Inflammation and Blood Brain Barrier Integrity as Biomarkers of Suicidal Behavior

Depression Clinical Trial

— IBBBiS  

Official title:

Inflammation and Blood Brain Barrier Integrity as Biomarkers of Suicidal Behavior

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06047613
• Other study ID #: RECHMPL22_0103
• Status: Recruiting
• Phase: N/A
• Start date: October 5, 2023
• Est. completion date: October 2025

Study information

• Verified date: November 2023
• Source: University Hospital, Montpellier
• Contact: Philippe COURTET, MD PhD
• Phone: +33 4 67 33 85 81
• Email: p-courtet[@]chu-montpellier.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Recent studies have revealed an association between history of suicide attempt and inflammatory markers in both the cerebrospinal fluid and the plasma. Post mortem studies have shown an increase in microglial activation in the brain tissue of suicide victims. However the relationship between peripheral and central inflammation in suicide is probably mediated by complex biological processes that are yet elucidated. An increase of blood S100B levels (biomarker of neurovascular damage; PMID 14530574) has been reported in adolescents with suicidal ideation vs. controls and independently of psychiatric disorder.

The investigators hypothesize that peripheral inflammation may alter the blood brain barrier, which normally acts as a filter to ensure proper neuronal functioning, in suicidal patients.

They propose to investigate peripheral inflammation, neurovascular permeability and miRNAs in suicidal behavior pathophysiology as biomarkers of suicidal behavior in depression

Description:

150 participants will be enrolled, divided into 3 groups:

• 50 Suicide attempters, i.e. currently depressed patients with a suicide attempt within the 8 last days (with a maximal lifetime number of 3 previous suicide attempts, including the most recent);

• 50 Affective controls, i.e. currently depressed patients without any lifetime history of suicide attempt;

• 50 Healthy controls (age- and gender-matched to patients' groups) with no lifetime history of psychiatric disorders.

The protocol includes two visits for patients (suicide attempters and affective controls) and only one visit (inclusion) for healthy controls.

The first visit is the inclusion visit (Day 0-Day 8). Day 0 is the date of the last suicide attempt for the suicide attempters group and the date of signature of the consent for the affective control and healthy control groups. All the visit exams will be performed within 8 days after Day 0.

The second visit takes place one month +/- one week after inclusion. At each visit, a clinical assessment will be performed to characterise psychopathology and suicidal characteristics. Blood samples will be obtained in order to measure inflammatory markers. An MRI will be performed on order to study white matter microstructure and brain functional connectivity networks.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: October 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Common inclusion criteria:

• Aged between 18 and 55 years old,

• Affiliated to a French National Social Security System

• Able to understand the nature, purpose and methodology of the study

• Able to give written informed consent

Specific inclusion criteria

Suicide attempters:

• Subject with a main psychiatric diagnosis of current major depressive episode according to DSM-5 criteria (the existence of psychiatric comorbidities is not a non-inclusion criterion)

• Subject with a recent history of proven suicide attempt (within the 8 days before inclusion)

• Subject with a history of maximum 2 previous lifetime proven SA

Affective controls:

• Subject with a main psychiatric diagnosis of current major depressive episode according to DSM-5 criteria (the existence of psychiatric comorbidities is not a non-inclusion criterion),

• Subject without any lifetime history suicidal behavior (proven, interrupted or aborted)

Healthy controls:

• Subject who have no current or past personal history of psychiatric disorders according to DSM5 criteria.

Non inclusion criteria

• History of psychotic disorders

• Diagnostic of illicit substance / alcohol use disorder within the last 6 months

• Current inflammation-related symptoms including fever and infectious or inflammatory disease

• Severe symptomatic or unstable medical condition (e.g., unstable endocrine or cardiovascular disease)

• Medical disorders affecting CNS function (e.g., history of severe head trauma, epilepsy, tumor)

• Current use of specific medications known to affect the immune system, such as corticosteroids, non-steroid anti-inflammatory drugs, aspirin and statins

• Contraindication to MRI or impossibility to assess, or doubt about a contraindication to the MRI: metallic artificial heart valve, pacemaker, cerebrovascular clips ferromagnetic materials, metallic foreign body that can be mobilized, in particular cerebral or intraocular, prosthesis ferromagnetic, impossibility of absolute immobility in supine position, claustrophobia.

• Vaccination in the last month

• Law protected or deprived of liberty subject

• Pregnant and breastfeeding women

• BMI > 30 kg/m2

• Having reached 6000€ annual compensation for participating to clinical trials

• Being in exclusion period for another study

Related Conditions & MeSH terms

• Depression
• Inflammation
• Suicide

Intervention

Biological:
• Blood samples
Blood samples will be collected at both visit between 8:30 a.m. and 10 a.m. and fasting from midnight.

Other:
• Hetero-questionnaires and auto-questionnaires
Questionnaires will be administrated at both visits to assess the suicide spectrum, the depression level and some personality traits. Heteroquestionnaires will be administrated during a clinical interview (1h) conducted by a psychiatrist or psychologist. Autoquestionnaires (45 min) will be completed by the participant himself.
• Magnetic Resonance Imaging (MRI)
MRI will be processed (at both visits for patients and at inclusion visit for healthy controls) to study between groups white matter microstructure and brain functional connectivity networks

Locations

Country	Name	City	State
France	University hospital	Montpellier

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Montpellier

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Level of blood S100B assayed in the 3 groups, a marker of cerebral and vascular lesions.		At inclusion
Primary	Level of blood S100B assayed in the 3 groups, a marker of cerebral and vascular lesions.		At 1 month follow-up
Secondary	Cytokines' concentration by multiplex ELISA (pg/ml)	C-C motif chemokine ligand (CCL)2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL20, CCL22, CCL26, C-X-C motif chemokine ligand (CXCL)10, Interleukin (IL)-1a, IL 1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23 p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL- 27, IL-31, interferon (IFN)-?, Tumor Necrosis Factor ðTNFÞ a, TNF ß and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)	At inclusion
Secondary	Cytokines' concentration by multiplex ELISA (pg/ml)	C-C motif chemokine ligand (CCL)2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL20, CCL22, CCL26, C-X-C motif chemokine ligand (CXCL)10, Interleukin (IL)-1a, IL 1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23 p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL- 27, IL-31, interferon (IFN)-?, Tumor Necrosis Factor ðTNFÞ a, TNF ß and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)	At 1 month follow-up
Secondary	Specific proteins measurement (pg/ml)	Specific proteins measurement (i.e. GFAP, NFL, UHC-L1, sGPR56, S100B, MBP and related proteins) using digital or classical ELISA or western blot	At inclusion
Secondary	Specific proteins measurement (pg/ml)	Specific proteins measurement (i.e. GFAP, NFL, UHC-L1, sGPR56, S100B, MBP and related proteins) using digital or classical ELISA or western blot	At 1 month follow-up
Secondary	FACS analysis on fresh blood	Determination of the number of white cells	At inclusion
Secondary	FACS analysis on fresh blood	Determination of the number of white cells	At 1 month follow-up
Secondary	FACS analysis on fresh blood	Description of the phenotype of white cells	At inclusion
Secondary	FACS analysis on fresh blood	Description of the phenotype of white cells	At 1 month follow-up
Secondary	FACS analysis on fresh blood	Percentage of cellular inflammatory marker	At inclusion
Secondary	FACS analysis on fresh blood	Percentage of cellular inflammatory marker	At 1 month follow-up
Secondary	Extraction of small and long RNA	Use of RNA-seq, RT-qPCR and digital PCR to quantify RNA	At inclusion
Secondary	Extraction of small and long RNA	Use of RNA-seq, RT-qPCR and digital PCR to quantify RNA	At 1 month follow-up
Secondary	Test of the capacity of leukocytes isolated from patients to provoke vascular inflammation and BBB permeabilization	These experiments will be performed using an in vitro model of vascular cell co-culture. The reactivity of leukocytes to pro-inflammatory challenges and cytokines will be tested.	At inclusion
Secondary	Test of the capacity of leukocytes isolated from patients to provoke vascular inflammation and BBB permeabilization	These experiments will be performed using an in vitro model of vascular cell co-culture. The reactivity of leukocytes to pro-inflammatory challenges and cytokines will be tested.	At 1 month follow-up
Secondary	White matter microstructure analysis	The ihMT (ihMTR) and MT (MTR) ratios will be performed in the apparently normal white and gray matter regions from regional white matter and gray matter atlases	At inclusion
Secondary	White matter microstructure analysis	The ihMT (ihMTR) and MT (MTR) ratios will be performed in the apparently normal white and gray matter regions from regional white matter and gray matter atlases	At 1 month follow-up
Secondary	White matter microstructure analysis	Value of the fraction of anisotropy (FA) along the skeleton of the Tract-based spatial statistics TBSS	At inclusion
Secondary	White matter microstructure analysis	Value of the fraction of anisotropy (FA) along the skeleton of the Tract-based spatial statistics TBSS	At 1 month follow-up
Secondary	White matter microstructure analysis	Extraction by anatomical region of FA, mean, axial and radial diffusivity [FSL software)	At inclusion
Secondary	White matter microstructure analysis	Extraction by anatomical region of FA, mean, axial and radial diffusivity [FSL software)	At 1 month follow-up
Secondary	White matter microstructure analysis	Value of diffusion of blood water D* (pseudocoefficient =perfusive composante) from different region based on regional atlases	At inclusion
Secondary	White matter microstructure analysis	Value of diffusion of blood water D* (pseudocoefficient =perfusive composante) from different region based on regional atlases	At 1 month follow-up
Secondary	White matter microstructure analysis	Value of diffusion of the tissue (ADC) from different region based on regional atlases	At inclusion
Secondary	White matter microstructure analysis	Value of diffusion of the tissue (ADC) from different region based on regional atlases	At 1 month follow-up
Secondary	White matter microstructure analysis	Value of fraction of perfusion fD* ( incoherent blood signal divided by total incoherent signal) from different region based on regional atlases	At inclusion
Secondary	White matter microstructure analysis	Value of fraction of perfusion fD* ( incoherent blood signal divided by total incoherent signal) from different region based on regional atlases	At 1 month follow-up
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Regional homogeneity	At inclusion
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Regional homogeneity	At 1 month follow-up
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Amplitude of low frequency fluctuations	At inclusion
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Amplitude of low frequency fluctuations	At 1 month follow-up
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Functional homotopy	At inclusion
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Functional homotopy	At 1 month follow-up
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Graph theory metrics	At inclusion
Secondary	Brain functional connectivity networks analysis : extraction of resting state functional connectivity metrics from functional atlas or by voxel	Graph theory metrics	At 1 month follow-up
Secondary	Cerebral morphometric extraction (3DT1): automatic segmentation	Evaluation of the volume from cerebral anatomical atlas	At inclusion
Secondary	Cerebral morphometric extraction (3DT1): automatic segmentation	Evaluation of the volume from cerebral anatomical atlas	At 1 month follow-up
Secondary	Cerebral morphometric extraction (3DT1): automatic segmentation	Evaluation of the surface from cerebral anatomical atlas	At inclusion
Secondary	Cerebral morphometric extraction (3DT1): automatic segmentation	Evaluation of the surface from cerebral anatomical atlas	At 1 month follow-up
Secondary	Cerebral morphometric extraction (3DT1): automatic segmentation	Evaluation of the cortical thickness from cerebral anatomical atlas	At inclusion
Secondary	Cerebral morphometric extraction (3DT1): automatic segmentation	Evaluation of the cortical thickness from cerebral anatomical atlas	At 1 month follow-up
Secondary	Cerebral blood analysis	Extraction of blood flow values from 3D PCASL acquisition from vascular atlas	At inclusion
Secondary	Cerebral blood analysis	Extraction of blood flow values from 3D PCASL acquisition from vascular atlas	At 1 month follow-up