Treatment Resistant DepressionNCT04199143
Brain Reactivity to Nitrous Oxyde in Depression : an MRI and Ultrasound Study (PROTOBRAIN Pilote)
A study testing Nitrous Oxide-Oxygen, Tissue Pulsatility Imaging - TPI and Magnetic Resonance Imaging - MRI in people with Treatment Resistant Depression and Nitrous Oxyde, run by University Hospital, Tours at 1 site in France.
Trial summary
Recent evidence suggest that Nitrous Oxyde (N2O) could exhibit antidepressant effect in treatment-resistant depression (TRD). However, the pathophysiology of this effect remains unclear and could include glutamatergic activity but also cerebrovascular effects and changes in brain connectivity. Read more about this study
- Who is it for?
- Ages 25 to 50 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Treatment Resistant Depression, Nitrous Oxyde
- What is being tested?
- Nitrous Oxide-Oxygen, Tissue Pulsatility Imaging - TPI and Magnetic Resonance Imaging - MRI
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteFrance
- Study dates
- 20 Feb 2020to 10 Jun 2021
- 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 25 to 50 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Female between 25 and 50 years of age
- A person who can undergo N2O diffusion via a facial mask.
- A person who has signed an informed consent.
- Person affiliated with a social security scheme.
- Major Depressive Episode according to DSM-5 criteria, confirmed by the MINI - International Neuropsychiatric Interview.
- Patients with an MADRS score greater than 20 (Montgomery
Show all 10Show fewer
- Asberg Depression Rating Scale).
- Patients resistant to at least one well-conducted antidepressant treatment, as documented by the MGH-ATRQ scale.
- Absence of: bipolar disorder, schizophrenic disorder, neurodegenerative disease, schizophrenic disorder, neurodegenerative disease, addiction to one or more toxics documented by the MINI.
- Absence of: bipolar disorder, schizophrenic disorder, neurodegenerative disease, schizophrenic disorder, neurodegenerative disease, addiction to one or more toxics documented by the MINI, current or past.
Who cannot join
- Unstable somatic pathology (including unstable neurological or cardiological pathologies at risk of interfering with N2O diffusion)
- Presence of active and significant psychotic symptoms, at investigator's discretion
- Contraindications to mixture 50%N2O/ 50%O2: intracranial hypertension, altered state of consciousness, head trauma, pneumothorax, emphysema bubbles, abdominal gaseous distension, administration of less than 3 months of ophthalmic gas (SF6, C3F8,C2F6) used in eye surgery, known and unsubstituted deficiency in vitamin B12 or folic acid, recent and unexplained neurological abnormalities.
- Contraindications to MRI, including claustrophobia.
- Female who is pregnant or breastfeeding or able to procreate without an effective contraceptive method
- Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, purpose or consequences of the study (including major under legal protection).
- A person participating in a drug clinical trial or during a period of exclusion from any clinical study due to previous involvement.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Cerebrovascular Reactivity to Nitrous Oxyde in Resistant Depression: the PROTOBRAIN Pilote Study
Recent evidence suggest that Nitrous Oxyde (N2O) could exhibit antidepressant effect in treatment-resistant depression (TRD). However, the pathophysiology of this effect remains unclear and could include glutamatergic activity but also cerebrovascular effects and changes in brain connectivity. The goal of our study is to characterize brain reactivity to N2O in TRD patients, as assessed with Ultrasound Tissue Pulsatility Imaging (TPI) and Magnetic Resonance Imaging (MRI) (including Arterial Spin Labeling - ASL - for brain perfusion and Blood-Oxygen-Level Dependent - BOLD - for brain connectivity and pulsatility).
Ultrasound and MRI Neuroimaging will be measured before, during and after a single one-hour exposure of a 50%N20/50%O2 mixture, in depressed individuals (n=20) and healthy volunteers (n=10). We make the hypothesis that brain reactivity will be lower in depressed individuals nonresponders to N2O compared to responders and healthy controls. This study would provide further characterisation of the pathophysiology of the antidepressant response to N2O, as well as providing potential biomakers (Ultrasound and MRI) for treatment response to N2O in TRD.
Read the detailed description
Neuroimaging examinations will include:
- Ultrasound Tissue Pulsatility Imaging for assessment of Brain Tissue Pulsatility (BTP) which reflects reactivity in brain movements and mechanical brain properties
- MRI with structural and functional assessments, namely brain volumes, white matter lesions, ASL for brain perfusion and BOLD for resting-state connectivity and brain pulsatility
MRI will be performed before and after a single one-hour exposure of 50%N2O/50%O2 mixture. Ultrasound will be performed before, after and also during gas exposure. Changes in these neuroimaging parameters will constitute the primary assessment of the study. Psychometric and safety assessements will complete the neuroimaging outcomes.
Follow-up will includes 1) a baseline visit for baseline MRI and Psychometric assessements, 2) a second visit for gas exposure and neuroimaging assessements, 3) a third and fourth visits for psychometric and safety assessements, respectively 24 hours and one week after gas exposure.
- Conditions
- Treatment Resistant Depression, Nitrous Oxyde
- Being tested
- Nitrous Oxide-Oxygen, Tissue Pulsatility Imaging - TPI, Magnetic Resonance Imaging - MRI
- Keywords
- Magnetic Resonance Imaging, Ultrasound, Tissue Pulsatility Imaging, Treatment Resistant Depression, Nitrous Oxyde
- 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.
Nitrous Oxide-OxygenDrug
Also called KALINOX® 50 %/50 %
The medical product used in this study is a gas for common medical use in various domains including anesthesic, consisting in the equimolar mixture of nitrous oxide and oxygen. Subjects will receive a mixture of 50% N2O / 50% O2 for 1 hour.
Tissue Pulsatility Imaging - TPIDevice
Tissue Pulsatility Imaging (TPI) is a variation of ultrasonic Doppler strain imaging we are developing to measure the local expansion and relaxation of the brain tissue over the cardiac cycle to characterize and image perfusion.
Magnetic Resonance Imaging - MRIDevice
Structural and Functionnal (including BOLD and ASL) MRI will be aquired in this study
| Study group | Role | What they receive |
|---|---|---|
| healthy voluntary controls | Experimental | A single Non-blinded One-hour administration of 50% Nitrous oxyde (N2O) 50%oxygen (O2) Gas Mixture Receives: Drug: Nitrous Oxide-Oxygen; Device: Tissue Pulsatility Imaging - TPI; Device: Magnetic Resonance Imaging - MRI |
| Depressive Patients | Experimental | A single Non-blinded One-hour administration of 50% Nitrous oxyde (N2O) 50%oxygen (O2) Gas Mixture Receives: Drug: Nitrous Oxide-Oxygen; Device: Tissue Pulsatility Imaging - TPI; Device: Magnetic Resonance Imaging - MRI |
What is being measured
The primary outcome is the main question the study is designed to answer.
Brain Tissue Pulsatility (BTP) as measured with Ultrasound TPI
BTP will be measured before, during and after N2O exposure
Measured: 3 months after LVLS
Secondary outcomes (15)
Brain Volumes (MRI)
Measured: 6 months after LVLS
White Matter Lesions (MRI)
Measured: 6 months after LVLS
Resting-State Connectivity (BOLD-MRI)
Measured: 6 months after LVLS
Brain Pulsatility (BOLD-MRI)
Measured: 6 months after LVLS
Brain Perfusion in Arterial Spin Labelling (ASL-MRI)
Measured: 6 months after LVLS
Hamilton scale for depression, 17-items
Measured: 6 months after LVLS
POMS - Profile of Mood State
Measured: 6 months after LVLS
QIDS-SR - Quick Inventory of depressive Symptomatology Self Report
Measured: 6 months after LVLS
CGI - Clinical Global Impressions
Measured: 6 months after LVLS
STAI-Y-A - State-Trait Anxiety Inventory
Measured: 6 months after LVLS
subjective VAE- Visual Analog Evaluation
Measured: 6 months after LVLS
SSI - Scale for Suicidal Ideation
Measured: 6 months after LVLS
YMRS - Young Mania Rating Scale
Measured: 6 months after LVLS
CADSS - Clinician administered dissociative States
Measured: 6 months after LVLS
BPRS - Brief Psychiatric Rating Scale
Measured: 6 months after LVLS
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Dec 2019
- Study start20 Feb 2020
- Primary completion10 Jun 2021
- Study completion10 Jun 2021
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 Treatment Resistant 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
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- Open-label, Longitudinal, Monocentric, Physiological study comparing depressive patients (responders versus non-respondeurs to Nitrous Oxyde) and healthy volunteers
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Tours
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas DESMIDT, Principal investigator, CHRU de TOURS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04199143
- Sponsor's protocol ID
- DR190058
- Status last verified
- Dec 2025
- First submitted
- 5 Dec 2019
- Last updated
- 23 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Desmidt T, Dujardin PA, Andersson F, Brizard B, Remenieras JP, Gissot V, Arlicot N, Barantin L, Espitalier F, Belzung C, Tanti A, Robert G, Bulteau S, Gallet Q, Kazour F, Cognet S, Camus V, El-Hage W, Poupin P, Karim HT. Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study. Mol Psychiatry. 2023 Sep;28(9):3900-3908. doi: 10.1038/s41380-023-02217-6. Epub 2023 Aug 17.
PubMed 37592013
Study at a glance
From the registry record, last updated by the sponsor on 23 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cerebrovascular Reactivity to Nitrous Oxyde in Resistant Depression: the PROTOBRAIN Pilote Study
- ClinicalTrials.gov ID
- NCT04199143
- Acronym / sponsor ID
- DR190058
- Conditions
- Treatment Resistant Depression, Nitrous Oxyde
- Keywords
- Magnetic Resonance Imaging, Ultrasound, Tissue Pulsatility Imaging, Treatment Resistant Depression, Nitrous Oxyde
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University Hospital, ToursUniversity, hospital or other
- Study start
- 20 Feb 2020 (actual)
- Primary completion
- 10 Jun 2021 (actual)
- Study completion
- 10 Jun 2021 (actual)
- First posted
- 13 Dec 2019 (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.
Recent evidence suggest that Nitrous Oxyde (N2O) could exhibit antidepressant effect in treatment-resistant depression (TRD). However, the pathophysiology of this effect remains unclear and could include glutamatergic activity but also cerebrovascular effects and changes in brain connectivity. The goal of our study is to characterize brain reactivity to N2O in TRD patients, as assessed with Ultrasound Tissue Pulsatility Imaging (TPI) and Magnetic Resonance Imaging (MRI) (including Arterial Spin Labeling - ASL - for brain perfusion and Blood-Oxygen-Level Dependent - BOLD - for brain connectivity and pulsatility).
Ultrasound and MRI Neuroimaging will be measured before, during and after a single one-hour exposure of a 50%N20/50%O2 mixture, in depressed individuals (n=20) and healthy volunteers (n=10). We make the hypothesis that brain reactivity will be lower in depressed individuals nonresponders to N2O compared to responders and healthy controls. This study would provide further characterisation of the pathophysiology of the antidepressant response to N2O, as well as providing potential biomakers (Ultrasound and MRI) for treatment response to N2O in TRD.
Detailed description
Neuroimaging examinations will include:
- Ultrasound Tissue Pulsatility Imaging for assessment of Brain Tissue Pulsatility (BTP) which reflects reactivity in brain movements and mechanical brain properties
- MRI with structural and functional assessments, namely brain volumes, white matter lesions, ASL for brain perfusion and BOLD for resting-state connectivity and brain pulsatility
MRI will be performed before and after a single one-hour exposure of 50%N2O/50%O2 mixture. Ultrasound will be performed before, after and also during gas exposure. Changes in these neuroimaging parameters will constitute the primary assessment of the study. Psychometric and safety assessements will complete the neuroimaging outcomes.
Follow-up will includes 1) a baseline visit for baseline MRI and Psychometric assessements, 2) a second visit for gas exposure and neuroimaging assessements, 3) a third and fourth visits for psychometric and safety assessements, respectively 24 hours and one week after gas exposure.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Open-label, Longitudinal, Monocentric, Physiological study comparing depressive patients (responders versus non-respondeurs to Nitrous Oxyde) and healthy volunteers
| Arm | Type | Receives |
|---|---|---|
| healthy voluntary controls | Experimental | Drug: Nitrous Oxide-Oxygen, Device: Tissue Pulsatility Imaging - TPI, Device: Magnetic Resonance Imaging - MRIA single Non-blinded One-hour administration of 50% Nitrous oxyde (N2O) 50%oxygen (O2) Gas Mixture |
| Depressive Patients | Experimental | Drug: Nitrous Oxide-Oxygen, Device: Tissue Pulsatility Imaging - TPI, Device: Magnetic Resonance Imaging - MRIA single Non-blinded One-hour administration of 50% Nitrous oxyde (N2O) 50%oxygen (O2) Gas Mixture |
Who may qualify
- Ages
- 25 to 50 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- Female between 25 and 50 years of age
- A person who can undergo N2O diffusion via a facial mask.
