Nitrous oxide for late-life depression with inadequate antidepressant response: a randomised controlled trial

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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.

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