Woman Sleeping Between the Posts, Elizabeth Hiltz Thomas
Orexin antagonists barely improve depression, but not the ones on the market
STUDY: Pereira SIDS et al, J Affect Disord 2026
STUDY TYPE: Systematic review and meta-analysis
FUNDING: National Institute for Health and Care Research (NIHR) Pre-Doctoral Clinical Fellowship
Background
Orexin receptor antagonists — suvorexant, lemborexant, daridorexant — block wake-promoting signals in the brain and are approved for insomnia. Several trials have tested whether they reduce depression, and this analysis pulls those together. None of the trials involved orexin antagonists on the market.
The Study
- Five randomized, double-blind, placebo-controlled 6-week trials enrolling 1,346 adults with major depressive disorder and an inadequate response to an SSRI or SNRI.
- Trials tested investigational drugs (1 of filorexant, 3 of seltorexant, and 1 of tebideutorexant)
- Patients received an adjunctive orexin receptor antagonist (seltorexant, filorexant, or tebideutorexant) or placebo added to their existing antidepressant.
Results
Depression scores improved modestly on the Depression scale (MADRS), the Depression scale (PHQ-9), and the MADRS without the sleep item, suggesting the antidepressant signal wasn’t just sleep improvement bleeding into the mood score.
The Hamilton Depression Rating Scale (HAM-D17) showed no significant improvement, and pooling the studies together found a small overall effect in depression (effect size 0.15).
Sleep improved more convincingly on the Sleep Disturbance scale (PROMIS-SD), with a mean difference of 3.4 points favoring the orexin blocker.
Orexin antagonists made a significant difference on MADRS but not HAM-D depression scores
Orexin antagonists made a significant difference on PHQ-9 depression scores above
Limitations
- Small samples, long-term effects unknown. Two studies were unpublished.
- When individual studies were removed in sensitivity analyses, some findings lost statistical significance, suggesting the results hinge on a small number of trials.
Practice Implications
- The three orexin antagonists on the market have not been tested for depression, although lemborexant improved sleep in depressed and anxious subjects. We don’t know if this will translate to them.
- The orexin blockers studied here lowered depression by about 2 points on the MADRS, which falls below the 3-point threshold typically considered clinically meaningful.
- Their sleep benefits, however, were more substantial, and other studies show these agents improve sleep quality, and next day functioning without raising the fall risk.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
