Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial
This double-blind, placebo-controlled, within-subjects proof-of-concept study (n=20) investigated the antidepressant efficacy of inhaled nitrous oxide (50/50 nitrous oxide/oxygen vs. 50/50 nitrogen/oxygen) in patients with treatment-resistant depression (TRD). Nitrous oxide resulted in treatment response in 20% of patients and symptom remission in 15%, an effect size comparable to that of ketamine.
Authors
- Nagele, P.
- Duma, A.
- Kopec, M.
Published
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.
Research Summary of 'Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial'
Introduction
Treatment-resistant depression (TRD) is described as a severe form of major depressive disorder in which patients fail multiple standard antidepressant treatments and face poor long-term prognosis; the authors note that about one in three patients with major depression meet criteria for TRD. The NMDA (N-methyl-D-aspartate) receptor has been implicated in depression neurobiology, and earlier studies have shown that NMDA receptor antagonists such as ketamine can produce rapid antidepressant effects at subanesthetic doses. Given a similar primary mechanism of action, nitrous oxide was proposed as a candidate rapid-acting treatment for TRD because it is an inhalational general anaesthetic that acts as a noncompetitive NMDA receptor inhibitor. Nagele and colleagues therefore conducted a proof-of-concept clinical trial to test whether a single session of nitrous oxide inhalation produces immediate (2-hour) and sustained (24-hour) antidepressant effects in well-characterised patients with TRD. The trial aimed to detect an early efficacy signal that could justify larger studies and to collect preliminary safety and tolerability data in this population.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- APA Citation
Nagele, P., Duma, A., Kopec, M., Gebara, M. A., Parsoei, A., Walker, M., Janski, A., Panagopoulos, V. N., Cristancho, P., Miller, J. P., Zorumski, C. F., & Conway, C. R. (2015). Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial. Biological Psychiatry, 78(1), 10-18. https://doi.org/10.1016/j.biopsych.2014.11.016
References (4)
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Paul, R. K., Singh, N. S., Khadeer, M. et al. · Anesthesiology (2014)
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De Filippo, R., Schmitz, D. · Neuroscience and Biobehavioral Reviews (2024)
Lii, T. R., Smith, A. E., Flohr, J. R. et al. · Nature Mental Health (2023)
Dai, R., Larkin, T. E., Huang, Z. et al. · NeuroImage (2023)
Quach, D. F., de Leon, V. C., Conway, C. R. · Journal of the Neurological Sciences (2022)
Nagele, P., Palanca, B. J., Gott, B. et al. · Science Translational Medicine (2021)
Kohtala, S., Alitalo, O., Rosenholm, M. et al. · Pharmacology and Therapeutics (2020)
Garcia-Romeu, A., Kersgaard, B., Addy, P. H. · Experimental and Clinical Psychopharmacology (2016)
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