REPURPOSING OF GAMMA-HYDROXYBUTYRATE IN DEPRESSION: A RANDOMIZED PLACEBO-CONTROLLED PROOF-OF-CONCEPT CLINICAL TRIAL
Authors: Bavato *Francesco , Schnider Laura K , Dornbierer Dario A , Quednow Boris B , Landolt Hans-Peter , Bosch Oliver G , Seifritz Erich 
Published: February 2025

Abstract

Introduction
Gamma-hydroxybutyrate (GHB, clinically administrated as sodium oxybate) is an endogenous GHB/GABAB receptor agonist that regulates important homeostatic functions such as eating, sexual behavior, and the sleep-wake cycle. Its action is clinically used in narcolepsy and fibromyalgia, in which GHB improves nighttime slow wave sleep (SWS) while reducing next-day sleepiness. In major depressive disorder (MDD), main clinical features include subjective and objective alterations of sleep quality, increased sleep-inertia and reduced daytime wakefulness. However, specific treatment options to promote sleep in patients with MDD are still limited, as most sleep medications either negatively influence SWS (e.g. benzodiazepines) or increase daytime sleepiness (e.g., mirtazapine, trazodone, quetiapine).

Aims & Objectives
To investigate the sleep-promoting properties of GHB in individuals with MDD using a randomized placebo-controlled double-blinded crossover design. The study protocol was registered at ClinicalTrials.gov (NCT04082806).

Methods
The study was performed in a controlled sleep laboratory environment and consisted of one screening night, one adaptation night, and three experimental nights, separated by a 7-day washout phase each. Twenty-three adults with MDD having a current depressive episode and stable antidepressant treatment were recruited. A single dose of GHB (50mg/kg, liquid solution given orally at 03:30am) was compared to a single dose of trazodone (1mg/kg, capsule given orally at 23:30pm), and placebo (liquid: sodium chloride given orally at 03:30am; capsule: mannitol given orally at 23:30pm).
Objective sleep quality was assessed using polysomnographic recording. Subjective sleep quality, next- day sleepiness, and affective state were assessed using self-report questionnaires including a morning questionnaire (MQ), the Karolinska sleepiness scale (KSS) and the Positive and Negative Affect Schedule (PANAS). The Psychomotor Vigilance Task (PVT) was used to measure next-day alertness.

Results
GHB increased total SWS time as assessed by polysomonographic measures (mean± SD SWS in min for GHB vs. trazodone vs. placebo: 145.2±58.7, 98.0±53.3, 76.4±34.1; p&lt;0.001) while reducing time awake and REM sleep (p&lt;0.05). Both GHB and trazodone reduced self-reported time awake (MQ), while trazodone reduced next-day energy levels (MQ, p&lt;0.05). Increased next-day sleepiness (KSS) was observed for trazodone (p=0.027) but not for GHB (p&gt;0.05). No effects of either medication on PANAS and PVT were observed on the subsequent morning (p&gt;0.05). No serious adverse events occurred in the course of the trial. In the GHB condition, 8/22 participants reported mild side effects. In the trazodone condition, 1/23 moderate and 7/23 mild side effects were reported.

Discussion & Conclusions
A single administration of GHB effectively promotes SWS without affecting next-day wakefulness. Future studies should investigate the potential use of GHB in clinical settings including repeated administrations to treat sleep disorders in individuals with MDD.