Nitrous Oxide (N2O) as a Treatment for Refractory Depression: A Word of Caution.

A letter to the editor raises concerns about using nitrous oxide (N2O) for treatment-resistant major depressive disorder (trMDD). The authors note that cobalamin dysregulation and folate deficiency are already documented in trMDD, citing evidence that cerebrospinal fluid metabolite abnormalities appear in over half of such patients, with cerebral folate deficiency most common, and that vitamin B12 levels predict deep white matter hyperintensities in MDD. They argue that N2O could worsen these effects, especially since its antidepressant effects are transitory, and call for clarifying why one-carbon metabolism dysregulation exists before considering N2O as a treatment.

Study at a glance

Abstract

To the Editors: N agele et al 1 have suggested medical utility of nitrous oxide (N2O) for the management of treatment-resistant major depression disorder (trMDD). Their work described basic concepts in N2O administration for the lay psychiatrist as well as the compound's known pharmacology and potential risks from repeated exposure, including N2O-induced inactivation of cobalamin and folate deficiencies. In their assessment, however, the authors failed to acknowledge that cobalamin dysregulation and folate deficiency are already documented clinical features in trMDD. Pan et al recently showed that cerebrospinal fluid metabolite abnormalities were identified in more than half of participants with trMDD, with cerebral folate deficiency being the most common. Vitamin B12 levels were also predictive of deep white matter hyperintensities in patients with MDD. Therefore, it is highly concerning that the authors propose a treatment modality (ie, N2O) that could potentially exacerbate these effects, especially if used as an ongoing therapeutic since the antidepressant effects of N2O are uniquely transitory. Not only do we have concern regarding the use of N2O as a therapeutic in trMDD, but there also needs to be a clarification as to why such dysregulation in 1-carbon metabolism exists in the first place before N2O should even be considered as a treatment option. A great deal of work has been focused on the elucidation of environmental risk factors that may be increasing risk of neuropsychiatric conditions that are often comorbid in MDD, including attention-deficit hyperactivity disorder (ADHD); (https://