Alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by gaboxadol and zolpidem

Abstract

Objective: to evaluate cyclic alternating pattern (CAP) in a phase advance model of transient insomnia and the effects of gaboxadol and zolpidem.

Design: a randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h.

Setting: 6 sleep research laboratories in US PARTICIPANTS: 55 healthy subjects (18-57 y)

Interventions: Gaboxadol 15 mg (GBX), zolpidem 10 mg (ZOL), and placebo (PBO).

Measurements: routine polysomnographic (PSG) measures, CAP, spectral power density, and self-reported sleep measures

Results: The phase advance model of transient insomnia produced significant changes in CAP parameters. Both GBX and ZOL significantly and differentially modified CAP parameters in the direction of more stable sleep. GBX brought the CAP rate in stage 1 sleep and slow wave sleep (SWS) closer to baseline levels but did not significantly change the CAP rate in stage 2. ZOL reduced the CAP rate in stage 2 to near baseline levels, whereas the CAP rate in stage 1 and SWS was reduced substantially below baseline levels. The CAP parameter A1 index (associated with SWS and sleep continuity) showed the highest correlation with self-reported sleep quality, higher than any traditional PSG, spectral, or other self-reported measures.

Conclusion: disruptions in CAP produced by phase advanced sleep were significantly and differentially modulated by gaboxadol and zolpidem. The relative independence of CAP parameters from other electrophysiological measures of sleep, their high sensitivity to sleep disruption, and their strong association with subjective sleep quality suggest that CAP variables may serve as valuable endpoints in future insomnia research.

Keywords: CAP; Gaboxadol; extrasynaptic GABA agonist; phase advance; spectral analysis; transient insomnia; zolpidem.

Figure 1

Spearman (rank) correlation between difference in baseline and PBO values of QOS and corresponding differences in the values of each of CAP, PSG, spectral variables, as well as self-reported measures. Variables are presented in 4 groups, CAP, PSG, Self. (Self-reported), and Spectral. Values of correlations are shown in the horizontal axis and repeated to the right of the bars. P-values show the corresponding regions to the left (for negative correlations) and to the right (for positive correlations) of the vertical bars where the correlations are significantly different from zero.