Late-Life DepressionPROTO-BRAINNCT05007028
Nitrous Oxide for Late-Life Depression - PROTO-BRAIN
A study testing EMONO and Medical Air in people with Late-Life Depression and Resistant Depression, Treatment, run by University Hospital, Tours at 1 site in France.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 60 to 90 years
- Conditions the study is for
- Late-Life Depression, Resistant Depression, Treatment
- What is being tested?
- EMONO and Medical Air
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteFrance
- Study dates
- 16 Nov 2021to 19 Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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).
Read the 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
- Being tested
- EMONO, Medical Air
- Keywords
- Nitrous Oxide, Magnetic Resonance Imaging, Ultrasound Tissue Pulsatility Imaging
- Medical subject headings
- Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EMONODrug
Exposure to 1 hour of EMONO via facial mask
Medical AirDrug
Exposure to 1 hour of Medical Air via facial mask
| Study group | Role | What they receive |
|---|---|---|
| Nitrous Oxide | Experimental | Active Drug: EMONO (Equimolar Mixture of Oxygen and Nitrous Oxide) Receives: Drug: EMONO |
| Medical air | Placebo comparator | Control Drug: Medical air : 78% N2 / 22% O2 Receives: Drug: Medical Air |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in MADRS
montgomery asberg depression scale for symptoms severity
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Secondary outcomes (11)
Change in Brain Tissue Pulsatility
Indexes of BTP, including BTP amplitudes
Measured: Baseline and immediately after the intervention
MRI
Structural and Functional MRI
Measured: At Baseline
Change in HDRS 17 items
Hamilton Depression Rating Scale
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in QIDS-SR
Quick Inventory of Depressive Symptomatology Self Report, Depression severity
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in CGI
Clinical Global Impression
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in VAS
Visual Analog Scale for global well-being self assessement
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in STAI
State-Trait Anxiety Inventory
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in SSI
Scale for Suicidal Ideation
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in YMRS
Young Mania Rating Scale
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in Clinician Administered Dissociative States Scale
CADSS
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in BPRS
Brief Psychiatric Rating Scale
Measured: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Aug 2021
- Study start16 Nov 2021
- Primary completion19 Dec 2024
- Study completion19 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Late-Life DepressionStudies of the same condition, open and under way.
- More trials run by University Hospital, ToursThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized double blind trial with comparator
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Tours
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05007028
- Sponsor's protocol ID
- DR180133
- Other IDs
- 2019-002769-37, 2019
- Acronym
- PROTO-BRAIN
- Status last verified
- Nov 2025
- First submitted
- 27 May 2021
- Last updated
- 24 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Salame A, Bulteau S, Robert G, Vandevelde A, Gissot V, Agier MS, Gallet Q, Nkodo JA, Leroy V, Brunault P, Bourgoin H, Arlicot N, Espitalier F, Le Gouge A, El-Hage W, Camus V, Poupin P, Desmidt T. Nitrous oxide for late-life depression with inadequate antidepressant response: a randomised controlled trial. EClinicalMedicine. 2026 Apr 2;94:103860. doi: 10.1016/j.eclinm.2026.103860. eCollection 2026 Apr.
PubMed 42005916
Study at a glance
From the registry record, last updated by the sponsor on 24 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nitrous Oxide for Late-Life Depression : a Randomized Controlled Trial With Comparator - PROTO-BRAIN
- ClinicalTrials.gov ID
- NCT05007028
- Acronym / sponsor ID
- PROTO-BRAIN / DR180133
- Keywords
- Nitrous Oxide, Magnetic Resonance Imaging, Ultrasound Tissue Pulsatility Imaging
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- University Hospital, ToursUniversity, hospital or other
- Study start
- 16 Nov 2021 (actual)
- Primary completion
- 19 Dec 2024 (actual)
- Study completion
- 19 Dec 2024 (actual)
- First posted
- 16 Aug 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Randomized double blind trial with comparator
| Arm | Type | Receives |
|---|---|---|
| Nitrous Oxide | Experimental | Drug: EMONOActive Drug: EMONO (Equimolar Mixture of Oxygen and Nitrous Oxide) |
| Medical air | Placebo comparator | Drug: Medical AirControl Drug: Medical air : 78% N2 / 22% O2 |
Who may qualify
- Ages
- 60 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EMONOExposure to 1 hour of EMONO via facial mask | Drug | Nitrous Oxide |
| Medical AirExposure to 1 hour of Medical Air via facial mask | Drug | Medical air |
Primary outcome
Change in MADRS
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
montgomery asberg depression scale for symptoms severity
11 secondary outcomes
Change in Brain Tissue Pulsatility
Time frame: Baseline and immediately after the intervention
MRI
Time frame: At Baseline
Change in HDRS 17 items
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in QIDS-SR
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in CGI
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in VAS
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in STAI
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in SSI
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in YMRS
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in Clinician Administered Dissociative States Scale
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Change in BPRS
Time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Nov 2025.
- Derived from this study: PubMed 42005916Salame A, Bulteau S, Robert G, Vandevelde A, Gissot V, Agier MS, Gallet Q, Nkodo JA, Leroy V, Brunault P, Bourgoin H, Arlicot N, Espitalier F, Le Gouge A, El-Hage W, Camus V, Poupin P, Desmidt T. Nitrous oxide for late-life depression with inadequate antidepressant response: a randomised controlled trial. EClinicalMedicine. 2026 Apr 2;94:103860. doi: 10.1016/j.eclinm.2026.103860. eCollection 2026 Apr.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing EMONO and Medical Air in people with Late-Life Depression and Resistant Depression, Treatment, run by University Hospital, Tours at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in MADRS (time frame: Baseline, 2 hours, 24 hours, 1 week, 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05007028, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Nov 2025.