Curcuminoids, a major turmeric component, have a sleep-enhancing effect by targeting the histamine H1 receptor.

Turmeric (Curcuma longa) had been considered as a universal panacea in functional foods and traditional medicines. In recent, the sedative-hypnotic effect of turmeric extract (TE) was reported. However, sleep-promoting compounds in TE have been not yet demonstrated. Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the major constituents of turmeric being responsible for its various biological activities. Therefore, they can be first assumed to be sedative-hypnotic compounds of TE. In the present study, we aimed to investigate the effects and underlying mechanisms of curcuminoids and each constituent on the sleep-wake cycle of mice. Molecular docking studies, histamine H1 receptor (H1R) binding assays, and H1R knockout animal studies were used to investigate the molecular mechanisms underlying the sleep-promoting effects. Curcuminoids and their constituents reduced sleep latency and increased sleep duration in the pentobarbital-induced sleep test in mice. In addition, curcuminoids significantly increased the duration of NREMS and reduced sleep latency without altering the REMS and delta activity. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin were predicted to interact with H1R in the molecular model. In the binding affinity assay, we found that curcuminoids, as well as their constituents, significantly bind to H1R with the Ki value of 1.49 µg mL-1. Furthermore, sleep latency was reduced and NREMS frequency was increased following curcuminoid administration in wild-type mice but not in H1R knockout mice. Therefore, we conclude that curcuminoids reduce sleep latency and enhance the quantity of NREMS by acting as modulators of H1R, indicating their usefulness in treating insomnia.

Difference in spectral power density of sleep electroencephalography between individuals without insomnia and frequent hypnotic users with insomnia complaints.

Previous spectral analysis studies on insomnia have shown inconsistent results due to their heterogeneity and small sample sizes. We compared the difference of electroencephalogram (EEG) spectral power during sleep among participants without insomnia, insomniacs with no hypnotic use, hypnotic users with no insomnia complaints, and hypnotic users with insomnia complaints using the Sleep Heart Health Study data, which is large sample size and has good quality control. The fast Fourier transformation was used to calculate the EEG power spectrum for total sleep duration within contiguous 30-s epochs of sleep. For 1985 participants, EEG spectral power was compared among the groups while adjusting for potential confounding factors that could affect sleep EEG. The power spectra during total sleep differed significantly among the groups in all frequency bands (pcorr < 0.001). We found that quantitative EEG spectral power in the beta and sigma bands of total sleep differed (pcorr < 0.001) between participants without insomnia and hypnotic users with insomnia complaints after controlling for potential confounders. The higher beta and sigma power were found in the hypnotic users with insomnia complaints than in the non-insomnia participants. This study suggests differences in the microstructures of polysomnography-derived sleep EEG between the two groups.

Oleamide, a Sleep-Inducing Supplement, Upregulates Doublecortin in Hippocampal Progenitor Cells via PPARα.

BACKGROUND: Doublecortin (DCX), a microtubule associated protein, has emerged as a central biomarker of hippocampal neurogenesis. However, molecular mechanisms by which DCX is regulated are poorly understood. OBJECTIVE: Since sleep is involved with the acquisition of memory and oleamide or 9-Octadecenamide (OCT) is a sleep-inducing supplement in human, we examined whether OCT could upregulate DCX in hippocampal progenitor cells (HPCs). METHODS: We employed real-time PCR, western blot, immunostaining, chromatin immunoprecipitation, lentiviral transduction in HPCs, and the calcium influx assay. RESULTS: OCT directly upregulated the transcription of Dcx in HPCs via activation of peroxisome proliferator-activated receptor α (PPARα), a lipid-lowering transcription factor. We observed that, HPCs of Ppara-null mice displayed significant impairment in DCX expression and neuronal differentiation as compared to that of wild-type mice. Interestingly, treatment with OCT stimulated the differentiation process of HPCs in wild-type, but not Ppara-null mice. Reconstruction of PPARα in mouse Ppara-null HPCs restored the expression of DCX, which was further stimulated with OCT treatment. In contrast, a dominant-negative mutant of PPARα significantly attenuated the stimulatory effect of OCT on DCX expression and suppressed neuronal differentiation of human neural progenitor cells. Furthermore, RNA microarray, STRING, chromatin immunoprecipitation, site-directed mutagenesis, and promoter reporter assay have identified DCX as a new target of PPARα. CONCLUSION: These results indicate that OCT, a sleep supplement, directly controls the expression of DCX and suggest that OCT may be repurposed for stimulating the hippocampal neurogenesis.

