[Insomnia and the biological clock]. / Insomnie et horloge biologique.

INSOMNIA AND THE BIOLOGICAL CLOCK. Multiple physiological and biological rhythms known as «circadian¼ are generated by the biological clock that controls them within the suprachiasmatic nuclei of the hypothalamus. However, the most emblematic circadian rhythm is that of sleep and awakening. It is therefore crucial to check how the clock may be involved in chronic insomnia. What is the influence of the clock on the time and quality of sleep? What are the typical clock disorders that explain insomnia in adolescents, shift and night workers, the elderly and the blind individuals? What are the tools to recommend in general and specialized medicine in the evaluation of the clock in insomnia? What influence finally of the light on the clock and the light therapy to recommend? So many questions and elements of understanding often-poorly known of chronic insomnia.

INSOMNIE ET HORLOGE BIOLOGIQUE. De multiples rythmes physiologiques et biologiques dits « circadiens ¼ sont influencés par l'horloge biologique qui les contrôle au sein des noyaux suprachiasmatiques de l'hypothalamus. Mais le rythme circadien le plus emblématique est celui du sommeil et de l'éveil. Il est donc indispensable de vérifier comment l'horloge biologique peut être impliquée dans une insomnie chronique : quelle est son influence sur les horaires et la qualité du sommeil ? Quels sont les troubles caractéristiques de l'horloge biologique expliquant l'insomnie des adolescents, des travailleurs postés et de nuit, des personnes âgées et des non-voyants ? Quels outils conseiller en médecine générale et spécialisée pour évaluer l'horloge biologique face à une insomnie ? Quelle influence, enfin, de la lumière sur l'horloge biologique et quels conseils donner vis-à-vis de la lumière ? Autant de questions et d'éléments de compréhension sur l'insomnie chronique éclaircis.

[Pharmacotherapies for insomnia]. / Traitements médicamenteux de l'insomnie.

PHARMACOTHERAPIES FOR INSOMNIA. The first line of treatment in adult chronic insomnia is cognitive behavioral therapy (CBT). However, its difficult accessibility limited its use and medications are still often prescribed. Considering the drugs with marketing authorization, Z-drugs (zolpidem and zopiclone) if taken at the right hour and dosage promote sleep initiation and have less deleterious effects than benzodiazepines, especially the long-acting ones which should be avoided. This class of drugs cannot be prescribed longer than 28 days. Some antihistaminic licensed drugs are authorized as hypnotics, with a low proof of efficacy and a risk of adverse event as sedation and somnolence the next day. Their prescription should be avoided in old subjects. Some clinicians used antidepressant sedative medications, at low dosage, as hypnotic drugs but "off label", outside authorization. Now melatonin, an endogenous synchronizer of biologic rhythms, has obtained the authorization for the treatment of insomniac troubles, in subjects of at least 55 years old, in its slow- release formula, replacing the physiological decline of this hormone with aging. Melatonin is not a hypnotic, but has soporific properties, inducing sleep, improving sleep efficacy, sometimes sleep duration and morning alertness. When discontinued, it induced no withdrawal syndrome. It has shown no risk of abuse potential and no deleterious side-effects, if used at the right dose and in the absence of hepatic interaction with other compounds. Finally, a new class of hypnotics, "the orexin antagonists" has its first representative on the French market: daridorexant. The place of these molecules in the therapeutic strategy for chronic insomnia needs to be clarified.

