Nitrous Oxide: an emerging novel treatment for treatment-resistant depression

Introduction

Over several decades antidepressant development focused on monoamine systems, yet an estimated 20-25% of people with major depressive disorder (MDD) do not respond to standard pharmacotherapies and are commonly described as having treatment-resistant depression (TRD). Interest in novel mechanisms has therefore intensified, with NMDA receptor antagonists such as ketamine and its enantiomer esketamine showing rapid antidepressant effects and prompting investigation of other NMDA-targeting agents. Nitrous oxide (N2O), a long‑used inhalational anaesthetic and analgesic, has emerged as a candidate because preclinical and early clinical evidence suggest it may have antidepressant properties. Quach and colleagues set out to review the emerging literature on nitrous oxide as a treatment for depression. The review aims to describe how N2O is administered in psychiatric settings, summarise clinical evidence for its antidepressant efficacy and tolerability, outline proposed mechanisms of action, and identify gaps and priorities for future research and clinical development.