Soporific effect of modified Suanzaoren Decoction on mice models of insomnia by regulating Orexin-A and HPA axis homeostasis.

AIM: Modified Suanzaoren Decoction (MSZRD) is obtained by improving Suanzaoren Decoction (SZRT), a traditional Chinese herbal prescription that has been used to treat insomnia for more than thousands of years. Our previous study showed that MSZRD can improve the gastrointestinal discomfort related insomnia by regulating Orexin-A. This study is the first study to evaluate the effects and possible mechanisms of MSZRD in mice with insomnia caused by p-chlorophenylalanine (PCPA) combined with multifactor random stimulation. METHODS: After 14 days of multifactor stimulation to ICR mice, a PCPA suspension (30 mg/mL) was injected intraperitoneally for two consecutive days to establish an insomnia model. Three different doses of MSZRD (3.6, 7.2, and 14.4 g/kg/day) were given to ICR mice for 24 days. The food intake and back temperature were measured, and behavioral tests and pentobarbital sodium-induced sleep tests were conducted. The levels of Orexin-A, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical hormones (CORT) in the serum and 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) in hypothalamus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The levels of γ-aminobutyric acid (GABA) and glutamic acid (Glu) were measured by high-performance liquid chromatography (HPLC). The expression of 5HT1A receptor (5-HTRIA) and orexin receptor 2 antibody (OX2R) was measured by Western blot (WB) and immunohistochemical staining (ICH). Hematoxylin and eosin (H&E) staining and Nissl staining were used to assess the histological changes in hypothalamus tissue. RESULTS: Of note, MSZRD can shorten the sleep latency of insomnia mice (P < 0.05, 0.01), prolonged the sleep duration of mice (P < 0.05, 0.01), and improve the circadian rhythm disorder relative to placebo-treated animals. Furthermore, MSZRD effectively increased the content of 5-HT and 5-HTR1A protein in the hypothalamus of insomnia mice (P < 0.05, 0.01), while downregulated the content of DA and NE (P < 0.05, 0.01). Importantly, serum GABA concentration was increased by treatment with MSZRD (P < 0.05), as reflected by a decreased Glu/GABA ratio (P < 0.05). Moreover, MSZRD decreased the levels of CORT, ACTH, and CRH related hormones in HPA axis (P < 0.05, 0.01). At the same time, MSZRD significantly downregulated the serum Orexin-A content in insomnia mice (P < 0.05), as well as hypothalamic OX2R expression (P < 0.05). In addition, MSZRD also improved the histopathological changes in hypothalamus in insomnia mice. CONCLUSION: MSZRD has sleep-improvement effect in mice model of insomnia. The mechanism may be that regulating the expression of Orexin-A affects the homeostasis of HPA axis and the release of related neurotransmitters in mice with insomnia.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

Nelumbo nucifera promotes non-rapid eye movement sleep by regulating GABAergic receptors in rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Nelumbo nucifera are used in folk medicine for anti-depressant, anti-convulsant, neuroprotective, and many other purposes. AIM OF THE STUDY: The present work evaluated the sleep potentiating effects of water extract from lotus seed in rat, and the neuropharmacological mechanisms underlying these effects. MATERIALS AND METHODS: Pentobarbital-induced sleep test and electroencephalogram (EEG) analysis were applied to investigate sleep latency, duration, total sleeping time and sleep quality of Lotus extract. In addition, real-time PCR and HPLC analysis were applied to analyze the signaling pathway. RESULTS: We found that the amounts of the possible active compounds GABA (2.33 mg/g) and L-tryptophan (2.00 mg/g) were higher than quinidine (0.55 mg/g) and neferine (0.16 mg/g) in lotus seed extract. High dose (160 mg/kg) administration of lotus extract led to a tendency towards decreased sleep latency time and an increase in sleep duration time compared to the control group in a pentobarbital-induced sleep model (p < 0.05). After high dose administration, total sleep and NREM were significantly increased compared to control, while wake time and REM were significantly decreased. Lotus extract-treated rats showed significantly reduced wake time and increased sleep time in a caffeine-induced model of arousal. The transcription level of GABAA receptor, GABAB receptor, and serotonin receptor tended to increase with dose, and lotus extract showed a strong dose-dependent binding capacity to the GABAA receptor. CONCLUSION: The above results strongly suggest that GABA contained in lotus seed extract acts as a sleep potentiating compound, and that sleep-potentiating activity involves GABAA receptor binding.

Sleep Induction by Mechanosensory Stimulation in Drosophila.

People tend to fall asleep when gently rocked or vibrated. Experimental studies have shown that rocking promotes sleep in humans and mice. However, the mechanisms underlying the phenomenon are not well understood. A habituation model proposes that habituation, a form of non-associative learning, mediates sleep induction by monotonous stimulation. Here, we show that gentle vibration promotes sleep in Drosophila in part through habituation. Vibration-induced sleep (VIS) leads to increased homeostatic sleep credit and reduced arousability, and can be suppressed by heightened arousal or reduced GABA signaling. Multiple mechanosensory organs mediate VIS, and the magnitude of VIS depends on vibration frequency and genetic background. Sleep induction improves over successive blocks of vibration. Furthermore, training with continuous vibration does not generalize to intermittent vibration, demonstrating stimulus specificity, a characteristic of habituation. Our findings suggest that habituation plays a significant role in sleep induction by vibration.

Chronotherapeutic efficacy of suvorexant on sleep quality and metabolic parameters in patients with type 2 diabetes and insomnia.

AIMS: This study aimed to assess the chronotherapeutic efficacy of suvorexant on subjective sleep parameters and metabolic parameters in patients with type 2 diabetes and insomnia. METHODS: Thirteen patients with type 2 diabetes who met the Pittsburg Sleep Quality index criteria for primary insomnia took suvorexant 20 mg/day (15 mg/day for ≥65 years) for 14 ± 2 weeks. The following parameters were assessed before and after the treatment: sleep diary for sleep duration and quality (i.e., sleep onset latency, waking after sleep onset, and sleep efficiency [sSE]), Insomnia Severity Index, clinical and biochemical data, continuous glucose monitoring (CGM), and validated self-administered questionnaire on food intake. RESULTS: Suvorexant significantly improved sSE, abdominal circumference, and sucrose intake (all p < 0.05), but did not change HbA1c, CGM parameters, or body weight. Correlation analysis revealed that changes in sSE were associated with those in HbA1c and body weight (r = -0.61 and r = -0.66, respectively; both p < 0.05). CONCLUSIONS: Suvorexant significantly improved sleep quality and obesity-associated parameters in patients with type 2 diabetes in 14 weeks. Improvements in sleep quality were associated with improvements in glycemic control. Sleep disorder treatment using suvorexant may provide metabolic benefits for patients with type 2 diabetes.

Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders.

INTRODUCTION: The last two decades have witnessed a rapid increase in the knowledge about the role of the orexin system, particularly in the regulation of wakefulness and arousal. Dual orexin receptor antagonists (DORAs) have been approved for the treatment of insomnia disorders (suvorexant, lemborexant) and drugs with a distinctive profile (daridorexant) or orexin-2 receptor selectivity (seltorexant) are in development. AREAS COVERED: This review discusses pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety properties of orexin receptor antagonists (ORAs). EXPERT OPINION: In general, the drugs described have a similar effect on sleep characteristics although their pharmacokinetic variables differ. ORAs have the potential to revolutionize the pharmacological treatment of insomnia because they not only improve sleep, but, in addition, appear to have no dependence - and tolerance-inducing effects, which makes them suitable for long-term-treatment. The safety and tolerability profile of ORAs clearly differ from those of more traditional sleep-promoting drugs. Further research is needed to demonstrate benefits to patients suffering from insomnia disorder, e.g., with respect to improving not only sleep but also daytime functioning. In addition, ongoing and future research will show whether ORAs may have beneficial effects in patients with various psychiatric and neurodegenerative disorders, including Alzheimer's disease.

Zolpidem overutilisation among Korean patients with insomnia.

This study aimed to investigate zolpidem overutilisation among Korean patients with insomnia. We analysed the National Patient Sample (NPS) data compiled by the Health Insurance Review & Assessment Service (HIRA-NPS) in 2016. Zolpidem overutilisation was defined as when a patient used zolpidem for longer than 30 consecutive days and prescriptions overlapped with more than 10% of total prescription periods. Demographic and clinical factors associated with the overutilisation of zolpidem were investigated using a logistic regression model. The proportion of zolpidem overutilisers was estimated at 5.0%. Factors such as age (0-39 years), consuming controlled-release dosage formulations of zolpidem, presence of psychiatric disorders (depression, bipolar disorder, schizophrenia and anxiety disorder) and other medical conditions (hypertension, diabetes mellitus and arthritis) were observed to be risk predictors for zolpidem overutilisation. The formulation was selected owing to the absence of a quantity restriction for zolpidem CR in Korea during the study period. Possible approaches to prevention and control of zolpidem overutilisation include regulatory or legal provisions promoting rational drug use, management of psychiatric and medical co-morbid disorders, and widespread implementation of cognitive behavioural therapy for insomnia as a first-line treatment option.

Prescription Drugs Used in Insomnia.

The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are discussed: benzodiazepines and its receptor agonists, the dual orexin receptor antagonist suvorexant, melatonin and its receptor agonists, sedating antidepressants, and antipsychotics. Together with the neurobiologic and pharmacologic properties of these drugs, clinical effects are described, including subjective and objective effects on sleep duration, continuity, and architecture. Medical prescription information is given when available. Recently published American and European guidelines for the treatment of insomnia serve as reference frame.

Long-term sleep disturbance and prescription sleep aid use among cancer survivors in the United States.

PURPOSE: Insomnia and related sleep disorders are common complaints among cancer patients, and use of prescription sleep aids can be high in the treatment setting. The prevalence of sleep disturbance and prescription sleep aid use in the community-dwelling cancer survivorship population, however, remains relatively unexplored. We aim to ascertain the extent to which a cancer diagnosis is associated with sleep disturbances and prescription sleep aid use as measured in several cross sections of individuals across multiple disease sites and time since cancer diagnosis. METHODS: We used data from five cross-sectional cycles of the National Health and Nutrition Evaluation Survey (NHANES) from 2005 to 2014. We identified a total of 2371 individuals who reported a diagnosis of cancer (averaging 61 years old) and 25,788 individuals who did not report a cancer diagnosis (averaging 45 years old). We considered several patient-reported sleep-related outcomes. Multivariate regression analyses, as well as propensity score matching, were used to clarify the relationship between sleep disturbances, prescription sleep aid use, and cancer diagnosis, stratified by time since diagnosis and primary disease site. RESULTS: Reported sleep disturbance was common in cancer survivors, with approximately 34% of patients with a history of cancer reporting having ever been told they had trouble sleeping, compared to 23% of non-cancer patients in the general population with no history of cancer (p < 0.001). Propensity score matching supported a significantly higher rate of trouble sleeping among cancer survivors compared to matched controls. Compared to the general adult population without cancer, cancer survivors 11 or more years past diagnosis were more likely to report being diagnosed with trouble sleeping or a sleep disorder. Further, patients with gynecological cancers were more likely to report prescription sleep aid use, sleep disorders, and trouble sleeping compared to adults without a history of cancer. CONCLUSIONS: Sleeping problems are common in the cancer survivorship population, especially in patients with a long survivorship history and a history of gynecological cancers. Consideration of symptoms of insomnia and sleep disturbance may be helpful in the follow-up care of these patients.