TRAITEMENTS MÉDICAMENTEUX DE L'INSOMNIE. Le traitement de première intention des adultes atteints d'insomnie chronique est la thérapie cognitivo-comportementale. Toutefois, compte tenu des difficultés d'accès à cette thérapeutique, les prescriptions médicamenteuses restent fréquentes. Considérant les médicaments qui ont une autorisation de mise sur le marché (AMM) dans cette indication, les Z-drugs (zolpidem et zopiclone), prises à bon escient, à la bonne posologie et à la bonne heure, favorisent l'initiation du sommeil et ont moins d'effets indésirables que les benzodiapézines, notamment celles à longue durée d'action, dont la prescription doit être évitée. Cette classe de médicaments est soumise à une réglementation particulière de durée de prescription (28 jours au maximum). Certains antihistaminiques peuvent être utiles comme hypnotiques, avec un faible niveau de preuve d'efficacité et des effets indésirables, notamment sur la vigilance du lendemain ; ils sont à éviter chez les sujets âgés. Certains antidépresseurs sédatifs sont prescrits, à faible dose, hors AMM. Plus récemment, la mélatonine, synchroniseur endogène des rythmes biologiques, a obtenu une AMM dans les troubles du sommeil du sujet âgé de 55 ans ou plus, dans sa formulation à longue durée d'action, suppléant la baisse physiologique de cette hormone avec l'âge. Induisant une somnolence, elle favorise l'endormissement, l'efficacité du sommeil, peut améliorer sa durée et assure un réveil de bonne qualité, sans accoutumance, sans syndrome de sevrage, et sans effet délétère majeur si l'on fait attention à la posologie et aux interactions médicamenteuses. Enfin, une nouvelle classe de médicaments, les anti-orexines, compte un premier représentant commercialisé en France : le daridorexant. La place de ces molécules dans la stratégie thérapeutique de l'insomnie chronique devra être précisée.

Eco-anxiety: An adaptive behavior or a mental disorder? Results of a psychometric study.

OBJECTIVE: Eco-anxiety is a complex construct that has been created to grasp the psychological impact of the consequences of global warming. The concept needs a reliably valid questionnaire to better evaluate its impact on the risk of anxiety and depressive disorders. The Eco-Anxiety Questionnaire (EAQ-22) evaluates two dimensions: 'habitual ecological anxiety' and 'distress related to eco-anxiety'. However, a version in French, one of the world's widely spoken languages, was until now lacking. We aimed to translate and validate the French EAQ-22 and to evaluate the prevalence of the level of the two dimensions of eco-anxiety and the relationship with anxiety and depressive symptoms in a representative adult sample of the French general population. METHODS: This study was performed under the auspices of the Institut national du sommeil et de la vigilance (INSV). Participants (18-65 years) were recruited by an institute specialized in conducting online surveys of representative population samples (quota sampling). Two native French speakers and two native English speakers performed a forward-backward translation of the questionnaire. The Hospital Anxiety and Depression scale (HAD) was administered to assess anxiety (HAD-A) and depressive (HAD-D) symptoms and for external validity. Internal structural validity and external validity were analysed. RESULTS: Evaluation was performed on 1004 participants: mean age 43.47 years (SD=13.41, range: [19-66]); 54.1% (n=543) women. Using the HAD, 312 (31.1%) patients had current clinically significant anxiety symptoms (HAD-A>10) and 150 (14.9%) had current clinically significant depressive symptoms (HAD-D>10). Cronbach's alpha coefficient was 0.934, indicating very good internal consistency. Correlation between EAQ-22 and HAD scores was low (r[1004]=0.209, P<0.001), 'habitual ecological anxiety' was correlated less with HAD-A and HAD-D than 'distress related to eco-anxiety', indicating good external validity. CONCLUSION: This study validates the French EAQ-22 and paves the way for using the EAQ-22 as a global tool for assessing eco-anxiety. Further prospective studies are now required to better evaluate the impact of eco-anxiety on the occurrence of anxiety and depressive disorder.

