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, clinically 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. Therefore, 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-V criteria for MDD were enrolled. A single dose of GHB (50mg/kg) was compared with a single 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 slow wave sleep ([SWS], as % of total sleep time [TST]) assessed by polysomnography and next-day vigilance (median response time and number of lapses in the psychomotor vigilance test [PVT]). GHB robustly prolonged SWS compared to both trazodone and placebo. GHB also prolonged TST and enhanced sleep efficiency (TST % of time-in-bed), while reducing sleep stages N1, N2, and wake-after-sleep-onset. While the median response time on the PVT was unaffected, GHB reduced the number of lapses compared to trazodone and placebo. No serious adverse events occurred. 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.