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

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.

Study Overview

• Status: Recruiting
• Conditions: Inflammation; Cognitive Dysfunction; Genetic Predisposition to Disease; Endotoxemia; Major Depressive Disorder; Blood Brain Barrier Defect
• Intervention / Treatment: 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

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Egle Milasauskiene, MD; Phone Number: +37063458861; Email: egle.milasauskiene@lsmu.lt

Study Locations

• Lithuania
  • Kaunas, Lithuania, 50161
    • Recruiting
    • Psychiatry Department, Hospital of Lithuanian University of Health Sciences Kaunas Clinics
    • Contact: Egle Milasauskiene, MD; Phone Number: +37063458861; Email: egle.milasauskiene@lsmu.lt
  • Kaunas, Lithuania
    • Recruiting
    • Psychiatry Department, Hospital of Lithuanian University of Health Sciences Kaunas Clinics
    • Contact: Egle Milasauskiene, MD; Email: egle.milasauskiene@lsmu.lt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• 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.

Description

Inclusion Criteria:

• ≥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.

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.; to determine cognitive dysfunction; Diagnostic test: Venous blood samples; to measure levels of cytokines, endotoxin, and genetic markers.; Diagnostic test: brain MRI; to evaluate BBB permeability to water, brain structure volumes, white matter integrity, cerebral perfusion, and neurometabolite concentrations; