Nitrous oxide therapy-induced changes in brain modules of treatment-resistant depression: a randomized controlled study

Currently, treatment options for patients with treatment-resistant depression (TRD) are extremely limited. Although the rapid antidepressant effects of nitrous oxide have been preliminarily validated, the underlying neurophysiological mechanisms remain unclear. In this study, we intended to explore impact on brain modules induced by nitrous oxide through a randomized controlled study. A total of 44 patients with TRD were recruited. Subjects were randomly allocated to nitrous oxide-intervention group (1-hour inhalation of 50% nitrous oxide/50% oxygen) or placebo-control group (1-hour inhalation of 50% oxygen/50% air). The eye-closed resting state EEG signals were recorded. Our findings reveal that nitrous oxide treatment significantly altered the segregation of interconnected brain functional modules. The result of General Linear Model (repeated measurements) demonstrates superior antidepressant efficacy of nitrous oxide compared to placebo, as evidenced by reductions in both the participation coefficient and connector hub after treatment. Furthermore, changes in modular metrics moderately correlated with reductions in depressive symptoms. These findings offer valuable insights into mechanism underlying the treatment of TRD using nitrous oxide from a modular perspective.