Evaluation of the Antidepressant Effects of Nitrous Oxide in People with Major Depressive Disorder


Evaluation of the Antidepressant Effects of Nitrous Oxide in People with Major Depressive Disorder


Major depressive disorder (MDD) is a very common disease, with a lifetime prevalence of 15% and an annual incidence of about 7%. Nearly one-third of patients with MDD are severely depressed. MDD is associated with a two-fold increased risk of death compared with non-depressed individuals and is predicted to be the leading cause of disability in Western countries by 2030.

Although there is no definitive definition of treatment-resistant depression (TRD), an evolving consensus is failure to respond to a series of two adequate dose-duration antidepressant treatments. TRD is common, occurring in up to one-third of MDD patients, and is associated with a sense of ingrained hopelessness, high suicide risk, physical health decline, impairment in work, social and family life, and increased health care utilisation.

In collaboration with the Department of Anaesthesia at the Alfred Hospital, we are conducting a randomised trial to evaluate the antidepressant effects of nitrous oxide in people with major depressive disorder. This project will further evaluate these effects and identify the optimal dose and regimen to guide current practice, and to plan a future large pragmatic trial.


Primary Aim: To determine whether a series of 4 x 60 min treatment sessions of inhaled nitrous oxide (once per week) has significant antidepressant activity.


Secondary Aims:

1.    To determine the acute (but post-drug elimination) effect of inhaled nitrous oxide at 24 hours after first treatment.

2.    To determine the persistent effect of inhaled nitrous oxide over a further 4 weeks’ post-treatment follow-up period (i.e. 7 weeks after initiation of study).

3.  To evaluate tolerability and safety profile of the 4-cycle treatments with nitrous oxide.

4.   To compare two doses (inhaled concentrations 25% and 50%) of nitrous oxide to establish whether the inhaled concentration is related to clinical response.

5.   To obtain pilot data to inform the design of a future large phase III trial.


Adult (≥18 years, both sexes), with MDD diagnosis without psychosis are invited to take part in this study.


This will be a randomised, patient- and assessor-blinded (double-blind), parallel-group, controlled trial, with patients randomly assigned (1:1) to nitrous oxide (Nitrous group) or oxygen-air mixture (FiO2 ≈0.3, Control group).  The Nitrous group will be further randomly assigned to either 50% nitrous oxide or 25% nitrous.

All patients will receive four treatment sessions, spaced at one week intervals (1st treatment = week 0), and will then be followed up for a further four weeks. Both nitrous oxide groups will be combined for the primary analysis. Ethics Committee approval and individual participant informed consent will be obtained before commencement of the trial.  

Project status

The study has began recruitment in December 2018. It is expected minimum 172 participants will be recruited across two sites.

For more information, please contact Ms Alisa Turbic via email at maprc-nitrous@monash.edu or call 03 9076 6591


 MAPrc Monash Alfred Psychiatry Research Centre, Level 4, 607 St Kilda Road, Melbourne 3004

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