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Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

Orexins (also called hypocretins) are hypothalamic neuropeptides that carry out essential functions in the central nervous system; however, little is known about their release and range of action in vivo owing to the limited resolution of current detection technologies. Here we developed a genetically encoded orexin sensor (OxLight1) based on the engineering of circularly permutated green fluorescent protein into the human type-2 orexin receptor. In mice OxLight1 detects optogenetically evoked release of endogenous orexins in vivo with high sensitivity. Photometry recordings of OxLight1 in mice show rapid orexin release associated with spontaneous running behavior, acute stress and sleep-to-wake transitions in different brain areas. Moreover, two-photon imaging of OxLight1 reveals orexin release in layer 2/3 of the mouse somatosensory cortex during emergence from anesthesia. Thus, OxLight1 enables sensitive and direct optical detection of orexin neuropeptides with high spatiotemporal resolution in living animals. OxLight1 is a genetically encoded sensor for the orexin neuropeptides. It has been applied in fiber photometry recordings and two-photon imaging in mice during a variety of behaviors.

Traumatic brain injury (TBI) can cause sleep-wake disturbances and excessive daytime sleepiness. The pathobiology of sleep disorders in TBI, however, is not well understood, and animal models have been underused in studying such changes and potential underlying mechanisms. We used the rat lateral fluid percussion (LFP) model to analyze sleep-wake patterns as a function of time after injury. Rapid-eye movement (REM) sleep, non-REM (NREM) sleep, and wake bouts during light and dark phases were measured with electroencephalography and electromyography at an early as well as chronic time points after LFP. Moderate TBI caused disturbances in the ability to maintain consolidated wake bouts during the active phase and chronic loss of wakefulness. Further, TBI resulted in cognitive impairments and depressive-like symptoms, and reduced the number of orexin-A-positive neurons in the lateral hypothalamus.

Background and Objectives: Intermittent fasting (IF) has emerged as a nutritional strategy capable of modulating circadian alignment, metabolic efficiency, and neuroendocrine regulation in individuals with obesity. Among the neurobiological mediators potentially involved, Orexin-A—a hypothalamic neuropeptide regulating arousal, appetite, and energy balance—may represent a key link between fasting patterns and metabolic homeostasis. This study aimed to evaluate the long-term metabolic and neuroendocrine effects of two intermittent fasting protocols, time-restricted feeding (16:8) and alternate-day fasting (5:2), compared with a hypocaloric Mediterranean diet used as a reference condition. Materials and Methods: Thirty adults with obesity (aged 20–40 years) were allocated to one of three dietary interventions—low-calorie Mediterranean diet, IF 16:8, or IF 5:2—based on habitual dietary patterns and followed prospectively for 12 months. Anthropometric parameters, metabolic indices, inflammatory markers (CRP, TNF-α, IL-6, IL-10), and circulating Orexin-A concentrations were assessed at baseline and at three-month intervals (T0–T3). Results: Both intermittent fasting protocols induced more rapid improvements in body mass index, adiposity, lipid profile, fasting glucose, and inflammatory markers compared with the Mediterranean diet. Among the IF strategies, the 16:8 regimen showed the most consistent and physiologically coherent pattern of adaptation, characterized by a progressive and sustained increase in Orexin-A levels. This response was strongly associated with enhanced metabolic flexibility, reduced systemic inflammation, and improved energy regulation over time. In contrast, the 5:2 protocol produced more variable metabolic and neuroendocrine responses, likely due to alternating cycles of marked caloric restriction and compensatory intake. Conclusions: Intermittent fasting, particularly the 16:8 time-restricted feeding protocol, appears to be an effective and sustainable chrononutritional strategy for obesity management. By reinforcing circadian organization, improving inflammatory balance, and activating orexinergic pathways, the 16:8 model emerges as a promising intervention to address key metabolic and neuroendocrine dysfunctions associated with obesity.

The Swedish National Board of Health and Welfare recently updated the national guidelines for at-risk consumption of alcohol. Nearly 30% of the Swedish population now falls under the at-risk category and should be provided with support. This project aims to identify and evaluate efficient, scalable tools to support individuals with risk-prone alcohol consumption. The project seeks to explore innovative, accessible technologies that could be implemented in large-scale public health interventions. A pilot-scale clinical study was conducted to assess the feasibility of using emerging technologies for this purpose. Eight healthy volunteers participated in controlled alcohol consumption while being monitored through 2 methods: an eye-scanning tool integrated into a standard mobile phone and saliva sampling for biomarkers such as serotonin and orexin. Eye-scanning parameters began to shift in some participants at approximately 0.4 to 0.5 per mille blood alcohol concentration, particularly in the form of impaired eye convergence. Furthermore, at around 0.5 per mille, participants encountered practical difficulties in managing the eye-scanning app. Salivary biomarkers did not show any clear correlation with alcohol intake, presumably due to the low number of participants. Beyond biological findings, the study also generated important procedural insights for designing a large-scale clinical study. Eye scanning showed potential as a noninvasive and accessible method for detecting and monitoring moderate alcohol consumption effects, while serotonin and orexin biomarkers were not informative in this context. On the basis of these findings and procedural learnings, eye-scanning tools warrant further investigation in larger clinical studies aimed at developing scalable support for risk-prone alcohol consumption.

