In a double-blind randomized controlled trial, 25 adults with bipolar I or II disorder and treatment-resistant depression received either nitrous oxide (25% concentration for 20 minutes) plus intravenous saline or medical air plus intravenous midazolam (2 mg total). No significant between-group differences emerged in depression severity change or treatment response 24 hours after treatment. However, the nitrous oxide group showed significantly greater same-day reductions in depression severity. Lower baseline regional cerebral blood flow predicted greater 24-hour improvement with nitrous oxide but not midazolam. Midazolam was associated with regional cerebral blood flow reductions compared to nitrous oxide. These secondary findings suggest differential associations of the two agents with depression severity and brain hemodynamics, warranting larger studies.
A randomized, double-blind trial will test whether a single administration of nitrous oxide (N2O) improves mood and increases frontal cerebral blood flow in adults with treatment-resistant bipolar depression. Participants with bipolar I or II disorder currently in a major depressive episode will be assigned to either inhaled N2O plus intravenous saline or inhaled room air plus intravenous midazolam. Mood will be assessed with the Montgomery-Asberg Depression Rating Scale, and cerebral blood flow measured by arterial spin labelling MRI. The authors suggest N2O may act as a cerebral vasodilator to counteract hypoperfusion in depression, and if effective, could become a low-cost, safe, and accessible acute treatment.