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.

Trial registration: ClinicalTrials.gov NCT00440323.

Figure 1

Schematic representation of the protocol. This was a four-period crossover study, each period consisting of two consecutive nights (Night 1: adaptation; Night 2: treatment). During Night 2 for all sessions, randomised subjects were administered two double-blinded doses of study medication (ie, either placebo or SB-649868 (10 or 30 mg); or either placebo or zolpidem 10 mg), while exposed to the traffic-noise model of situational insomnia.

Figure 2

Distribution of latency to REM sleep during the four conditions.

Figure 3

REM sleep and slow wave sleep (SWS) per third of sleep episode during noise exposure after treatment with placebo, 10 mg SB-649868, 30 mg SB-649868, and 10 mg zolpidem. Error bars indicate one SEM. ^*P<0.05; ^§P<0.01; ^#P<0.001, compared with placebo.

Figure 4

Effect of SB-649868 (10 and 30 mg) and zolpidem (10 mg) on electroencephalogram (EEG) power density spectra during non-REM sleep. All data are geometric means expressed relative to placebo (=100%). Vertical bars indicate 95% confidence intervals. A total of 36–38 subjects contributed to each of the comparisons for frequencies up to 15 Hz. Data are plotted at the upper limits of the frequency bins. Thus, values plotted at 1 Hz represent the 0.25–1.0 Hz bin.