A Phase 2 Study of Inhaled Nitrous Oxide for Treatment-Resistant Major Depression

Peter NAGELE, Ben J. PALANCA, Brit Gott, Frank BROWN, Linda BARNES, Thomas Nguyen, Willa Xiong, Naji C. SALLOUM, Gemma D. ESPEHO, Christina N. LESSOV-SCHLAGGAR, NISHA Jainism, Wei LAND WL CHEN, Helga Komen, Branden Yee, Jacob D. BORZENIUS, Alvin Jansky, Robert Gibbons, Charles F. ZOLAMSKY, Charles R. CONWAY

Science Translational Medicine June 9, 2021

Commentary

According to the results of this study, inhaled 50% nitrous oxide as a treatment for depressed patients has an early antidepressant effect in patients with treatment-resistant major depression (TRMD), but this concentration can cause side effects. And a phase II clinical trial examined the effects of a single one-hour treatment with 25% nitrous oxide and found that it was as effective as 50% nitrous oxide, but with significantly fewer side effects. Thus, the results emphasize that low concentrations of nitrous oxide may be useful in the treatment of TRMD.

To begin with, nitrous oxide at 50% inhalation concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD), and in this Phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were treated with (i) 50% nitrous oxide, (ii) 25% nitrous oxide as a single inhalation for 1 hour, and (iii) nitrous oxide as a single inhalation for 1 hour. In the study (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments: (i) 50% nitrous oxide, (ii) 1-hour single inhalation of 25% nitrous oxide, or (iii) placebo (air/oxygen).

The study focused on changes in the Hamilton Depression Rating Scale (HDRS-21) and results showed a significant improvement in depressive symptoms compared to placebo ( P= 0.01), with no difference in concentration and a significant decrease in adverse events with dose. ( P< 0.001).