A simple method using anesthetics to test effects of sleep-inducing substances in mice.

We investigated the effects of sleep-inducing agents with different mechanisms of action on the loss of the righting reflex induced by isoflurane or a mixture of medetomidine, midazolam, and butorphanol (MMB), followed by atipamezole reversal. Chlorpromazine and brotizolam delayed recovery from both types of anesthesia, whereas the melatonin receptor agonist ramelteon had no effect. The orexin receptor antagonist suvorexant delayed recovery from anesthesia only in the case of MMB, while the sleep-promoting supplement glycine only delayed recovery in the case of isoflurane. These results suggest that the simple comparison method is applicable for testing substances expected to exert sleep-inducing effects.

Prospective randomized controlled study on improving sleep quality and impact of zolpidem after total hip arthroplasty.

BACKGROUND: Total hip arthroplasty (THA) is a proven surgical option for patients with end-stage osteoarthritis in terms of improved function and pain relief. A prospective study was conducted to examine and evaluate the effect and impact of zolpidem postoperatively on the sleep quality, pain alleviation, and quality of life of patients who underwent total hip arthroplasty. METHODS: A total of 160 patients was randomized 1:1 to receive either zolpidem or placebo 2 days preoperative to 5 days postoperatively. Pain scores using visual analog scale (VAS), sleep quality using Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale, quality of life using QoR-40, and Hip disability and Osteoarthritis Outcome Score were recorded. The total amount of opioid analgesics and antiemetics taken was recorded as well. RESULTS: Patients in the intervention group had higher VAS score and took less analgesic and antiemetic. Moreover, the study demonstrated that QoR-40 was higher and Hip disability and Osteoarthritis Outcome Score had relatively lower mean value (P < 0.05) in the treatment group. Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale were also lower in the treatment group (P < 0.05). CONCLUSION: Patients taking zolpidem achieved greater improvement in the quality of life and reported better satisfaction. The study demonstrated zolpidem 10 mg can improve sleep quality effectively, relieve pain, increase early range of motion and muscle strength, reduce the perioperative anxiety and depression, and improve perioperative experience and satisfaction, thereby reducing the hospital stay and medical costs and promote the rapid recovery and quality of life. TRIAL REGISTRATION: The trial was registered on Chinese Clinical Trial Registry, ChiCTR-IOR-16007861 .

Faringoplastia de expansión: utilidad de la somnoscopia (DISE) / Expansion sphincter pharyngoplasty: Usefulness of DISE

Objetivos: El objetivo de este estudio es presentar las indicaciones y resultados de la faringoplastia de expansión como tratamiento del síndrome de apnea-hipopnea obstructiva del sueño (SAHOS). En segundo lugar, comparar los hallazgos de la somnoscopia (drug-induced sleep endoscopy -DISE-) antes y después de la cirugía. Material y métodos: El diseño del estudio fue una cohorte prospectiva de pacientes tratados quirúrgicamente de 2015 a 2016. Todos los pacientes fueron diagnosticados de SAHOS leve a grave y no toleraban la CPAP. Todos tenían DISE y polisomnografía previa a la cirugía, y posterior a la misma. Los criterios de inclusión fueron la edad, entre 18 años y 70 años, amígdalas pequeñas (tamaños 1 y 2), estadio clínico de Friedman II y III, y colapso lateral mayoritario en la DISE preoperatoria. Se les realizó únicamente cirugía del paladar, usando la técnica de faringoplastia de expansión. Resultados: Se incluyeron 17 pacientes, el 52,94% eran pacientes con SAHOS grave. La edad media fue de 42 años, el índice de masa corporal media fue de 28. La tasa de éxito quirúrgico según los criterios de Sher fue del 82,35%. El 41,17% presentó un índice de apnea-hipopnea postoperatoria inferior a 10. El 75% de los pacientes lograron no tener que usar la CPAP. Conclusión: La faringoplastia de expansión es una técnica segura como tratamiento del SAHOS en pacientes con amígdalas pequeñas, grado Friedman I y II y colapso de paredes laterales en somnoscopia, en ausencia de colapso multinivel. La DISE postoperatoria demostró la mejoría del colapso lateral obtenida con la expansión

