Nitrous oxide for late-life depression with inadequate antidepressant response: a randomised controlled trial.
EClinicalMedicine April 2, 2026 DOI: 10.1016/j.eclinm.2026.103860 via PubMed Central
Summary
A single 60-minute inhalation of 50% nitrous oxide (N2O) significantly reduced depressive symptoms in older adults (aged 60–90) with late-life depression who had not responded to at least one adequate antidepressant trial. In a double-blind, randomized, placebo-controlled trial with 60 participants, those receiving N2O showed a greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at two weeks compared to placebo (−6.2 points; 95% CI: −9.1 to −3.4). Improvements were rapid, appearing within 24 hours and persisting at one week. All adverse events were mild and transient. The findings suggest N2O may be a safe and effective rapid-acting treatment for this difficult-to-treat population, though further studies are needed to confirm long-term efficacy and safety.
Study at a glance
| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 60 |
| Population | Adults aged 60–90 years with late-life depression and inadequate antidepressant response |
| Registration | NCT05007028 |
| Key finding | A single 60-minute inhalation of 50% nitrous oxide produced a significantly greater reduction in depressive symptoms at two weeks compared to placebo, with rapid onset and mild, transient adverse events. |
Abstract
Background Late-life depression with inadequate antidepressant response is a pressing clinical issue with limited proven therapies. Nitrous oxide (N 2 O) may offer a new therapeutic avenue with rapid and safe antidepressant effects in late-life depression with inadequate antidepressant response. Methods We conducted a double-blind, randomised, placebo-controlled, single-dose trial (November 2021–December 2024) in three old-age psychiatry departments at French university hospitals. Eligible participants were aged 60–90 years with a current major depressive episode, a Montgomery-Åsberg Depression Rating Scale (MADRS) score >20 and documented non-response to ≥1 adequate antidepressant trial. Participants were randomly assigned (1:1) to a single 60-min inhalation of either 50% N 2 O/50% O 2 (N 2 O group) or medical air (placebo group). The primary outcome was change in MADRS score from baseline to 2 weeks, analysed under the intention-to-treat principle with a linear mixed-effects model using all available data. Secondary outcomes included clinician- and self-rated depressive symptom scales and safety. The study is complete and registered in ClinicalTrials.gov (NCT05007028). Findings Among the 60 participants enrolled in the study, those who received N 2 O experienced a significant and sustained reduction in depressive symptoms compared to the placebo group. The antidepressant effect was rapid, with significant improvements noted as early as 24 h and at one week. At the two-week endpoint, the N2O group showed a significantly greater reduction in MADRS scores (−6.2 points; 95% CI: −9.1 to −3.4; P < 0.001). These positive findings were supported by both clinician- and self-rated questionnaires, and all reported adverse events were mild and transient. Interpretation While further studies are needed to confirm its long-term efficacy and safety, our findings suggest that N 2 O offers a new therapeutic strategy with rapid, sustained and safe antidepressant effects in late-life depression with inadequate antidepressant response. Funding This study was supported by a grant from the French Ministry of Health and Prevention.