A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression

Abstract

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Nitrous oxide for the treatment of psychiatric disorders: A systematic review of the clinical trial landscape

“…Four studies were from the past 2 years, with two published in 2020 14,22 and two published in 2021 11,12 (Figure 2A). Four studies were from the USA, [12][13][14]22 and one was from Brazil.…”

“…Four studies were from the past 2 years, with two published in 2020 14,22 and two published in 2021 11,12 (Figure 2A). Four studies were from the USA, [12][13][14]22 and one was from Brazil. 11 Two studies enrolled participants with MDD, 11,22 and two recruited patients with TRD 12,13 (Figure 2B).…”

“…Nitrous oxide (N 2 O) is one such alternative being examined for depression. [11][12][13][14] Also known as the "laughing gas," it is commonly used in medical and dental procedures as an inhalational anesthetic. 15 N 2 O inhalation is associated with limited side effects but can occasionally increase the risk of nausea, vomiting, and headaches.…”

Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry

“…Those with TRD may be less likely to respond to treatment of interest compared to those with MDD since the lower response rate was observed in the later treatment step in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial 7 . Furthermore, the primary endpoint was not clarified in one study for nitrous oxide 19 . Fourth, the superiority/inferiority of each compound to ketamine cannot be examined because a direct comparison of only MIJ821 with ketamine is reported.…”

“…One clinical trial comparing two facial injection sites is ongoing (NCT03484754). In another phase II crossover DBRCT of 24 patients with TRD, a single 1-hour inhalation of 50 % and 25 % nitrous oxide in oxygen did not demonstrate significant reduction in the HAMD 21 total score compared to placebo gas at hours 2, 24 and week 1, but did at week 2 (primary outcome, the estimated differences between 25 % nitrous oxide and placebo: −0.75 at 2 hours (p = 0.73), −1.41 at 24 hours (p = 0.52), −4.35 at week 1 (p = 0.05), and −5.19 at week 2 (p = 0.02); the estimated differences between 50 % nitrous oxide and placebo: −0.87 at 2 hours (p = 0.69), −1.93 at 24 hours (p = 0.37), −2.44 at week 1 (p = 0.25), and −7.00 at week 2 (p = 0.001) (NCT03283670)[19]. The response rates at 2 weeks were 41.7 % in the 50 % nitrous oxide group (Relative Risk (RR) = 2.9; 95 % CI = 0.6-18.0), 33.3 % in the 25 % nitrous oxide group (RR = 2.5; 95 % CI = 0.4-16.3), and 11.1 % in the placebo group.…”