Clinical trial NCT04199143: Brain Reactivity to Nitrous Oxyde in Depression : an MRI and Ultrasound Study (PROTOBRAIN Pilote)
Official title: Cerebrovascular Reactivity to Nitrous Oxyde in Resistant Depression: the PROTOBRAIN Pilote Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Treatment Resistant Depression
Nitrous Oxyde
Keywords: Magnetic Resonance Imaging
Ultrasound
Tissue Pulsatility Imaging
Treatment Resistant Depression
Nitrous Oxyde
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2019-12-13
Enrollment: 30
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, Longitudinal, Monocentric, Physiological study comparing depressive patients (responders versus non-respondeurs to Nitrous Oxyde) and healthy volunteers
Primary purpose: BASIC_SCIENCE

Brief 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. 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.

Eligibility criteria: Inclusion Criteria:

* Inclusion criteria common to all participants
* 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.
* Inclusion Criteria for Depressive Patients
* Major Depressive Episode according to DSM-5 criteria, confirmed by the MINI - International Neuropsychiatric Interview.
* Patients with an MADRS score greater than 20 (Montgomery
* 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.
* Inclusion criteria for healthy voluntary controls
* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Brain Tissue Pulsatility (BTP) as measured with Ultrasound TPI
timeFrame: 3 months after LVLS
Secondary outcomes:
measure: Brain Volumes (MRI)
timeFrame: 6 months after LVLS
measure: White Matter Lesions (MRI)
timeFrame: 6 months after LVLS
measure: Resting-State Connectivity (BOLD-MRI)
timeFrame: 6 months after LVLS
measure: Brain Pulsatility (BOLD-MRI)
timeFrame: 6 months after LVLS
measure: Brain Perfusion in Arterial Spin Labelling (ASL-MRI)
timeFrame: 6 months after LVLS
measure: Hamilton scale for depression, 17-items
timeFrame: 6 months after LVLS
measure: POMS - Profile of Mood State
timeFrame: 6 months after LVLS
measure: QIDS-SR - Quick Inventory of depressive Symptomatology Self Report
timeFrame: 6 months after LVLS
measure: CGI - Clinical Global Impressions
timeFrame: 6 months after LVLS
measure: STAI-Y-A - State-Trait Anxiety Inventory
timeFrame: 6 months after LVLS
measure: subjective VAE- Visual Analog Evaluation
timeFrame: 6 months after LVLS
measure: SSI - Scale for Suicidal Ideation
timeFrame: 6 months after LVLS
measure: YMRS - Young Mania Rating Scale
timeFrame: 6 months after LVLS
measure: CADSS - Clinician administered dissociative States
timeFrame: 6 months after LVLS
measure: BPRS - Brief Psychiatric Rating Scale
timeFrame: 6 months after LVLS
Other outcomes:
Locations:
city: Tours
country: France
facility: University Hospital of Tours
Study officials:
affiliation: CHRU de TOURS
name: Thomas DESMIDT
role: PRINCIPAL_INVESTIGATOR
References: