Nitrous Oxide Reduced Suicidal Ideation in Treatment-Resistant Major Depression in Exploratory Analysis

Nitrous oxide (N₂O) is a colorless, odorless gas commonly used as an anesthetic in dental and obstetric settings.¹ Previously, our group demonstrated that N₂O has rapid antidepressant effects.^2,3 N₂O has N-methyl-d-aspartate receptor antagonist properties shared with ketamine; esketamine, an enantiomer, has received FDA approval for rapid reduction in suicidal ideation in major depressive disorder (MDD). In the present analysis, we examined N₂O’s ability to reduce suicidal ideation in a pooled secondary analysis of data from 3 crossover trials investigating N₂O in subjects with treatment-resistant major depression (TRMD).

Methods

Data were pooled from 3 completed N₂O trials at Washington University School of Medicine (ClinicalTrials.gov identifiers: NCT02139540, NCT03283670, and NCT02994433). All studies were double-blind, randomized, placebo-controlled, outpatient crossover trials assessing depression reduction as the primary outcome. Subjects were adults with MDD as determined by the Mini-International Neuropsychiatric Interview.⁴ All trials enrolled TRMD subjects (at least 3 lifetime adequate dose-duration antidepressant failures, with 1 or more in the current episode). All subjects received separate, 60-minute inhalations of 50% N₂O (50% N₂O in 50% oxygen) and placebo (air/oxygen mixture). Washout period between conditions was variable across the studies, with inhalations delivered 1–6 weeks apart.

Suicidal ideation (SI) was measured using the standard Hamilton Depression Rating Scale (HDRS)⁵ suicide item (item 3) at 2 and 24 hours post-inhalation. A clinically meaningful reduction in SI was defined as at least a 2-point score reduction on item 3. Hence, subjects had to start with a score of at least a 2 (“wish he/she were dead or any thoughts of possible death to self”) or a 3 (“suicidal ideas or gestures”) on item 3; ie, those rating a 1 (“feels life is not worth living”) were excluded from the SI reduction analysis. Of note, there were no subjects with a score of 4 (“attempts at suicide”) or any active suicidal intention or planning, as more severe forms of suicidality were excluded from these outpatient trials. A 2-sided Fisher exact test was used to compare the proportion of subjects with clinically meaningful reduction in suicidality across N₂O and placebo conditions.

Results

Twenty-four subjects were pooled from the 3 N₂O TRMD trials (12/6/6 as per the 3 clinical trials, respectively). A total of 13 subjects in the N₂O arm and 17 subjects in the placebo arm scored at least 2 and were included in the analysis.

Using a 2-point decrease in the HDRS suicide item score to define reduction in SI, no trend in SI reduction was observed at the earlier time point (2 hours; P = 1). However, at 24 hours post-inhalation, there was a significant change in SI (N₂O vs placebo; P = .019). Figure 1 is a “heat map” showing SI reduction effects of N₂O compared to placebo. Of note, 7/13 (54%) of the subjects who received N₂O had a meaningful reduction in SI, whereas only 2/17 (12%) in the placebo group showed a similar change. There was a strong relationship between reduction in SI and reduction in total depressive scores for the treatment arm at the 24 hour time mark (Spearman ρ = 0.763).

Discussion

While preliminary, this post hoc analysis of 3 crossover trials demonstrated that N₂O, as compared to placebo, reduced SI in a TRMD sample. Similar to ketamine, this SI reduction occurred within 24 hours of exposure.^6,7 These findings suggest that N₂O may have rapid antisuicidal effects in depressed subjects. Further post hoc analyses demonstrated that the reduction in SI was strongly linked to reduction in depression; further study is needed to elucidate the persistence of the SI and MDD symptom reduction association.

There are several limitations to this secondary analysis: (1) a small sample size; (2) stability of SI prior to study inclusion and randomization is not known; (3) possible carryover effects, as existing N₂O studies suggest that antidepressant effects persist at least 2 weeks; and (4) all subjects had TRMD, limiting generalizations to non-resistant depressed populations. Despite the limitations, these findings are promising, and additional study of the potential antisuicidal ideation effects of N₂O is warranted.

