title: 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.
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.
authors.affiliation: Neuroscience CEDD Discovery Medicine, GlaxoSmithKline, Verona, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bettica
authors.forename: Lisa
authors.initials: L
authors.lastname: Squassante
authors.forename: John A
authors.initials: JA
authors.lastname: Groeger
authors.forename: Brian
authors.initials: B
authors.lastname: Gennery
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Winsky-Sommerer
authors.forename: Derk-Jan
authors.initials: DJ
authors.lastname: Dijk
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001572:Benzofurans / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D058785:GABA-A Receptor Agonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D064446:Orexin Receptors; D017286:Polysomnography; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D012895:Sleep, REM / Q000187:drug effects*; D011795:Surveys and Questionnaires; D013844:Thiazoles / Q000627:therapeutic use*; D014851:Wakefulness / Q000187:drug effects; D055815:Young Adult; D000077334:Zolpidem
chemical_list: D001572:Benzofurans; D058785:GABA-A Receptor Agonists; C557781:N-((1-((5-(4-fluorophenyl)-2-methyl-4-thiazolyl)carbonyl)-2-piperidinyl)methyl)-4-benzofurancarboxamide; D064446:Orexin Receptors; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013844:Thiazoles; D000077334:Zolpidem