Nitrous Oxide for Late-Life Depression - PROTO-BRAIN

Study Overview
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Brief Summary
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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).

Detailed Description
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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

Official Title
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Nitrous Oxide for Late-Life Depression : a Randomized Controlled Trial With Comparator - PROTO-BRAIN

Conditions
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Late-Life Depression, Resistant Depression, Treatment

Intervention / Treatment
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* Drug: EMONO
* Drug: Medical Air


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized double blind trial with comparator
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitrous Oxide<br>Active Drug: EMONO (Equimolar Mixture of Oxygen and Nitrous Oxide) | Drug: EMONO<br>* Exposure to 1 hour of EMONO via facial mask<br>|
| Placebo Comparator: Medical air<br>Control Drug: Medical air : 78% N2 / 22% O2 | Drug: Medical Air<br>* Exposure to 1 hour of Medical Air via facial mask<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MADRS | montgomery asberg depression scale for symptoms severity | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brain Tissue Pulsatility | Indexes of BTP, including BTP amplitudes | Baseline and immediately after the intervention | 
| MRI | Structural and Functional MRI | At Baseline | 
| Change in HDRS 17 items | Hamilton Depression Rating Scale | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in QIDS-SR | Quick Inventory of Depressive Symptomatology Self Report, Depression severity | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in CGI | Clinical Global Impression | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in VAS | Visual Analog Scale for global well-being self assessement | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in STAI | State-Trait Anxiety Inventory | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in SSI | Scale for Suicidal Ideation | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in YMRS | Young Mania Rating Scale | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in Clinician Administered Dissociative States Scale | CADSS | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 
| Change in BPRS | Brief Psychiatric Rating Scale | Baseline, 2 hours, 24 hours, 1 week, 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nitrous Oxide, Magnetic Resonance Imaging, Ultrasound Tissue Pulsatility Imaging