Objective evaluation of excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) is multifactorial. It combines, among other things, an excessive propensity to fall asleep ("physiological sleepiness") and a continuous non-imperative sleepiness (or drowsiness/hypo-arousal) leading to difficulties remaining awake and maintaining sustained attention and vigilance over the long term ("manifest sleepiness"). There is no stand-alone biological measure of EDS. EDS measures can either capture the severity of physiological sleepiness, which corresponds to the propensity to fall asleep, or the severity of manifest sleepiness, which corresponds to behavioral consequences of sleepiness and reduced vigilance. Neuropsychological tests (The psychomotor vigilance task (PVT), Oxford Sleep Resistance Test (OSLeR), Sustained Attention to Response Task (SART)) explore manifest sleepiness through several sustained attention tests but the lack of normative values and standardized protocols make the results difficult to interpret and use in clinical practice. Neurophysiological tests explore the two main aspects of EDS, i.e. the propensity to fall asleep (Multiple sleep latency test, MSLT) and the capacity to remain awake (Maintenance of wakefulness test, MWT). The MSLT and the MWT are widely used in clinical practice. The MSLT is recognized as the "gold standard" test for measuring the severity of the propensity to fall asleep and it is a diagnostic criterion for narcolepsy. The MWT measures the ability to stay awake. The MWT is not a diagnostic test as it is recommended only to evaluate the evolution of EDS and efficacy of EDS treatment. Even if some efforts to standardize the protocols for administration of these tests have been ongoing, MSLT and MWT have numerous limitations: age effect, floor or ceiling effects, binding protocol, no normal or cutoff value (or determined in small samples), and no or low test-retest values in some pathologies. Moreover, the recommended electrophysiological set-up and the determination of sleep onset using the 30­sec epochs scoring rule show some limitations. New, more precise neurophysiological techniques should aim to detect very brief periods of physiological sleepiness and, in the future, the brain local phenomenon of sleepiness likely to underpin drowsiness, which could be called "physiological drowsiness".

Auto-adjusted versus fixed positive airway pressure in patients with severe OSA: A large randomized controlled trial.

BACKGROUND AND OBJECTIVE: Continuous positive airway pressure (CPAP) in the treatment of severe obstructive sleep apnoea (OSA) can be used in fixed CPAP or auto-adjusted (APAP) mode. The aim of this prospective randomized controlled clinical study was to evaluate the 3 month-efficacy of CPAP used either in fixed CPAP or APAP mode. METHODS: Eight hundred one patients with severe OSA were included in twenty-two French centres. After 7 days during which all patients were treated with APAP to determine the effective pressure level and its variability, 353 and 351 patients were respectively randomized in the fixed CPAP group and APAP group. After 3 months of treatment, 308 patients in each group were analysed. RESULTS: There was no difference between the two groups in terms of efficacy whatever the level of efficient pressure and pressure variability (p = 0.41). Exactly, 219 of 308 patients (71.1%) in the fixed CPAP group and 212 of 308 (68.8%) in the APAP group (p = 0.49) demonstrated residual apnoea hypopnoea index (AHI) <10/h and Epworth Score <11. Tolerance and adherence were also identical with a similar effect on quality of life and blood pressure evaluation. CONCLUSION: The two CPAP modes, fixed CPAP and APAP, were equally effective and tolerated in severe OSA patients.

Better characterizing sleep beliefs for personalized sleep health promotion: the French sleep beliefs scale validation study.

Background: The Sleep Beliefs Scale (SBS) is a well-known tool to design and monitor personalized sleep health promotion at an individual and population level. The lack of an established French version limits the development of effective interventions targeting these populations. Thus, the aim of this study was to validate the French version of the SBS in a representative sample of the general population. Methods: Quota sampling was used to recruit 1,004 participants (18-65 years, mean age: 43 years, 54% of female) who underwent an online survey to complete the SBS, and to assess sleep schedules, sleep quality and disorders, and mental health. Cronbach's α coefficient, confirmatory factor analysis, item-internal consistency (IIC), and item discriminant validity (IDV) of the SBS were computed to assess internal validity while bivariate associations with sleep schedules, sleep quality and disorders, and mental health were used to assess external convergent and discriminant validity. Results: The mean score on the SBS was 12.3 ± 4.9. Item 19 ("Quiet & Dark") showed the highest rate of correct answers (n = 801, 79.8%), while item 20 ("Recovering sleep") showed the lowest rate of correct answers (n = 246, 24.5%). Overall, the SBS showed satisfactory internal consistency (α = 0.87) and confirmed the three-factor structure proposed by the original study. All items were found consistent (IIC > 0.4) and discriminant (IIC > IDV) except for item 20 ("recovering lost sleep by sleeping for a long time"). Females, older participants, and subjects with short time-in-bed, poor sleep quality, insomnia, and circadian rhythm disorder had higher SBS scores while participants with depressive symptoms had lower SBS scores. Conclusion: We successfully translated and validated the French version of the SBS in a representative sample, making it a reliable instrument for researchers and clinicians to assess and target sleep beliefs. Correct answers vary from 25 to 80% which underlines the importance of continuing sleep health promotion campaigns by targeting poorly understood behaviors. Our findings also shed light on the fickleness of beliefs that are prone to vary within individuals across time, in step with societal changes. Several associated factors were identified, thus contributing to our understanding of sleep beliefs and offering insights for personalized approaches to enhance sleep health and overall well-being.

