A sleep med that might also treat depression
STUDY: Kishi T et al Mol Psychiatry. 2026 Apr 6.
STUDY TYPE: Systematic review and meta-analysis
FUNDING: Independent
Background
The orexin receptor antagonists are a new class of sleep meds that stand out in two ways
- Safety, confirmed in large trials of older adults and risky populations like sleep apnea
- Cognitive benefits. Unlike other sleep meds, they improve next-day cognition
But hopes that they would improve depression have not panned out, at least not for the ones that are on the market: suvorexant, lemborexant, and daridorexant. That may be because they attach more to the orexin-2 receptor (which is more involved in sleep and waking) than the orexin-1 receptor (which is more involved in emotional processing).
I’m not a fan of brain-receptor theories like that, but this one seems to hold up in this new analysis that compared these drugs in depression. The one that stands out is the only one that is selective for orexin-2: Seltorexant.
The Study
Five double-blind, placebo-controlled trials were pooled, covering adults with MDD treated with orexin antagonists that are under development (filorexant, seltorexant, or tebideutorexant).
Orexin antagonists outperformed placebo on depression symptoms, but the effect was small (SMD 0.16). Remission rates were higher with active treatment than placebo (risk ratio 1.52). Seltorexant 20 mg drove most of the signal — it significantly reduced symptom scores (SMD 0.36) and was associated with higher remission rates. The 40 mg dose didn’t outperform placebo and was linked to more discontinuations and nightmares. Filorexant and tebideutorexant showed no antidepressant benefit. Tolerability was generally good — no increased somnolence or dizziness across the pooled group.
Seltorexant also regulates the hypothalamic–pituitary–adrenal axis, a key mechanism underlying depression.
Practice Implications
- Sleep and depression are tightly linked, but very few sleep meds improve depression. Eszopiclone is an exception, and if seltorexant comes to market it may prove effective as well.
- Meanwhile, CBT-insomnia has the best evidence, both for insomnia and depression.
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— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Are you seeing other psychiatric effects with orexin-antagonists?
