually advanced rise times seem to wear off, suggesting that the continuation of bright light and melatonin treatment is beneficial to maintain positive effects over time.

Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial.

AIM: The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep. METHODS: In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day(-1) vs. placebo during 12 months. The primary endpoint quality of life parameter 'vitality' was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations. RESULTS: Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group. CONCLUSIONS: The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6-12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.

Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type.

BACKGROUND: Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucidated. In this study, the endogenous circadian period, τ, of FRT patients with normal vision was compared with that of healthy individuals whose circadian rhythms are entrained to a 24-hour cycle. METHODS: Six FRT patients and 17 healthy individuals (9 intermediate chronotypes and 8 evening chronotypes) were subjected to a 7-day, 28-hour sleep-wake schedule according to the forced desynchrony protocol. Phase shifts in melatonin rhythm were measured under constant routine conditions to calculate τ. RESULTS: In FRT patients, τ was significantly longer than in intermediate chronotypes, whereas in evening chronotypes, it ranged widely and was not significantly different from that in FRT patients. Moreover, τ of melatonin rhythm in FRT patients showed no significant correlation with τ of sleep-wake cycles measured before the study. CONCLUSIONS: The findings suggest that although a prolongation of τ may be involved in the onset mechanism of FRT, a prolonged τ is not the only factor involved. It appears that several factors including abnormal entrainment of circadian rhythms are involved in the onset of FRT in a multilayered manner.

Sleep and rhythm consequences of a genetically induced loss of serotonin.

BACKGROUND: A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. OBJECTIVE: We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. PATIENT: The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. METHODS: A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. RESULTS: Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P < 0.0001), and improved cognition. CONCLUSION: In this unique genetic paradigm, the melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

Circadian rhythmicity and the pharmacologic management of insomnia.

The circadian clock modulates timing of sleep and wakefulness. In certain situations, the circadian potentiation of wakefulness may interfere with desired sleep-scheduling, particularly in the elderly and shift workers. Known abnormalities of circadian regulation are defined by their impact on sleep-wake state expression. In delayed sleep phase syndrome, patients have trouble going to sleep and arising at reasonable hours and are alert in the evening and sleepy in the morning. Patients with advanced sleep phase syndrome are sleepy in the evening and awaken very early and alert in the morning. In shift-work sleep disorder, individuals attempt to wake and sleep out of phase with the circadian clock. As with jet lag, the clock is functioning normally, but the requirements on the clock are abnormal. Typical insomnia can also be associated with circadian rhythm alterations. Practice guidelines and clinical studies data are needed to lead appropriate therapy selection and effective management.

Circadian rhythm sleep disorders in the blind and their treatment with melatonin.

People who are blind, in addition to having to cope with partial or no sight, have an added handicap; the transmission of ocular light from the retina to their circadian clock is impaired. At its worse, for example in people with both eyes enucleated, this lesion results in desynchronisation of the biological clock (located in the hypothalamic suprachiasmatic nuclei) from the 24h day/night environment. While in a desynchronised state, symptoms akin to jet lag are experienced (e.g., daytime sleepiness, poor night sleep, reduced alertness and performance during waking). This is a lifelong condition. Daily administration of exogenous melatonin is the current treatment of choice for this so-called "non-24h sleep/wake disorder". Melatonin has been shown to correct the underlying circadian rhythm abnormality as well as improve sleep and reduce daytime napping. The effectiveness of melatonin therapy depends upon its time of administration relative to the timing of the person's circadian clock. If practicable, assessment of an individual's circadian phase (by measurement of the endogenous melatonin rhythm in plasma, saliva or urine) is recommended prior to commencing treatment to optimise melatonin's effectiveness.

Clinical management of delayed sleep phase disorder.

Delayed Sleep Phase Disorder is a circadian rhythm disorder that results in a late timed sleep pattern. Individuals have difficulty falling asleep at a conventional hour and difficulty waking in the morning. We discuss the contributing factors and consequences of a delayed sleep phase and describe treatment approaches. These include therapies to phase change the delayed sleep circadian rhythm such as morning bright light exposure, exogenous melatonin administration, and chronotherapy as well as some behavioral strategies.

Shift work sleep disorder: burden of illness and approaches to management.

More than 6 million Americans work night shifts on a regular or rotating basis. The negative consequences of shift work have been established, and recent evidence suggests that patients with shift work sleep disorder (SWSD) are at increased risk of these consequences and co-morbidities. SWSD is a relatively common but under-recognised, and hence undertreated, condition with potentially serious medical, social, economic and quality-of-life consequences. In addition to increased risk of gastrointestinal and cardiovascular disease, patients with SWSD experience clinically significant excessive sleepiness or insomnia associated with work during normal sleep times, which has important safety implications. A number of studies have evaluated countermeasures or interventions in shift workers; proposed treatments include chronobiotic interventions, such as light exposure, melatonin, hypnotic agents, caffeine and CNS stimulants (amphetamine), and the wake-promoting agents modafinil and armodafinil. However, most studies evaluating pharmacological therapies and nonpharmacological interventions simulate night-shift work under conditions that may not accurately reflect real-world activities. Pharmacological and nonpharmacological countermeasures evaluated mostly in simulated laboratory conditions have been shown to improve alertness or sleep in shift workers but have not yet been evaluated in patients with SWSD. To date, three randomised, double-blind clinical studies have evaluated pharmacological therapies in patients with SWSD. These studies showed that modafinil and armodafinil significantly improve the ability to sustain wakefulness during waking activities (e.g. working, driving), overall clinical condition, and sustained attention or memory in patients with SWSD. In conclusion, SWSD is a common condition that remains under-recognised and undertreated. Further research is needed to evaluate different treatment approaches for this condition, to clarify the substantial health and economic consequences of SWSD, and to determine the potential for interventions or treatments to reduce the negative consequences of this condition.