AbstractBackgroundThere remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). 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‐scanner single‐session nitrous oxide treatment of bipolar depression with repeated measures of CBF.MethodsIn this double‐blind randomized controlled trial, 25 adults with BD I/II and current treatment‐refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery‐Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging).ResultsThere were no significant between‐group differences in 24‐h post‐treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same‐day reductions in depression severity. Lower baseline regional CBF predicted greater 24‐h post‐treatment MADRS reductions with nitrous oxide but not midazolam. In region‐of‐interest and voxel‐wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide.ConclusionsPresent 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.