Objectives: The aim of this study was first to present the indications and results using expansion sphincter pharyngoplasty to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS). And second, to compare the findings of drug-induced sleep endoscopy (DISE) before and after the surgery. Material and methods: The study design was a prospective cohort of patients surgically treated between 2015 and 2016. All patients were diagnosed with mild to severe obstructive sleep apnoea and did not tolerate CPAP. All had pre- and post-surgery DISE and polysomnography. The inclusion criteria were age, between 18 years and 70 years, small tonsils (sizes 1 and 2), Friedman II and III clinical stage, and lateral collapse in preoperative DISE. We performed surgery to the palate only, using expansion sphincter pharyngoplasty. Results: Seventeen patients were included, 52.94% had severe OSAHS. Average age was 42 years, average body mass index was 28. The surgical success rate according to Sher criteria was 82.35%. 41.17% had a postoperative apnoea-hypopnoea index of less than 10. Seventy-five percent of the patients had no further need for CPAP. Conclusion: Expansion sphincter pharyngoplasty is a safe technique for treating OSAHS, in patients with small tonsils, Friedman grade I and II and collapse of lateral walls in DISE, in the absence of multilevel collapse. The postoperative DISE showed improvement of the lateral collapse was achieved with the expansion

French national health insurance database analysis and field study focusing on the impact of secure prescription pads on zolpidem consumption and sedative drug misuse: ZORRO study protocol.

INTRODUCTION: In recent years, data collected by the French Addictovigilance Network have shown the potential for abuse and addiction associated with zolpidem (the most sold hypnotic drug in France). Since 10 April 2017, new regulations have come into force that require zolpidem to be prescribed on special secure prescription pads, in order to reduce the risk of abuse or misuse. This measure has far-reaching repercussions that are not only limited to the consumption of zolpidem but also extend to the usage of sedative medication on a whole. The objective of the ZOlpidem and the Reinforcement of the Regulation of prescription Orders (ZORRO) study is to evaluate the overall impact of the new regulatory framework requiring zolpidem to be prescribed on special secure prescription pads. Three axes will be evaluated: the number of consumers, the type of consumption (chronic use versus occasional use, problematic consumption versus non-problematic use) and the consumption of other sedative molecules.The study has been registered in the Protocol Registration and Results System under the number NCT03584542 at stage "Pre-results". METHODS AND ANALYSIS: The ZORRO study is an epidemiological, observational, national multicentre, non-controlled, prospective research project supported by the French National Agency for Medicines and Health Products Safety. The evaluation of the impact of the regulatory framework change relative to zolpidem will be done according to two axes: via an epidemiological study of the French National Health Insurance database and by the implementation of field studies of prescribers and consumers of zolpidem. ETHICS AND DISSEMINATION: The Nantes Research Ethics Committee (Groupe Nantais d'Ethique dans le Domaine de la Santé), the Committee for the Protection of the Population and the Committee of Expertise in Research, Studies and Evaluations in the Field of Health approved this study. Results will be presented in national and international conferences and submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03584542; Pre-results.

The effects of zolpidem in obstructive sleep apnea - An open-label pilot study.

