Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial

Abstract

Objective: Major depressive disorder (MDD) is related to glutamatergic dysfunction. Antagonists of glutamatergic N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have antidepressant properties. Nitrous oxide (N 2 O) is also a NMDAR antagonist. Thus, this study aimed to evaluate the effects of augmenting antidepressant treatment with N 2 O. Methods: This double blind, placebo-controlled randomized parallel pilot trial was conducted from June 2016 to June 2018 at the Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. Twenty-three subjects with MDD (aged 18 to 65, on antidepressants, with a score > 17 on the 17-item-Hamilton Depression Rating Scale [HAM-D 17 ]) received 50% N 2 O (n=12; 37.17±13.59 years) or placebo (100% oxygen) (n=11; 37.18±12.77 years) for 60 minutes twice a week for 4 weeks. The primary outcome was changes in HAM-D 17 from baseline to week 4. Results: Depressive symptoms improved significantly in the N 2 O group (N 2 O: from 22.58±3.83 to 5.92±4.08; placebo: from 22.44±3.54 to 12.89±5.39, p < 0.005). A total of 91.7% and 75% of the N 2 O group subjects achieved response (≥ 50% reduction in HAM-D 17 score) and remission (HAM-D 17 < 7), respectively. The predominant adverse effects of N 2 O treatment were nausea, vomiting, and headache. Conclusion: N 2 O treatment led to a statistically significant reduction in HAM-D 17 scores compared to placebo. Clinical trial registration: Brazilian Register of Clinical Trials, RBR-5rz5ch

Which is the best way of using nitrous oxide for treatment and research in neuropsychiatry?

“…Interestingly, this latest work 1 confirms our findings that the antidepressant action of N 2 O occurred immediately and endured after gas administration. 2 , 3 It also supports our unpublished observation that the gas could be used as an adjuvant to routine antidepressant medication.…”

“…I welcome the excellent paper by Guimarã es et al 1 which extends research on nitrous oxide (N 2 O) in neuropsychiatry -a neglected field, since our initial work in 1982 and then 1985 2 indicating that low, anxiolytic, and nonanaesthetic doses of N 2 O ameliorate depression. 3 Research has demonstrated that N 2 O, at subanaesthetic concentrations acts on opioid receptors.…”

“…2,3 It also supports our unpublished observation that the gas could be used as an adjuvant to routine antidepressant medication. 2,3 Like Nagele's group, 1 Guimarães et al 1 believe that N 2 O and ketamine are antidepressant mainly via antagonism of the N-methyl-D-aspartate receptor (NMDAr). However, they provide two key references disputing NMDAr involvement.…”

“…Indeed, NMDAr blockade occurs only at N 2 O concentrations which are anaesthetic and not subanaesthetic, 4 making it unlikely that the NMDAr mediates the antidepressant action observed. 1,4 The dental technique (using identical equipment as here 1 ) never has a fixed goal-concentration, but titrates N 2 O using each individual's dose-response to reach concentrations achieving maximum relaxation while maintaining consciousness. In short, the concentration varies, depending on each individual's dose-response to N 2 O.…”

“…3 Guimaraes et al chose 50% N 2 O mistakenly believing that it produces minimal sedation and refer to the American Anesthesiology Association Guidelines. 1,5 These guidelines clearly states: ''less than 50%'' N 2 O is required to produce minimal sedation, which encompasses the dental titration method. 3 Since a fixed goal concentration ignores the individual sensitivities to the gas, it is unsurprising that they ''could find no data'' giving the ''best concentration of N 2 O'' 1 for depression.…”