Combination of Nitrous Oxide with Isoflurane or Scopolamine for Treatment-resistant Major Depression

The N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, are receiving increasing attention because ketamine rapidly causes a long-lasting reduction in depressive symptoms in patients whose major depression resists conventional treatment.1-4) We read with great interest the recent article by Nagele et al.5) about the efficacy of nitrous oxide (N2O), an inhaled general anesthetic and NMDA receptor antagonist, in patients with treatment-resistant major depression. The article describes a randomized, double-blind, placebo-controlled, cross-over study in which patients (n=20) were treated in two sessions 1 week apart with either nitrous oxide (50% nitrous oxide/50% oxygen or placebo [100% oxygen]) for 1 h. As measured by the 21-item Hamilton Depression Rating Scale (HDRS-21), depression symptoms improved significantly more at 2 h and 24 h after receiving nitrous oxide than after placebo (mean difference of HDRS-21: −4.8 points at 2 h, p=0.002, and −5.5 points at 24 h, p＜0.001). Furthermore, patients (n=10) treated with nitrous oxide first reported a significant improvement of depressive symptoms at 2 h, 24 h, and 1 week (mean difference of HDRS-21: −7.1 points at 2 h, −8.6 points at 24 h, −12.8 points at 1 week). Four patients’ (20%) improvement qualified as a treatment response (reduction ≥50% on HDRS-21), and three patients (15%) reported a full remission (≤7 points on the HDRS-21) after nitrous oxide inhalation.