The Relations Among Endotoxin, Inflammatory Cytokines, Cognitive Markers and Brain MRI Changes in Subjects With Depressive Disorder

NCT06203015 | Unknown

• 1 other identifier: DEPRINFLAMATION-Versija 3
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 2

Brief Summary

Major depressive disorder (MDD) is a chronic mental illness, with 60% lifetime risk of recurrence after the first MDD episode. Despite available treatment options for MDD, only about half to two-thirds of patients respond to first-line antidepressant treatment, and only 30% to 45% of patients achieve remission. Scholars assume that this low remission rate and high rate of treatment resistance are due to the polyetiological nature of the disease, the heterogeneity of the clinical picture of depression, and the lack of biomarkers to stratify MDD subtypes. The aetiology of MDD, although researched extensively, remains unclear. None of the known mechanisms alone explains the pathogenesis of depression, meaning that the interplay of several factors contributes to the development of MDD. Accumulated scientific evidence has supported the importance of the immune system in the etiopathogenesis of MDD. Until now, the cause of the low-grade inflammation observed in this subgroup of MDD patients has been unclear. In the proposed study, the investigators will test a new hypothesis of the immune theory of the development of MDD: the endotoxin hypothesis of neurodegeneration. This hypothesis states that endotoxin, causes or contributes to neurodegeneration. Blood plasma levels of LPS are normally low but are elevated during infections, gut inflammation, gum disease, and neurodegenerative diseases. Dysbiosis may promote increased intestinal permeability ("leaky gut"), which leads to bacterial translocation across the intestinal barrier and into the circulation, thus forming of LPS and LPS-binding protein complex, which triggers the secretion of cytokines. Data suggest that LPS-induced peripheral inflammation can activate neuroinflammation. However, it is not known whether a low-level persistent presence of LPS in the circulatory system can cause low-grade chronic neuroinflammation leading to neurodegeneration and/or symptoms of MDD. Based on existing preclinical and clinical research data, the investigators hypothesise that an increase in blood plasma endotoxin and peripheral cytokines induce BBB dysfunction, neuroinflammation and neurodegenerative processes in specific etiologically relevant structures of the brain and cause clinical manifestation of depressive symptoms and cognitive damage. In this study the investigators are also going to investigate the effects of single nucleotide polymorphisms of four genes in relation to blood plasma endotoxin and peripheral cytokines concentrations and clinical manifestation of MDD.

Conditions

Major Depressive Disorder; Inflammation; Cognitive Dysfunction; Endotoxemia; Genetic Predisposition to Disease; Blood Brain Barrier Defect

Keywords

Major depressive disorder; Inflammation; Endotoxin; Cognitive dysfunction; Genetic polymorphisms; Multiparametric Magnetic Resonance Imaging; Blood Brain Barrier

Outcome Measures

Primary Outcomes (2)

• Levels of blood plasma endotoxin and inflammatory cytokines between groups.

  To evaluate the concentrations of blood plasma endotoxin and inflammatory cytokines among patients with MDD and in a control group. We hypothesize that an increase in blood plasma endotoxin is associated with an increase in blood inflammatory cytokines in the group of patients with MDD.

  Day 1

• Severity and manifestation of depressive symptoms.

  Evaluate the severity and manifestation of different depressive symptoms. We hypothesize that endotoxin and inflammatory markers are associated with specific symptoms of MDD, allowing us to identify MDD patients with a specific LPS-induced/stimulated inflammatory depression subtype.

