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Completed

NCT Number: NCT05007028

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).

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Key information

Conditions

Late-Life Depression Depressive Disorder Depressive Disorder, Treatment-Resistant Mental Disorders Mood Disorders Resistant Depression, Treatment

Age range

60 year–90 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University Hospital of Tours

Tours, 37044, France

About this study

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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

EMONO

Drug

Exposure to 1 hour of EMONO via facial mask

Medical Air

Drug

Exposure to 1 hour of Medical Air via facial mask

Primary outcomes

  1. Change in MADRS

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    montgomery asberg depression scale for symptoms severity

Secondary outcomes

  1. Change in Brain Tissue Pulsatility

    Time frame: Baseline and immediately after the intervention

    Indexes of BTP, including BTP amplitudes

  2. MRI

    Time frame: At Baseline

    Structural and Functional MRI

  3. Change in HDRS 17 items

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Hamilton Depression Rating Scale

  4. Change in QIDS-SR

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Quick Inventory of Depressive Symptomatology Self Report, Depression severity

  5. Change in CGI

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Clinical Global Impression

  6. Change in VAS

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Visual Analog Scale for global well-being self assessement

  7. Change in STAI

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    State-Trait Anxiety Inventory

  8. Change in SSI

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Scale for Suicidal Ideation

  9. Change in YMRS

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Young Mania Rating Scale

  10. Change in Clinician Administered Dissociative States Scale

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    CADSS

  11. Change in BPRS

    Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks

    Brief Psychiatric Rating Scale

Sponsors and collaborators

Lead sponsor

University Hospital, Tours

Other

Registry information

Official study title

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

Acronym: PROTO-BRAIN

Important dates

Study start
2021
Primary completion
2024
Study completion
2024
First posted
Aug 16, 2021
Registry last updated
Nov 24, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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