Mandibular advancement device use in obstructive sleep apnea: ORCADES study 5-year follow-up data.

STUDY OBJECTIVES: Mandibular advancement devices (MADs) are an alternative to continuous positive airway pressure for the management of obstructive sleep apnea (OSA). The ORthèse d'avanCée mAndibulaire dans le traitement en DEuxième intention du SAHOS sévère (ORCADES) study is investigating the long-term effectiveness of MAD therapy in patients with OSA who refused or were intolerant of continuous positive airway pressure. Five-year follow-up data are presented. METHODS: Data were available in 172 of 331 patients treated with a custom-made computer-aided design/computer-aided manufacturing biblock MAD (Narval CC; ResMed, Saint-Priest, France). The primary end point was treatment success (≥50% decrease in apnea-hypopnea index from baseline). RESULTS: Five-year treatment success rates were 52% overall and 25%, 52%, and 63%, respectively, in patients with mild, moderate, or severe OSA. This reflects a decline over time vs 3-6 months (79% overall) and 2 years (68%). Rates declined in all patient subgroups but to the greatest extent in patients with mild OSA. The slight worsening of respiratory parameters over time was not associated with any relevant changes in sleepiness and symptoms. Moderate or severe OSA at baseline, treatment success at 3-6 months, and no previous continuous positive airway pressure use were significant independent predictors of 5-year treatment success on multivariate analysis. No new safety signals emerged during long-term follow-up. The proportion of patients using their MAD for ≥4 h/night on ≥4 days/wk was 93.3%; 91.3% of patients reported device use of ≥6 h/night at 5 years. At 5-year follow-up, 96.5% of patients reported that they wanted to continue MAD therapy. CONCLUSIONS: Long-term MAD therapy remained effective after 5 years in >50% of patients, with good levels of patient satisfaction and adherence. CITATION: Vecchierini MF, Attali V, Collet JM, et al. Mandibular advancement device use in obstructive sleep apnea: ORCADES study 5-year follow-up data. J Clin Sleep Med. 2021;17(8):1695-1705.

Efficacy and tolerability of a custom-made Narval mandibular repositioning device for the treatment of obstructive sleep apnea: ORCADES study 2-year follow-up data.

OBJECTIVE/BACKGROUND: Mandibular repositioning device (MRD) therapy is an alternative to continuous positive airway pressure (CPAP). The Orkney Complex Disease Study-ORCADES study is assessing the long-term efficacy and tolerability of MRD therapy in obstructive sleep apnoea syndrome (OSAS); two-year follow-up data are presented. PATIENTS/METHODS: OSAS patients who refused or were noncompliant with CPAP were fitted with a custom-made computer-aided design/computer-aided manufacturing (CAD/CAM) bi-block MRD (ResMed, Narval CC™); mandibular advancement was individually titrated. Sleep and respiratory parameters were determined at baseline, 3-6 months, and two years. The primary endpoint was treatment success (percentage of patients achieving a ≥50% reduction in the apnoea-hypopnoea index [AHI]). RESULTS: Of 315 enrolled patients, 237 remained on MRD treatment at two years, and 197 had follow-up data. The treatment success rate at two years was 67%; AHI <5/h, <10/h and <15/h was achieved in 30%, 56% and 72% of patients, respectively. On multivariate analysis, ≥50% decrease in AHI at 3-6 months and absence of nocturia at 3-6 months were significant predictors of MRD treatment continuation. Adverse events were generally mild, and the majority occurred in the first year of treatment. CONCLUSIONS: Two years' treatment with an MRD was effective and well tolerated in patients with mild to severe OSAS who refused or were intolerant of CPAP.

[Sleep habits and lifestyle of elderly patients with insomnia]. / Les habitudes de vie et de sommeil chez les patients âgés insomniaques.