New knowledge on hypnotics and their effects on the phenotypic causes of obstructive sleep apnea indicate that zolpidem has therapeutic potential for certain patients. Specifically, zolpidem increases the threshold for arousal threshold and pharyngeal dilator muscle responsiveness. However, the effects of a standard dose of zolpidem (10 mg) on obstructive sleep apnea severity and symptoms have not been investigated. In an open-label pilot study, 12 unselected people with obstructive sleep apnea were recruited following a diagnostic in-laboratory sleep study. Participants then returned for a single-night sleep study in which 10 mg of zolpidem was given just prior to sleep. Tolerability, next-day sleepiness and the effects of zolpidem on polysomnography variables were assessed. Zolpidem was well tolerated and significantly improved the sleep efficiency compared with the no-drug night (77 ±â€…12% versus 84 ±â€…9%, p = 0.005). Individual responses on obstructive sleep apnea severity to zolpidem in this unselected obstructive sleep apnea patient population were variable with no overall systematic difference in apnea-hypopnea index (29 ±â€…18.2 events per hr versus 33 ±â€…28 events per hr, p = 0.45) or other key respiratory parameters (e.g. event duration or hypoxemia). Next-day sleepiness assessed via the Karolinska Sleepiness Scale was not different between visits (4 ±â€…1 versus 4 ±â€…2, p = 0.85). These findings provide the first insight into the effects of a standard dose of zolpidem in obstructive sleep apnea, and highlight its tolerability and potential to improve sleep quality. The variable effects on obstructive sleep apnea severity observed in this pilot also underscore the need for larger trials that incorporate phenotypic characterisation (e.g. arousal threshold, Pcrit and muscle responsiveness) to understand inter-individual heterogeneity and the therapeutic potential of zolpidem for certain people with obstructive sleep apnea.

Insomnia treatment response as a function of objectively measured sleep duration.

OBJECTIVES: To examine the potential moderating effect of objectively measured sleep duration at baseline on the response to cognitive behavioral therapy for insomnia (CBT-I), administered singly or combined with medication (CBT-I + Med). METHODS: Based on the average PSG-derived sleep duration across two baseline nights and the type of treatment received, 159 adults with insomnia (50.3 ± 10.1 years; 61.0% women) were classified into one of four groups: participants with short sleep duration (ie, ≤ 6 h) treated with CBT-I (n = 26) or CBT-I+Med (n = 25), and participants with normal sleep duration (ie, > 6 h) treated with CBT-I (n = 54) or CBT-I+Med (n = 54). Primary outcome measures were sleep/wake parameters derived from a sleep diary and insomnia severity and secondary outcomes were beliefs about sleep, fatigue, depression and anxiety. RESULTS: Patients with both short and normal sleep durations at baseline improved significantly on most sleep continuity parameters with CBT-I administered singly or combined with medication. Irrespective of treatment received, participants with short sleep duration also showed significantly greater improvements in subjective sleep (ie, reduced wake after sleep onset, increased sleep efficiency) relative to those with normal sleep duration. Conversely, participants with normal sleep duration showed greater improvements on some measures of daytime functioning and sleep satisfaction. CONCLUSIONS: There was no moderating effect of baseline sleep duration on treatment response to cognitive behavioral therapy. Despite some marginal differential treatment response on selected daytime functioning outcomes, the benefits from CBT-I were not significantly different as a function of short or normal sleep duration at baseline. Further prospective investigation of insomnia phenotypes taking into account other variables than sleep duration is warranted in order to develop more targeted insomnia therapies. TRIAL REGISTRATION: www.clinicaltrials.gov (#NCT00042146).

Toward the Mysteries of Sleep.

Although sleep is a ubiquitous behavior in animal species with well-developed central nervous systems, many aspects in the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has triggered an intensive research examining the exact role of the orexinergic and other neural pathways in the regulation of sleep/wakefulness. The orexin receptor antagonist suvorexant, which specifically block the endogenous waking system, has been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened >8,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutation in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Since these dominant mutations cause strong phenotypic traits, we expect that the mutated genes will provide new insights into the elusive pathway regulating sleep/wakefulness. Indeed, through a systematic cross-comparison of the Sleepy mutants and sleep-deprived mice, we have recently found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.