The Selective Extrasynaptic GABAA Agonist, Gaboxadol, Improves Traditional Hypnotic Efficacy Measures and Enhances Slow Wave Activity in a Model of Transient Insomnia

Abstract

Evaluate the hypnotic efficacy of gaboxadol, a selective extrasynaptic GABAA agonist (SEGA), in a phase advance model of transient insomnia. A randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h. Sleep research laboratories. 109 healthy subjects (18-58 y). Gaboxadol 5 mg, 10 mg, and 15 mg (GBX5, GBX10, GBX15) versus placebo (PBO). Zolpidem 10 mg (ZOL10) was used as an active reference. Polysomnographic (PSG) and self-reported (s) sleep measures Wakefulness after sleep onset (WASO) decreased (P < 0.05) and total sleep time (TST) increased (P < 0.001) in all treatments versus PBO. Latency to persistent sleep was shorter (P < 0.05) than PBO for all treatments except GBX5. GBX10 and GBX15 increased slow wave activity (SWA; 0.75-4.5 Hz, P < 0.001) and theta activity (4.75-7.75Hz; P < 0.001) and reduced sigma activity (12.25-15.0 Hz; significant for GBX15 only, P < 0.001) compared to PBO in NREM sleep EEG, in a dose-response manner. Zolpidem suppressed power density over a broad low frequency range including delta and theta frequencies (2.25-8.0 Hz, P < 0.05) and also enhanced sigma activity (P < 0.001). Self-reported sWASO and sTST improved for all treatments versus PBO (P < 0.05). Self-reported sleep latency was reduced following GBX10 (P < 0.05) and ZOL10 (P < 0.001). Neither drug treatment was associated with residual effects the morning after treatment. Gaboxadol and zolpidem improved objective and subjective efficacy measures in this model of transient insomnia. The gaboxadol-induced enhancement of SWA and theta activity and the reduction of sigma activity contrasts with zolpidem's effects on the spectral EEG. These differences may reflect the different mechanisms of action of the two drugs.