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Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

ABSTRACT: The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

SUBMITTER: Hoever P

PROVIDER: S-EPMC3370822 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

Hoever P P Dorffner G G Beneš H H Penzel T T Danker-Hopfe H H Barbanoj M J MJ Pillar G G Saletu B B Polo O O Kunz D D Zeitlhofer J J Berg S S Partinen M M Bassetti C L CL Högl B B Ebrahim I O IO Holsboer-Trachsler E E Bengtsson H H Peker Y Y Hemmeter U-M UM Chiossi E E Hajak G G Dingemanse J J

Clinical pharmacology and therapeutics 20120601 6

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake ...[more]

PMID: 22549286

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Project description:BackgroundResearch on cooperative behavior and the social brain exists, but little research has focused on real-time motor cooperative behavior and its neural correlates. In this proof of concept study, we explored the conceptual notion of shared and complementary mental models through EEG mapping of two brains performing a real-world interactive motor task of increasing difficulty. We used the recently introduced participative "juggling paradigm," and collected neuro-physiological and psycho-social data. We were interested in analyzing the between-brains coupling during a dyadic juggling task, and in exploring the relationship between the motor task execution, the jugglers'skill level and the task difficulty. We also investigated how this relationship could be mirrored in the coupled functional organization of the interacting brains.MethodsTo capture the neural schemas underlying the notion of shared and complementary mental models, we examined the functional connectivity patterns and hyperbrain features of a juggling dyad involved in cooperative motor tasks of increasing difficulty. Jugglers' cortical activity was measured using two synchronized 32-channel EEG systems during dyadic juggling performed with 3, 4, 5 and 6 balls. Individual and hyperbrain functional connections were quantified through coherence maps calculated across all electrode pairs in the theta and alpha bands (4-8 and 8-12 Hz). Graph metrics were used to typify the global topology and efficiency of the functional networks for the four difficulty levels in the theta and alpha bands.ResultsResults indicated that, as task difficulty increased, the cortical functional organization of the more skilled juggler became progressively more segregated in both frequency bands, with a small-world organization in the theta band during easier tasks, indicative of a flow-like state in line with the neural efficiency hypothesis. Conversely, more integrated functional patterns were observed for the less skilled juggler in both frequency bands, possibly related to cognitive overload due to the difficulty of the task at hand (reinvestment hypothesis). At the hyperbrain level, a segregated functional organization involving areas of the visuo-attentional networks of both jugglers was observed in both frequency bands and for the easier task only.DiscussionThese results suggest that cooperative juggling is supported by integrated activity of specialized cortical areas from both brains only during easier tasks, whereas it relies on individual skills, mirrored in uncorrelated individual brain activations, during more difficult tasks. These findings suggest that task difficulty and jugglers' personal skills may influence the features of the hyperbrain network in its shared/integrative and complementary/segregative tendencies.

Dataset Information

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

Publications

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

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