Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep and EEG power spectra in a model of situational insomnia

Bettica, Paolo; Squassante, Lisa; Groeger, John A.; Gennery, Brian; Winsky-Sommerer, Raphaelle; Dijk, Derk-Jan

Abstract

Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABA A receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p < 0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB-6489698 30 mg dose (p < 0.001). Latency to persistent sleep was significantly reduced after both doses of SB-6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p < 0.001) and low delta activity (1.0 Hz) were increased, and 2.25-11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p < 0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Citation

Bettica, P., Squassante, L., Groeger, J. A., Gennery, B., Winsky-Sommerer, R., & Dijk, D.-J. (2012). Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep and EEG power spectra in a model of situational insomnia. Neuropsychopharmacology, 37(5), 1224-1233. https://doi.org/10.1038/npp.2011.310

• Journal Article Type: Article
• Acceptance Date: Nov 5, 2011
• Online Publication Date: Jan 11, 2012
• Publication Date: Apr 1, 2012
• Deposit Date: Nov 13, 2014
• Journal: Neuropsychopharmacology
• Print ISSN: 0893-133X
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 37
• Issue: 5
• Pages: 1224-1233
• DOI: https://doi.org/10.1038/npp.2011.310
• Keywords: Insomnia; Hypocretin; Hypnotics; Circadian; GABA; SB-649868
• Public URL: https://hull-repository.worktribe.com/output/467190
• Publisher URL: https://www.nature.com/articles/npp2011310
• Contract Date: Nov 13, 2014