Certain inappropriate routines can have a negative impact on sleep, leading to sleep disorders or even aggravating pre-existing sleep pathologies. An observational study of 176 patients aged 60 or over, suffering from chronic insomnia, has been carried out in order to find out more about these patients' sleep habits and lifestyles and to identify those that can be corrected to improve insomnia in this population.

[Medical treatment of obstructive sleep-disordered breathing in children and adolescents]. / Traitement médical des troubles respiratoires obstructifs du sommeil de l'enfant et de l'adolescent.

Obstructive sleep disordered breathing (OSDB), in children and adolescents, need to be treated quite soon to avoid complications. A paediatrician, a sleep specialist, an orthodontist, an ENT and a myofunctional therapist will examine together the children with OSDB and determine the best personalised surgical and medical treatments for each of them. Only medical treatments are reviewed in this article. An international consensus recommended adenotonsillectomy as the first line therapy in young with OSDB. Usually adenotonsillectomy is combined with several important adjunctive medical treatments. Overweight and obesity frequent in adolescents, worsen OSDB and increase persistent OSDB after adenotonsillectomy. Weight loss is obtained by dietary restriction, physical activity, psychological support and sleep hygiene rules. Anti-inflammatory drugs (corticosteroids and leukotriene receptor antagonists) have shown their efficacy in children with moderate OSDB. Orthodontic treatments, rapid maxillary expansion or oral appliance, are used in selected patients according to their maxillo-facial disturbances in adjunction to adenotonsillectomy. Nasal CPAP is rarely useful except in severe OSDB specially in persistent OSDB after adenotonsillectomy. Finally, active or passive, myofunctional therapy is, according to some authors, an indispensable adjunct treatment to avoid persistent OSDB after adenotonsillectomy. These personalized medical treatments of OSDB are either administered jointly with adenotonsillectomy or in a hierarchal order.

Sex differences in mandibular repositioning device therapy effectiveness in patients with obstructive sleep apnea syndrome.

PURPOSE: Mandibular repositioning devices (MRDs) are an effective treatment option for obstructive sleep apnea syndrome (OSAS), particularly in patients who refuse or cannot tolerate continuous positive airway pressure (CPAP). However, sex differences in the response to therapy and predictors of response are not clearly defined. This analysis of data from the long-term prospective ORCADES trial compared MRD efficacy in men and women with OSAS. METHODS: The ORCADES study included patients with newly diagnosed mild-to-moderate or severe OSAS who refused or were non-compliant with CPAP. MRD therapy was titrated over 3-6 months. The primary endpoint was treatment success (≥ 50% decrease in apnea-hypopnea index (AHI)). Complete response was defined using a range of AHI cut-off values (< 5/h, < 10/h, < 15/h). RESULTS: Overall treatment success rates were 89% in women and 76% in men (p = 0.019); corresponding rates in those with severe OSAS (AHI > 30/h) were 100% and 68% (p = 0.0015). In women vs. men, overall complete response rates at AHI cut-off values of < 5/h, <10/h, and < 15/h were 49 vs. 34% (p = 0.0052), 78 vs. 62% (p = 0.016), and 92 vs. 76% (p = 0.0032). On multivariate analysis, significant predictors of MRD treatment success were overbite and baseline apnea index in men, and neck circumference and no previous CPAP therapy in women. There were sex differences in the occurrence of side effects. Temporomandibular joint pain was the most common reason for stopping MRD therapy. CONCLUSIONS: MRD therapy was effective in women with OSA of any severity, with significantly higher response rates compared with men especially in severe OSAS. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01326143).

Sleep and its relation to cognition and behaviour in preschool-aged children of the general population: a systematic review.