- A person who has signed an informed consent.
- Person affiliated with a social security scheme.
- Major Depressive Episode according to DSM-5 criteria, confirmed by the MINI - International Neuropsychiatric Interview.
Key exclusion criteria (7 listed)
- Unstable somatic pathology (including unstable neurological or cardiological pathologies at risk of interfering with N2O diffusion)
- Presence of active and significant psychotic symptoms, at investigator's discretion
- Contraindications to mixture 50%N2O/ 50%O2: intracranial hypertension, altered state of consciousness, head trauma, pneumothorax, emphysema bubbles, abdominal gaseous distension, administration of less than 3 months of ophthalmic gas (SF6, C3F8,C2F6) used in eye surgery, known and unsubstituted deficiency in vitamin B12 or folic acid, recent and unexplained neurological abnormalities.
- Contraindications to MRI, including claustrophobia.
- Female who is pregnant or breastfeeding or able to procreate without an effective contraceptive method
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 |
|---|---|---|
| Nitrous Oxide-OxygenAlso: KALINOX® 50 %/50 %The medical product used in this study is a gas for common medical use in various domains including anesthesic, consisting in the equimolar mixture of nitrous oxide and oxygen. Subjects will receive a mixture of 50% N2O / 50% O2 for 1 hour. | Drug | Depressive Patients, healthy voluntary controls |
| Tissue Pulsatility Imaging - TPITissue Pulsatility Imaging (TPI) is a variation of ultrasonic Doppler strain imaging we are developing to measure the local expansion and relaxation of the brain tissue over the cardiac cycle to characterize and image perfusion. | Device | Depressive Patients, healthy voluntary controls |
| Magnetic Resonance Imaging - MRIStructural and Functionnal (including BOLD and ASL) MRI will be aquired in this study | Device | Depressive Patients, healthy voluntary controls |
Primary outcome
Brain Tissue Pulsatility (BTP) as measured with Ultrasound TPI
Time frame: 3 months after LVLS
BTP will be measured before, during and after N2O exposure
15 secondary outcomes
Brain Volumes (MRI)
Time frame: 6 months after LVLS
White Matter Lesions (MRI)
Time frame: 6 months after LVLS
Resting-State Connectivity (BOLD-MRI)
Time frame: 6 months after LVLS
Brain Pulsatility (BOLD-MRI)
Time frame: 6 months after LVLS
Brain Perfusion in Arterial Spin Labelling (ASL-MRI)
Time frame: 6 months after LVLS
Hamilton scale for depression, 17-items
Time frame: 6 months after LVLS
POMS - Profile of Mood State
Time frame: 6 months after LVLS
QIDS-SR - Quick Inventory of depressive Symptomatology Self Report
Time frame: 6 months after LVLS
CGI - Clinical Global Impressions
Time frame: 6 months after LVLS
STAI-Y-A - State-Trait Anxiety Inventory
Time frame: 6 months after LVLS
subjective VAE- Visual Analog Evaluation
Time frame: 6 months after LVLS
SSI - Scale for Suicidal Ideation
Time frame: 6 months after LVLS
YMRS - Young Mania Rating Scale
Time frame: 6 months after LVLS
CADSS - Clinician administered dissociative States
Time frame: 6 months after LVLS
BPRS - Brief Psychiatric Rating Scale
Time frame: 6 months after LVLS
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 23 Dec 2025.
- Results publication: PubMed 37592013Desmidt T, Dujardin PA, Andersson F, Brizard B, Remenieras JP, Gissot V, Arlicot N, Barantin L, Espitalier F, Belzung C, Tanti A, Robert G, Bulteau S, Gallet Q, Kazour F, Cognet S, Camus V, El-Hage W, Poupin P, Karim HT. Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study. Mol Psychiatry. 2023 Sep;28(9):3900-3908. doi: 10.1038/s41380-023-02217-6. Epub 2023 Aug 17.
- Individual participant dataSharing planned: No
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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.
Thomas DESMIDT principal investigator
CHRU de TOURS
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Nitrous Oxide-Oxygen, Tissue Pulsatility Imaging - TPI and Magnetic Resonance Imaging - MRI in people with Treatment Resistant Depression and Nitrous Oxyde, 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 10 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 23 Dec 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. 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?
Brain Tissue Pulsatility (BTP) as measured with Ultrasound TPI (time frame: 3 months after LVLS). 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 NCT04199143, 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 23 Dec 2025.