Glucocorticoid receptor antagonism in major depressive disorder with childhood trauma: a randomized controlled trial
In brief
Mifepristone fails to improve depression scores in trauma-exposed patients
In a double-blind trial of 158 adults with major depression and childhood trauma, a 7-day course of mifepristone (1200 mg/day) produced no greater reduction in IDS-SR depressive symptoms at six weeks than placebo, and secondary outcomes-including anxiety, sleep and disability-were unchanged. Although cortisol rose briefly, the drug caused more adverse events, indicating no clinical advantage for this high-risk group.
- Journal
- Psychiatry research (Q1)
- Published
- 31 July 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- F Linsen, C Broeder, A W Hoogendoorn, M S C Sep, J E Verhoeven, P M Bet, et al.
- PMID
- 42585798
- DOI
- 10.1016/j.psychres.2026.117354
Why clinicians should know about it
- Picked for Psychiatry and Mental Health (top studies of the week, 16 August 2026): Glucocorticoid receptor antagonism in major depressive disorder with childhood trauma
Abstract
Childhood trauma (CT) is a key risk factor for major depressive disorder (MDD) onset and persistence. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie this link, and preclinical studies suggest glucocorticoid receptor (GR) antagonism can reverse early life stress effects. This study tested whether the GR antagonist mifepristone reduces depressive symptoms in adults with MDD and CT. The RESET-medication study was a randomized, double-blind, placebo-controlled trial evaluating a 7-day course of mifepristone (1200 mg/day) or placebo in 158 adults with MDD and CT, assessed at baseline, 1 week, 6 weeks (primary endpoint), 3 months, and 6 months. The primary outcome was depressive symptom severity (IDS-SR) at week 6; secondary outcomes included symptom severity at other timepoints, clinical response, remission, anxiety, sleep, stress, disability, and salivary cortisol. At week 6, depressive symptoms declined in both groups, with no significant difference between mifepristone and placebo (b=-0.25, d=-0.03, 95% CI [-0.42, 0.36], pnom=0.887), and no group differences were found for secondary outcomes. Morning and evening cortisol were significantly higher with mifepristone at week 1, consistent with GR antagonism, but not at week 6. Adverse events were more frequent with mifepristone; mild and severe events occurred significantly more often, while the proportion reporting at least one adverse event was numerically higher but not statistically significant (93.6%vs. 82.5%, χ²(1)=3.60, p=0.058). Mifepristone produced the expected endocrine response but did not lead to clinical improvements in individuals with MDD and CT compared to placebo.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.