{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T14:36:31Z","timestamp":1783089391665,"version":"3.54.6"},"reference-count":45,"publisher":"Royal College of Psychiatrists","issue":"5","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"unspecified","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["BJPsych open"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec id=\"S2056472425108235_as1\">\n\t    <jats:title>Background<\/jats:title>\n\t    <jats:p>Nitrous oxide may possess antidepressant effects; however, limited data exist on repeated administrations and active placebo-controlled studies in treatment-resistant depression (TRD).<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S2056472425108235_as2\">\n\t    <jats:title>Aims<\/jats:title>\n\t    <jats:p>We aimed to test the feasibility of a randomised controlled trial examining a 4-week course of nitrous oxide or midazolam, an active placebo.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S2056472425108235_as3\">\n\t    <jats:title>Method<\/jats:title>\n\t    <jats:p>In this randomised, active, placebo-controlled pilot trial, 40 participants with TRD were assigned either a 1-h inhalation of 50% nitrous oxide plus intravenous saline (<jats:italic>n<\/jats:italic> = 20) or a 1-h inhalation of 50% oxygen plus intravenous midazolam (0.02 mg\/kg, up to 2 mg; <jats:italic>n<\/jats:italic> = 20) once weekly, for 4 weeks. Feasibility was assessed by examining rates of recruitment, withdrawal, adherence, missing data and adverse events. The main measure of clinical efficacy was the change in depression severity (Montgomery\u2013\u00c5sberg Depression Rating Scale (MADRS)) score from baseline to day 42.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S2056472425108235_as4\">\n\t    <jats:title>Results<\/jats:title>\n\t    <jats:p>The recruitment rate was 22.3% (95% CI 16.9\u201329.0). Withdrawal rates were 10% (95% CI 2.8\u201330.1) in both groups and adherence rates were 100.0% (95% CI 82.4\u2013100) in the nitrous oxide group and 94.4% (95% CI 74.2\u201399.0) in the placebo group. There were no missing primary clinical outcome data in either group (0.0%, 95% CI 0.0\u201317.6). MADRS score changed by \u221220.5% (95% CI \u221239.6 to \u22121.3) in the nitrous oxide group and \u22129.0% (95% CI \u221222.6 to 4.6) in the placebo group. Nearly all adverse events were mild to moderate and transient.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S2056472425108235_as5\">\n\t    <jats:title>Conclusions<\/jats:title>\n\t    <jats:p>The findings support the feasibility and necessity of conducting a full-scale trial comparing nitrous oxide and midazolam in patients with TRD.<\/jats:p>\n\t  <\/jats:sec>","DOI":"10.1192\/bjo.2025.10823","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T08:08:30Z","timestamp":1757664510000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":2,"title":["Sustained mood improvement with laughing gas exposure (SMILE): a randomised, placebo-controlled pilot trial of nitrous oxide for treatment-resistant depression"],"prefix":"10.1192","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7303-2458","authenticated-orcid":false,"given":"Karim 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