  Day 1

Secondary Outcomes (4)

• Brain MRI

  Day 1

• Cognitive dysfunction

  Day 1

• Covariates

  Day 1

• Genetic markers

  Day 1

Study Arms (2)

MDD patients

patients diagnosed with MDD (according to the WHO's \[2019\] International Classification of Diseases and related health problems categorization of mental disorders), diagnosed by a psychiatrist; ≥18 years old

Diagnostic Test: The Cambridge Neuropsychological Test Automated Battery.; Diagnostic Test: Venous blood samples; Diagnostic Test: brain MRI; Diagnostic Test: the Montgomery-Åsberg Depression Rating Scale; Other: questionnaire prepared by the researchers

Control group

Subjects who have not been diagnosed with any mental disorder in the past year; ≥18 years old

Diagnostic Test: The Cambridge Neuropsychological Test Automated Battery.; Diagnostic Test: Venous blood samples; Diagnostic Test: brain MRI; Diagnostic Test: the Montgomery-Åsberg Depression Rating Scale; Other: questionnaire prepared by the researchers

Interventions

The Cambridge Neuropsychological Test Automated Battery. DIAGNOSTIC_TEST

to determine cognitive dysfunction

Control group; MDD patients

Venous blood samples DIAGNOSTIC_TEST

to measure levels of cytokines, endotoxin, and genetic markers.

Control group; MDD patients

brain MRI DIAGNOSTIC_TEST

to evaluate BBB permeability to water, brain structure volumes, white matter integrity, cerebral perfusion, and neurometabolite concentrations

Control group; MDD patients

the Montgomery-Åsberg Depression Rating Scale DIAGNOSTIC_TEST

to measure severity of depressive symptoms

Control group; MDD patients

questionnaire prepared by the researchers OTHER

collecting sociodemographic data and information about smoking status, BMI, data on the course of MDD, past treatment, comorbid diseases, and current use of medications.

Control group; MDD patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The study is being conducted at the hospital of the Lithuanian University of Health Sciences Kaunas Clinics Psychiatry Clinic (inpatient department), and the Nervous System Diseases Outpatient Department.

You may qualify if:

• ≥18 years old
• signed informed consent
• patients diagnosed with MDD (according to the WHO's \[2019\] International Classification of Diseases and related health problems categorization of mental disorders) for MDD group.

You may not qualify if:

• diagnosis of other mental disorders during the past one-year period (for MDD group).
• diagnosis of any mental disorders within the past one-year period, previous suicide attempt, or current suicide risk identified in the study (for control group).
• diagnosis of somatic diseases that may affect changes in inflammatory factors in the body (for both groups)

Sponsors & Collaborators

• Lithuanian University of Health Sciences: lead

Study Sites (2)

Psychiatry Department, Hospital of Lithuanian University of Health Sciences Kaunas Clinics

Kaunas, 50161, Lithuania

RECRUITING

Psychiatry Department, Hospital of Lithuanian University of Health Sciences Kaunas Clinics

Kaunas, Lithuania

RECRUITING

Related Publications (1)

• Milasauskiene E, Burkauskas J, Jesmanas S, Gleizniene R, Borutaite V, Skemiene K, Vaitkiene P, Adomaitiene V, Lukosevicius S, Gradauskiene B, Brown G, Steibliene V. The links between neuroinflammation, brain structure and depressive disorder: A cross-sectional study protocol. PLoS One. 2024 Nov 20;19(11):e0311218. doi: 10.1371/journal.pone.0311218. eCollection 2024.

  PMID: 39565757 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood plasma

MeSH Terms

Conditions

Depressive Disorder, Major; Inflammation; Cognitive Dysfunction; Endotoxemia; Genetic Predisposition to Disease

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cognition Disorders; Neurocognitive Disorders; Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Disease Susceptibility; Disease Attributes

Study Officials

• Vesta Steibliene, PhD, MD

  Proffesor, Lithuanian University of Health Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Egle Milasauskiene, MD

CONTACT

+37063458861; egle.milasauskiene@lsmu.lt

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 2, 2024
• First Posted: January 12, 2024
• Study Start: June 1, 2022
• Primary Completion: June 1, 2024
• Study Completion: June 1, 2024
• Last Updated: January 12, 2024

Record last verified: 2024-01

Locations

LI (2)