This is the first systematic review of the literature on sleep and its relation to cognition and behaviour in preschool-aged children. In comparison with the literature focused on school-aged children, knowledge involving preschoolers is rather sparse. A total of 26 studies was included in this review, which revealed a high degree of heterogeneity regarding the type and means of measuring sleep variables and behavioural and cognitive variables, as well as the statistical methods employed. Amongst the 13 articles with the largest sample sizes (top 50% of the included studies, 12 different populations), 12 found that a higher quantity or quality of sleep was associated with better behavioural and/or cognitive outcomes. Results point to an association between sleep, behaviour and cognition as early as preschool years, but the strengths of associations reported in the articles were relatively small. Studies with a smaller sample size were less concordant. It is consistent with our findings that the strengths of association are small, and thus require large sample sizes to ensure statistical detection power. Different aspects of sleep were not associated with all cognitive or behavioural features in the same way, which underscores the need for specific measures rather than general ones such as 'sleep problems' or 'behaviour problems' to be able to decipher the relationships. There is also a need for large longitudinal studies using objective measures and accounting for confounding factors. The child's genotype has recently been shown to have a moderating role in the association between sleep and behaviour, and should be further explored.

Napping: A public health issue. From epidemiological to laboratory studies.

Sleep specialists have proposed measures to counteract the negative short- and long-term consequences of sleep debt, and some have suggested the nap as a potential and powerful "public health tool". Here, we address this countermeasure aspect of napping viewed as an action against sleep deprivation rather than an action associated with poor health. We review the physiological functions that have been associated positively with napping in both public health and clinical settings (sleep-related accidents, work and school, and cardiovascular risk) and in laboratory-based studies with potential public health issues (cognitive performance, stress, immune function and pain sensitivity). We also discuss the circumstances in which napping-depending on several factors, including nap duration, frequency, and age-could be a potential public health tool and a countermeasure for sleep loss in terms of reducing accidents and cardiovascular events and improving sleep-restriction-sensitive working performance. However, the impact of napping and the nature of the sleep stage(s) involved still need to be evaluated, especially from the perspective of coping strategies in populations with chronic sleep debt, such as night and shift workers.

Exploration of sleep disorders in the elderly: which particularities?

There are many reasons to take into consideration the sleep disorders in the elderly. The sleep quality degrades with age and is strongly affected by medical conditions, intrinsic sleep disorders, or by a combination of these factors. Other age-related conditions such as severe dementia, dependence or living in institution worsen sleep disturbances in older people. When living alone elderly people, being cognitively impaired and medically disabled, may not be able to complain about sleep problems. Sleep disorders are thus underdiagnosed, unmarked, and insufficiently investigated in the elderly. In this heterogeneous population, sleep assessment should include a global geriatric approach and be individually adapted for each subject. The sleep interview must specially include medical comorbidities, medication uses, and aged-related changes of lifestyle such as retirement, loss of spouse, hospitalization or institutionalization. In the elderly with loss of autonomy, standard sleep assessment is not always adequate and must be replaced by shorter, simpler or observation-based tests such as the Sleep disorders inventory, Observation-based nocturnal sleep inventory, Observation and interview based diurnal sleepiness inventory. When sleep log is impossible, actimetry is an excellent alternative for studying sleep-wake rhythm. Ventilatory polygraphy is a simpler test for detecting sleep apnea than polysomnography. Utilization of sophisticated investigations should be discussed when the feasibility and usefulness is limited.

A custom-made mandibular repositioning device for obstructive sleep apnoea-hypopnoea syndrome: the ORCADES study.

BACKGROUND: Mandibular repositioning devices (MRDs) are usually recommended as the first therapy option in patients with mild-to-moderate obstructive sleep apnoea (OSA). However, data on the long-term efficacy of MRDs are limited, not only in OSA patients who are noncompliant with continuous positive airway pressure (CPAP) but also in those with more severe OSA. The ORCADES study aimed to prospectively determine the long-term efficacy and tolerability of two custom-made Narval(™) MRDs for obstructive sleep apnoea-hypopnoea syndrome (OSAHS) patients. The interim 3- to 6-month data are reported. METHODS: Eligible patients had OSAHS and had refused or were noncompliant with prescribed CPAP. Outcome measurements after gradual mandibular advancement titration included: apnoea-hypopnoea index (AHI), oxygen saturation, sleepiness, symptoms, quality of life, side effects and compliance. RESULTS: A total of 369 patients were included. Overall, MRD treatment was successful (≥50% decrease in AHI) in 76.2% of the participants; complete response (AHI <10/h) was achieved in 63.5%. Severe OSAHS was effectively treated (AHI <15/h) in about 60% of the participants; 38% had complete symptom resolution. Mandibular repositioning devices significantly decreased subjective sleepiness, eliminated symptoms and improved quality of life. They were well tolerated and compliance was excellent. Only 8% of the participants stopped MRD treatment due to side effects. CONCLUSION: Custom-made Narval(™) MRDs are effective for mild to severe OSA in patients who refuse or are noncompliant with CPAP. They are well tolerated and have excellent compliance.

