Gamma-hydroxybutyrate to promote slow-wave sleep in major depressive disorder: a randomized crossover trial
Dr. Francesco Bavato
Physician and clinical scientist at the University Hospital of Psychiatry Zurich, Switzerland, and a postdoctoral fellow at Aarhus University, Denmark. His current research focuses on experimental treatments in psychiatric conditions.
GHB in depression
In major depressive disorder (MDD), main clinical features include insomnia and increased daytime sleepiness. However, current pharmacological options to treat sleep in patients with MDD show unsatisfactory outcomes, as most compounds may actually reduce restorative deep sleep (i.e., slow-wave sleep [SWS]) and increase daytime sleepiness. Gamma-hydroxybutyrate (GHB, administered as sodium oxybate) is a GHB/GABAB receptor agonist used clinically in narcolepsy, where it promotes restorative SWS while reducing next-day sleepiness. Hence, we performed a randomized, placebo- and active comparator-controlled, double-blind, crossover trial to investigate the sleeppromoting properties of GHB in individuals with MDD. A single nocturnal dose of GHB was compared with a single evening dose of the clinical competitor trazodone (one of the most frequently prescribed sleep medications in MDD) and placebo. Of 29 randomized patients, 23 received at least one intervention and were included in the analysis.
Primary outcomes were nocturnal slow wave sleep ([SWS] assessed by polysomnography), next-day vigilance (median response time and number of lapses on the psychomotor vigilance test [PVT]), next-day working memory (median speed and accuracy on an N-back task), and next-day plasma brain-derived neurotrophic factor (BDNF) levels. GHB robustly prolonged SWS compared to both trazodone and placebo. GHB also prolonged total sleep time and enhanced sleep efficiency, while reducing sleep stages N1, N2, and wake-after-sleep-onset. While the median response time on the next-day PVT was unaffected, GHB reduced the number of lapses compared to trazodone and placebo. No effects on next-day working memory performance and BDNF levels were observed. No serious adverse events occurred. Overall, a single nocturnal dose of GHB effectively promotes SWS and shows more favorable effects on next-day vigilance than trazodone and placebo. Future studies should investigate GHB in clinical settings, including repeated administration.
Links to Paper:
Bavato, F., Schnider, L.K., Dornbierer, D.A. et al. (2025) Gamma-hydroxybutyrate to promote slow-wave sleep in major depressive disorder: a randomized crossover trial. Neuropsychopharmacol. 50, 1237–1244
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