Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.
William S H Kim, Mikaela K Dimick, Danielle Omrin, Rachel H B Mitchell, Daniel Riegert, Anthony Levitt, Ayal Schaffer, Susan Belo, John Iazzetta, Garfield Detzler, Mabel Choi, Stephen Choi, Nathan Herrmann, Roger S McIntyre, Bradley J MacIntosh, Beverley A Orser, Benjamin I Goldstein
Bipolar Disorders May 1, 2023 DOI: 10.1111/bdi.13288 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 25 |
| Population | Adults with bipolar I or II disorder and current treatment-refractory depression |
| Interventions | Nitrous oxide Intravenous saline Medical air Intravenous midazolam |
| Dose | Nitrous oxide: 20 min at 25% concentration; Midazolam: 2 mg total |
| Duration | Single session, 24-hour follow-up |
| Measures | Montgomery-Asberg Depression Rating Scale (MADRS), arterial spin labeling magnetic resonance imaging |
| Topics | Depression |
| Keywords | Arterial spin labeling Bipolar depression Bipolar disorder Cerebral blood flow Midazolam Nitrous oxide |
| Key findings | Nitrous oxide produced greater same-day reductions in depression severity than midazolam, but no significant between-group differences in 24-hour outcomes; lower baseline regional cerebral blood flow predicted better 24-hour response to nitrous oxide. |
Abstract
There 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. In 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). There 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. 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.