Safety profile of tasimelteon, a melatonin MT1 and MT2 receptor agonist: pooled safety analyses from six clinical studies.

INTRODUCTION: Tasimelteon, a novel circadian regulator, is the first product for the treatment of Non-24-hour Sleep-Wake Disorder (Non-24) approved by either the FDA or the European Medicines Agency (EMA). Tasimelteon is a potent and specific melatonin (MT1 and MT2) receptor agonist with 2 - 4 times greater affinity for the MT2 receptor. METHODS: Safety was assessed in two controlled and two open-label studies in blind individuals with Non-24 and in two controlled studies of primary insomnia. Periodic assessments included collection of adverse events (AEs), laboratory testing, electrocardiograms (ECGs), vital sign monitoring, physical examinations and assessment for the potential for suicide. One study included additional assessments for endocrine function. RESULTS: A total of 184 blind individuals with Non-24 received tasimelteon nightly with a median exposure > 1 year. In placebo-controlled studies, 387 patients with insomnia and 42 patients with Non-24 received tasimelteon nightly for 4 - 26 weeks. The total patient years exposure for the six studies assessed here is 258.64 patient years. Discontinuations due to AEs were similar across treatment groups. Overall in the clinical studies described here, AEs attributable to tasimelteon treatment were headache, diarrhea, dry mouth, alanine aminotransferase increased, somnolence, dizziness and nightmare/abnormal dreams. There were no clinically significant differences in treatment group with ECGs, vital signs, withdrawal, endocrine function and suicidality assessments. CONCLUSION: Long-term tasimelteon administration was safe and well-tolerated. This is supported by placebo-controlled data in both Non-24 and insomnia patients.

Sleep debt and obesity.

Short sleep duration has been shown to be associated with elevated body mass index (BMI) in many epidemiological studies. Several pathways could link sleep deprivation to weight gain and obesity, including increased food intake, decreased energy expenditure, and changes in levels of appetite-regulating hormones, such as leptin and ghrelin. A relatively new factor that is contributing to sleep deprivation is the use of multimedia (e.g. television viewing, computer, and internet), which may aggravate sedentary behavior and increase caloric intake. In addition, shift-work, long working hours, and increased time commuting to and from work have also been hypothesized to favor weight gain and obesity-related metabolic disorders, because of their strong link to shorter sleep times. This article reviews the epidemiological, biological, and behavioral evidence linking sleep debt and obesity.

[Restless legs syndrome and its clinical forms: diagnosis]. / Syndrome des jambes sans repos et ses formes cliniques : bilan diagnostique.

Restless legs syndrome (RLS) diagnosis is clinically ascertained on four associated essential criteria according to the recommendations of the workshop at the National Institute of Health published in 2003. Supportive clinical features can help to resolve any diagnosis uncertainty. RLS severity is assessed by a validated rating scale also useful for therapeutic decision and evaluation. Idiopathic forms (familial or sporadic) are the most frequent. Nevertheless secondary forms must be recognized, and etiology, associated pathologies and risk factors investigated. Periodic leg movements (PLM) during wakefulness and more frequently during sleep are present in almost 80 % of patients with RLS. These PLM can be recorded during a suggested immobilization test or during a polysomnography. Deleterious consequences of RLS are important: attention-deficit hyperactivity or tiredness and asthenia, cognitive deficit, psychiatric illness and detrimental impact on quality of life. This high prevalent syndrome is actually better defined but still under-diagnosed probably due to the patients' difficulties to describe their feelings. Practitioners would benefit to interview more systematically their patients complaining of poor sleep about legs discomfort and movements in the evening and at night.