Nitrous Oxide for Late-Life Depression - PROTO-BRAIN (PROTO-BRAIN)

Nitrous Oxide for Late-Life Depression : a Randomized Controlled Trial With Comparator - 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).

Study Overview

• Status: Recruiting
• Conditions: Resistant Depression, Treatment; Late-Life Depression
• Intervention / Treatment: Drug: EMONO; Drug: Medical Air

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas Desmidt, MD, PhD; Phone Number: +33 02 34 37 89 52; Email: t.desmidt@chu-tours.fr

Study Locations

• France
  • Tours, France, 37044
    • Recruiting
    • University Hospital of Tours
    • Contact: Thomas Desmidt, MD, PhD; Phone Number: +33 02 34 37 89 52; Email: t.desmidt@chu-tours.fr
    • Principal Investigator: Thomas DESMIDT, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Tours

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: May 27, 2021
• First Submitted That Met QC Criteria: August 13, 2021
• First Posted (Actual): August 16, 2021

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Nitrous Oxide; Ultrasound Tissue Pulsatility Imaging
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: DR180133; 2019-002769-37 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No