Nitrous Oxide for Late-Life Depression - PROTO-BRAIN

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