Nitrous oxide inhalation produced time-dependent increases in brain entropy, particularly in the frontal lobe, among patients with treatment-resistant depression. These entropy changes, measured via multivariate multiscale entropy analysis of resting-state EEG, correlated with symptom severity and treatment efficacy, suggesting frontal region temporal-spatial brain entropy may serve as a biomarker for treatment-resistant depression and its treatment outcomes.
In a randomized controlled trial, 44 patients with treatment-resistant depression received either a one-hour inhalation of 50% nitrous oxide with 50% oxygen or a placebo of 50% oxygen with 50% air. Nitrous oxide treatment significantly altered the segregation of interconnected brain functional modules, as measured by EEG. The treatment showed superior antidepressant efficacy compared to placebo, with reductions in both the participation coefficient and connector hub after treatment. Changes in these modular metrics moderately correlated with reductions in depressive symptoms, offering insights into the neurophysiological mechanisms underlying nitrous oxide's rapid antidepressant effects.