Resistant Depression is a common condition in older adults and there is an urgent need for novel antidepressant in this population. Nitrous Oxide (N2O) has recently shown rapid antidepressant effect in midlife depression but no study has currently investigated the efficacy and safety of N2O in Late-Life Depression (LLD), while N2O may prove to be an ideal treatment for LLD because of glutamatergic antagonism and cerebrovascular effects and also a relatively good safety profile.

The goal of our study is to compare changes in depressive symptoms after 2 hours, 24 hours, 1 week and 2 week of a 1-hour exposure to EMONO (Equimolar Mixture of Oxygen and Nitrous Oxide) versus Medical Air.

Secondary Objectives include comparing differences in neuroimaging measures between 3 groups (responders and non-responders in the EMONO group, and patients in the control group).

Secondary objectives include:

• To compare changes in Brain Tissue Pulsatility (BTP) as measured with Ultrasound Tissue Pulsatility Imaging (TPI) between responders in the EMONO group (MADRS change of at least 50%), non-responders in the EMONO group (MADRS change of no more than 50%) and in the Air Medical group
• To compare baseline differences in structural (brain volumes, white matter hyperintensities) and functional (resting state connectivity in BOLD, Brain Pulsatility in BOLD, Brain Perfusion in ASL) among the 3 groups
• To compare changes in depressive and anxiety symptoms between the active and control group, as assess with Hamilton scale, CGI scale, QIDS-SR, VAS and the STAI scale
• To compare safety between the active and control group, as assessed with SSI, YMRS, CADSS, BPRS

Inclusion Criteria:

• Aged 60-90 years-old
• Major Depressive Episode according to DSM-5 criteria, confirmed by the MINI - Mini International Neuropsychiatric Interview
• MADRS score greater than 20 (Montgomery Asberg Depression Rating Scale)
• Patient resistant to at least one well-conducted antidepressant treatment, as documented by the MGH-ATRQ scale
• Patient who can undergo N2O diffusion via a facial mask
• Patient who has signed an informed consent
• Person affiliated with a social security scheme

Exclusion Criteria:

• Bipolar disorder, schizophrenic disorder, neurodegenerative disease, documented by the MINI and the MMSE (non-inclusion if MMSE < 24/30), addictive disorder
• Unstable somatic pathology (including unstable neurological or cardiological diseases at risk of interfering with N2O diffusion)
• Presence of active and significant psychotic symptoms, at investigator's discretion
• Contraindications to EMONO (50%N2O/ 50%O2) : pneumothorax, emphysema, bowel obstruction, intracranial hypertension, chronic deficiency in vitamin B12 or B9
• Contraindications to MRI, including claustrophobia
• Legal incapacity and/or other circumstances unabling the patient to understand the nature, purpose or consequences of the study
• A person participating in a drug clinical trial or during a period of exclusion from any clinical study