Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial

• Published in: Biological psychiatry (1969) Vol. 78; no. 1; pp. 10 - 18
• Main Authors: Nagele, Peter, Duma, Andreas, Kopec, Michael, Gebara, Marie Anne, Parsoei, Alireza, Walker, Marie, Janski, Alvin, Panagopoulos, Vassilis N, Cristancho, Pilar, Miller, J. Philip, Zorumski, Charles F, Conway, Charles R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2015
• Subjects: Adult; Antidepressive Agents - therapeutic use; Cross-Over Studies; Depression - drug therapy; Depressive Disorder, Major - drug therapy; Depressive Disorder, Treatment-Resistant - drug therapy; Double-Blind Method; Female; Humans; Major depression; Male; Middle Aged; Nitrous oxide; Nitrous Oxide - adverse effects; Nitrous Oxide - therapeutic use; Psychiatric Status Rating Scales; Psychiatry; Treatment Outcome; Treatment-resistant depression; Major depression; Nitrous oxide; Treatment-resistant depression
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2014.11.016

Abstract Background N -methyl-D-aspartate receptor antagonists, such as ketamine, have rapid antidepressant effects in patients with treatment-resistant depression (TRD). We hypothesized that nitrous oxide, an inhalational general anesthetic and N -methyl-D-aspartate receptor antagonist, may also be a rapidly acting treatment for TRD. Methods In this blinded, placebo-controlled crossover trial, 20 patients with TRD were randomly assigned to 1-hour inhalation of 50% nitrous oxide/50% oxygen or 50% nitrogen/50% oxygen (placebo control). The primary endpoint was the change on the 21-item Hamilton Depression Rating Scale (HDRS-21) 24 hours after treatment. Results Mean duration of nitrous oxide treatment was 55.6 ± 2.5 (SD) min at a median inspiratory concentration of 44% (interquartile range, 37%–45%). In two patients, nitrous oxide treatment was briefly interrupted, and the treatment was discontinued in three patients. Depressive symptoms improved significantly at 2 hours and 24 hours after receiving nitrous oxide compared with placebo (mean HDRS-21 difference at 2 hours, −4.8 points, 95% confidence interval [CI], −1.8 to −7.8 points, p = .002; at 24 hours, −5.5 points, 95% CI, −2.5 to −8.5 points, p < .001; comparison between nitrous oxide and placebo, p < .001). Four patients (20%) had treatment response (reduction ≥50% on HDRS-21) and three patients (15%) had a full remission (HDRS-21 ≤ 7 points) after nitrous oxide compared with one patient (5%) and none after placebo (odds ratio for response, 4.0, 95% CI, .45–35.79; OR for remission, 3.0, 95% CI, .31–28.8). No serious adverse events occurred; all adverse events were brief and of mild to moderate severity. Conclusions This proof-of-concept trial demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with TRD.