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

Jaehoon Seol, Yuya Fujii, Insung Park, Yoko Suzuki, Fusae Kawana, Katsuhiko Yajima, Shoji Fukusumi, Tomohiro Okura, Makoto Satoh, Kumpei Tokuyama, Toshio Kokubo, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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).

Original languageEnglish (US)
Pages (from-to)24353-24358
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Nov 26 2019


  • Benzodiazepines
  • Body sway
  • Hypnotics
  • Purdue pegboard test
  • Stroop color-word test

ASJC Scopus subject areas

  • General


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