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Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and\/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in\u2010scanner single\u2010session nitrous oxide treatment of bipolar depression with repeated measures of CBF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this double\u2010blind randomized controlled trial, 25 adults with BD I\/II and current treatment\u2010refractory depression received either: (1) nitrous oxide (20\u2009min at 25% concentration) plus intravenous saline (<jats:italic>n<\/jats:italic>\u00a0=\u00a012), or (2) medical air plus intravenous midazolam (2\u00a0mg total; <jats:italic>n<\/jats:italic>\u00a0=\u00a013). Study outcomes included changes in depression severity (Montgomery\u2010Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were no significant between\u2010group differences in 24\u2010h post\u2010treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same\u2010day reductions in depression severity. Lower baseline regional CBF predicted greater 24\u2010h post\u2010treatment MADRS reductions with nitrous oxide but not midazolam. In region\u2010of\u2010interest and voxel\u2010wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bdi.13288","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T08:34:29Z","timestamp":1672302869000},"page":"221-232","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Proof\u2010of\u2010concept randomized controlled trial of single\u2010session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1257-1348","authenticated-orcid":false,"given":"William S. 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