Gamma-hydroxybutyrate to promote slow-wave sleep in major depressive disorder: a randomized crossover trial

In major depressive disorder (MDD), main clinical features include insomnia and increased daytime sleepiness. However, specific treatment options to promote sleep in MDD are limited. Gamma-hydroxybutyrate (GHB, administered as sodium oxybate) is a GHB/GABA_B receptor agonist used clinically in narcolepsy, where it promotes restorative slow-wave sleep (SWS) while reducing next-day sleepiness. Hence, we performed a randomized, placebo- and active comparator-controlled, double-blind, crossover trial to investigate the sleep-promoting properties of GHB in individuals with MDD. Outpatients aged 20-65 years fulfilling the DSM-5 criteria for MDD were enrolled. A single nocturnal dose of GHB (50 mg/kg) was compared with a single evening dose of the clinical competitor trazodone (1.5 mg/kg) 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.