Purpose This study examined the applicability of hair analysis as an approach to identify suvorexant (SUV) and lemborexant (LEM) intake by analyzing black hair specimens collected from study participants after a single oral administration. Methods Hair specimens were collected form participants who took a single dose of 10 mg SUV or 5 mg LEM. Identification of the dual orexin receptor antagonists (DORAs) and their metabolites was performed by liquid chromatography-tandem mass spectrometry. Reference standards of S-M9 and L-M4, the metabolites of SUV and LEM, respectively, were synthesized in our laboratory. Sectional analysis of 1-mm segments of the single-hair strands was also performed to investigate the incorporation behavior of the drugs into hair. Results Unchanged SUV and LEM, and their metabolites S-M9 and L-M4 were detected even in the single-hair specimens. Results of the segmental hair analysis showed predominant incorporation of the drugs into hair through the hair bulb region rather than through the upper dermis zone of the hair root. The drug concentrations in the hair specimens, collected about 1 month after intake, were 0.033–0.037 pg/hair strand (0.17–0.19 pg/mg) for SUV and 0.054–0.28 pg/hair strand (0.28–1.5 pg/mg) for LEM. The calculated distribution ratios of the DORAs into hair to the oral doses were much lower than those of benzodiazepines and zolpidem reported in a previous study. Conclusions This is the first report of the detection of the DORAs in hair. The incorporation behavior of the DORAs into hair revealed herein are crucial for proper interpretation of hair test results.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1β, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

Abstract Study Objectives To assess long-term efficacy and safety of lemborexant (LEM), a novel dual orexin receptor antagonist, versus placebo in adults with insomnia disorder. Methods This was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (reported separately). A total of 949 participants with insomnia (age ≥18 years) were randomized, received treatment with an oral dose of placebo or LEM (5 mg [LEM5] or 10 mg [LEM10]) and were analyzed. Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Results Decreases from baseline in patient-reported (subjective) sleep onset latency and subjective wake after sleep onset, and increases from baseline in subjective sleep efficiency, were significantly greater with LEM5 and LEM10 versus placebo. Significant benefits over placebo were observed at the end of month 6, and at most time points assessed over the 6-month period, indicating long-term sustained efficacy of LEM. A significantly greater percentage of sleep onset responders and sleep maintenance responders were observed with LEM treatment versus placebo. Participants treated with LEM reported a significant improvement in quality of sleep after 6 months versus placebo. The majority of TEAEs were mild or moderate. There was a low rate of serious TEAEs and no deaths. Conclusions LEM5 and LEM10 provided significant benefit on sleep onset and sleep maintenance in individuals with insomnia disorder versus placebo, and was well tolerated. Clinical trial registration ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39

Sleep disorders, such as insomnia and narcolepsy, significantly impact quality of life. They are often associated with long-term health consequences, including cardiovascular disease, immune dysfunction, and cognitive impairment. While traditional treatments, such as sedatives and hypnotics, can be effective, they are limited by issues of tolerance and dependence. The orexinergic system, particularly the orexin 1 receptor (OXR1), has emerged as a promising therapeutic target due to its central role in regulating sleep–wake cycles. In this study, we investigate the molecular interactions of three OXR1 antagonists—daridorexant, lemborexant, and suvorexant—using an integrated computational approach combining molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and the molecular fractionation with conjugate caps (MFCC) methodology. The MFCC approach enabled the precise quantification of interaction energies between ligands and key receptor residues, providing detailed insights into the contributions of specific amino acids to binding stability. Our results reveal that residues such as GLU204, HIS216, and ASN318 play critical roles in stabilizing ligand–receptor interactions, with a marked decrease in binding energy magnitude as dielectric constants increase. Daridorexant exhibited the strongest interaction energy, driven by hydrogen bonds and hydrophobic contacts, while lemborexant and suvorexant showed distinct stabilization patterns mediated by hydrophobic interactions. These findings provide a robust molecular basis for the rational design of next-generation OXR1 antagonists with improved efficacy and safety profiles. By elucidating drug–receptor interactions at the atomic level, this research underscores the impact of integrated computational approaches in drug discovery. It supports the development of precise targeted therapies for sleep disorders.

The orexin (hypocretin) system comprises two neuropeptides (orexin-A and orexin-B) and two G-protein coupled receptors (the orexin type 1 and the orexin type 2 receptor). The system regulates several biological functions including appetite, the sleep–wake cycle, the stress response, and motivation and reward processing . Dysfunction of the orexin system has been implicated in the pathophysiology of depression in human and animal studies, although the exact nature of this dysfunction remains unclear. Orexin receptor antagonists (ORAs) are a class of compounds developed for the treatment of insomnia and have demonstrated efficacy in this area. Three dual orexin receptor antagonists (DORAs) have received licences for treatment of primary insomnia and some ORAs have since been investigated as potential treatments for major depressive disorder (MDD). In this leading article, we summarise the existing literature on use of ORAs in depression, in pre-clinical and clinical studies. In rodent models of depression, investigated ORAs have included the DORA almorexant and TCS1102, the selective orexin 1 receptor antagonists SB334867 and SB674042 and the selective orexin 2 receptor antagonists LSN2424100, MK-1064 and TCS-OX2-29. These pre-clinical studies suggest a possible antidepressant effect of systemic DORA treatment, however the evidence from selective ORAs is conflicting. To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo.