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. 2012 Apr;37(5):1224-33. doi: 10.1038/npp.2011.310. Epub 2012 Jan 11.


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.

Trial registration: ClinicalTrials.gov NCT00440323.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Analysis of Variance
  • Benzofurans / therapeutic use*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Electroencephalography
  • GABA-A Receptor Agonists / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Orexin Receptors
  • Polysomnography
  • Psychomotor Performance / drug effects
  • Pyridines / therapeutic use*
  • Reaction Time / drug effects
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Sleep, REM / drug effects*
  • Surveys and Questionnaires
  • Thiazoles / therapeutic use*
  • Wakefulness / drug effects
  • Young Adult
  • Zolpidem


  • Benzofurans
  • GABA-A Receptor Agonists
  • N-((1-((5-(4-fluorophenyl)-2-methyl-4-thiazolyl)carbonyl)-2-piperidinyl)methyl)-4-benzofurancarboxamide
  • Orexin Receptors
  • Pyridines
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Thiazoles
  • Zolpidem

Associated data

  • ClinicalTrials.gov/NCT00440323