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.

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.”

Authors: Peter Nagele, Andreas Duma, Michael Kopec, Marie Anne Gebara, Alireza Parsoei, Marie Walker, Alvin Janski, Vassilis N. Panagopoulos, Pilar Cristancho, J. Philip Miller, Charles F. Zorumski & Charles R. Conway

Summary

Nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, was found to have rapid antidepressant effects in patients with treatment-resistant depression. Four patients had treatment response and three patients had a full remission after receiving nitrous oxide compared with one patient and none after placebo.

Treatment-resistant depression (TRD) is a severe form of major depressive disorder that often fails multiple treatments with standard antidepressants.

Nitrous oxide has been shown to inhibit the NMDA receptor, which has been implicated in the pathophysiology of major depression. This proof-of-concept trial assessed the immediate and sustained antidepressant effects of nitrous oxide in a population of well-characterized patients with TRD.

Study Design and Oversight

In this study, 20 patients with TRD received nitrous oxide inhalations for two weeks. The sessions were indistinguishable in setting, setup, and monitoring, and patients were blinded as to the nature of the inhaled gas at each inhalation session.

Patients

Patients with TRD were recruited from an existing database and the Volunteers for Health patient pool at Washington University School of Medicine. They had to be aged 18 to 65 years and meet certain criteria. Patients with bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, or documented Axis II diagnoses were excluded, as were those with active substance abuse or dependence, acute medical illness, active suicidal intention, active psychosis, and pregnancy or breast-feeding in female patients.

Treatment

Patients received either 50% nitrous oxide and 50% oxygen (active treatment) or 50% nitrogen/50% oxygen (placebo) for 1 hour. They were monitored during and after the treatment with continuous three-lead electrocardiogram, pulse oximetry, noninvasive blood pressure, and end-tidal carbon dioxide.

Outcomes

Six time points were assessed for each patient: baseline, 2 hours after treatment, 24 hours after treatment, and 1 week after treatment. The primary study endpoint was the change in the HDRS-21 at 24 hours after treatment.

Statistical Analysis

We performed a repeated-measures mixed effects linear model with restricted maximum likelihood estimation to analyze the primary outcome (HDRS-21) and the secondary outcome (QIDS-SR).

The rates of treatment responses and remissions between the two treatments were compared using an exact binomial test.

This study was the first in-human patient pilot study of ketamine, and the sample size was based on available results from ketamine trials in similar populations.

Patients

We enrolled 24 patients with TRD into the trial, and 20 patients received both treatments and completed the follow-up assessment. The median HDRS-21 score at enrollment was 23.5, and the median QIDS-SR score was 19.8, indicative of severe depression.

Treatment

15 patients completed the full 60-min treatment with nitrous oxide; 2 patients were interrupted for 5 min and 3 were discontinued for emotional discomfort, regurgitation, claustrophobia, or nausea and vomiting.

Study Outcomes

Patients experiencing depressive symptoms experienced a significant improvement after receiving nitrous oxide compared to placebo (mean difference in HDRS-21 score at 2 hours, 24.8 points, 95% CI, 21.8 to 27.8 points, p 5 .002; at 24 hours, 25.5 points, 95% CI, 22.5 to 28.5 points, p 5 .001)

Four patients (20%) had treatment response after receiving nitrous oxide, compared with one patient (5%) after placebo treatment. Three patients (15%) had a full remission after nitrous oxide treatment.

7 of 20 patients who received nitrous oxide had at least a two-level improvement in depression severity compared to 2 patients who received placebo.

First Treatment Session–Only Analysis

In this crossover trial, patients who received nitrous oxide first showed markedly lower HDRS-21 scores after the 1-week interval, indicating a significant carryover effect. We additionally analyzed the first treatment session only, to address this carryover effect.

Patients who received nitrous oxide first had a significant improvement of depressive symptoms at 2 hours, 24 hours, and 1 week compared with patients who received placebo first (Figure 5).

DISCUSSION

This proof-of-concept trial demonstrated that nitrous oxide has rapid antidepressant effects in patients with TRD and that these effects are sustained for at least 24 hours and in some patients for 1 week.

The internal validity of our crossover trial was affected by the observed carryover effect and the placebo effect. The placebo effect may have masked or exaggerated the treatment effects of nitrous oxide.

Although the antidepressant efficacy results in this trial are promising, several potential limitations should be taken into consideration. For example, nitrous oxide induces sedation and has a slightly sweet smell and taste, which may have made patients aware of their group assignment.

Although the presence of euphoria and psychosis were clinically assessed at each time point, standardized testing was not done, and the use of the HDRS-21 and QIDS-SR scales to measure rapid antidepressant action was a limitation.

Nitrous oxide had a similar rapid onset of antidepressant action to ketamine, but was devoid of psychotomimetic side effects. This suggests that other neurotransmitter receptor systems may be important contributors to rapid antidepressant actions.

Ketamine and memantine have different effects on the brain, with ketamine having faster antidepressant effects and memantine having slower antidepressant effects. The presence of magnesium in the brain may also contribute to the differences.

Although nitrous oxide has been found to be generally safe, some patients may experience emotional discomfort, paradoxically increased anxiety levels, and nausea during nitrous oxide administration.

A pilot study of nitrous oxide in patients with treatment-resistant depression found that nitrous oxide had rapid and marked antidepressant effects. However, nitrous oxide is a drug of abuse and its abuse potential represents a potential limitation for its clinical utility in major depressive disorder.