Article Information

Published Online: August 16, 2023. https://doi.org/10.4088/JCP.22br14725
© 2023 Physicians Postgraduate Press, Inc.
J Clin Psychiatry 2023;84(5):22br14725
Submitted: November 10, 2022; accepted April 17, 2023.
To Cite: de Leon VC, Kumar A, Nagele P, et al. Nitrous oxide reduced suicidal ideation in treatment-resistant major depression in exploratory analysis. J Clin Psychiatry. 2023;84(5):22br14725.
Author Affiliations: Department of Psychiatry, Washington University School of Medicine in St Louis, Missouri (de Leon, Gott, Janski); Bristol Myers Squibb, Lawrenceville, New Jersey (Kumar); Department of Anesthesia and Critical Care, University of Chicago Medical Center, Illinois (Nagele); Department of Anesthesiology and Department of Psychiatry, Washington University School of Medicine in St Louis, Missouri (Palanca); Department of Psychiatry, Washington University School of Medicine in St Louis and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St Louis, Missouri (Zorumski, Conway).
Corresponding Author: Victoria C. de Leon, MD, 660 South Euclid Ave, MSC 8134-0017-04, St Louis, MO 63110 (deleonv@wustl.edu).
Relevant Financial Relationships: Drs de Leon, Kumar, and Janski and Ms Gott have no relevant financial relationships. Although Dr Kumar is affiliated with Bristol Myers Squibb; the company is in no way involved with this work, and Dr Kumar contributed to the work in his individual capacity. Dr Nagele has filed for intellectual property regarding nitrous oxide in major depression (“Compositions and methods for treating depressive disorders”; US20170071975A1). Dr Palanca has a patent pending on control of anesthetic state modulation and an agreement with Elemind on the use of non-pharmacologic potentiation of EEG slow waves. Dr Zorumski is on the Scientific Advisory Board of Sage Therapeutics and has equity in the company. Sage Therapeutics was not involved in this work. Dr Conway is on the Sage Therapeutics Advisory Board and has been a consultant for LivaNova, PLC.
Funding/Support: This work has no direct funding sources. Data used in this secondary analysis came from trials with the ClinicalTrials.gov identifiers NCT02139540, NCT03283670, and NCT02994433. These trials were supported by the Departments of Anesthesiology and Psychiatry and the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, St. Louis, Missouri; NARSAD Independent Investigator Award from the Brain and Behavior Research Foundation; and National Institute of Mental Health (NIMH). Dr de Leon is supported by Washington University Institute of Clinical and Translational Sciences, UL1 TR002345 and sub-award TL1 TR002344. Dr Nagele is receiving funding from NIMH, American Foundation for Suicide Prevention, and Brain and Behavior Research Foundation. Dr Palanca is supported by the Washington University Center for Perioperative Mental Health grant number P50 MH122351 from NIMH and NIMH grant U01MH128483. Dr Zorumski receives support from MH122379 and the Taylor Family Institute for Innovative Psychiatric Research. Dr Conway is supported by the American Foundation for Suicide Prevention, Barnes Hospital Foundation, Taylor Family Institute for Innovative Psychiatric Research, August Busch IV Foundation, and research funding through Washington University from LivaNova, PLC, and is the lead investigator of the RECOVER Trial.
Previous Presentations: Presented at Translational Science 2023, Washington, DC, April 18–20, 2023; 2023 SOBP Annual Meeting, San Diego, California, April 27–29, 2023; and 2023 IASR/AFSP International Summit on Suicide Research, Barcelona, Spain, October 15–18, 2023.
ORCID: Victoria C. de Leon: https://orcid.org/0000-0002-5811-2086; Peter Nagele: https://orcid.org/0000-0001-8369-3858; Ben J. Palanca: https://orcid.org/0000-0001-7535-5701; Charles F. Zorumski: https://orcid.org/0000-0002-9704-5154; Charles R. Conway: https://orcid.org/0000-0001-6849-9416