Distinct effects of orexin receptor antagonist and GABA _A agonist on sleep and physical/cognitive functions after forced awakening

Abstract

The majority of patients with insomnia are treated with hypnotic agents. In the present study, we evaluated the side-effect profile of an orexin receptor antagonist and γ-aminobutyric acid A (GABAA) receptor agonist on physical/cognitive functions upon forced awakening. This double-blind, randomized, placebo-controlled, cross-over study was conducted on 30 healthy male subjects. Fifteen minutes before bedtime, the subjects took a pill of suvorexant (20 mg), brotizolam (0.25 mg), or placebo and were forced awake 90 min thereafter. Physical- and cognitive-function tests were performed before taking the pill, after forced awakening, and the next morning. Polysomnographic recordings revealed that the efficacies of the hypnotic agents in prolonging total sleep time (∼30 min) and increasing sleep efficiency (∼6%) were comparable. When the subjects were allowed to go back to sleep after the forced awakening, the sleep latency was shorter under the influence of hypnotic agents (∼2 min) compared to the placebo trial (24 min), and the rapid eye movement latency was significantly shorter under suvorexant (98.8, 81.7, and 48.8 min for placebo, brotizolam, and suvorexant, respectively). Although brotizolam significantly impaired the overall physical/cognitive performance (sum of z score) compared with placebo upon forced awakening, there was no significant difference in the total z score of performance between suvorexant and placebo. Notably, the score for static balance with the eyes open was higher under suvorexant compared to brotizolam administration. The energy expenditure was lower under suvorexant and brotizolam compared with the placebo. The effect size of brotizolam (d = 0.24) to reduce the energy expenditure was larger than that of suvorexant (d < 0.01).

Metabolic flexibility during sleep

“…The relation between the actions of these neurosubstances and sleeping energy metabolism remains to be addressed in human studies. Of note, we observed that an orexin receptor antagonist induces sleep, modifies sleep architecture, and suppresses energy expenditure 27 .…”

“…Sleep was recorded polysomnographically using a PSG-1100 system (Nihon Kohden). The records were scored every 30 s to stage wakefulness (W), stage 1, stage 2, slow wave sleep (SWS), and rapid eye movement (REM) sleep according to standard criteria 8,27 .…”

Hypocretins (orexins): The ultimate translational neuropeptides

“…Its clinical development encompasses the largest and longest studies conducted with a hypnotic ([55–59], reviewed in [28, 60]). Suvorexant is generally well‐tolerated and, like almorexant, does not impair cognition [61]. PSG analyses also indicate a dominant effect on REM sleep in comparison to non‐REM (NREM) [34].…”

Rethinking the use of hypnotics for treatment of insomnia in the elderly

“…Moreover, DORAs -different to benzodiazepines, Z-drugs, and sedating antidepressants -do not impair physical and cognitive functions after e.g. forced awakening from night-sleep [31,32]. Orexin receptor antagonists therefore will very likely be first-choice agents in the treatment of insomnia with a special emphasis on the prevention of neurodegenerative disorders.…”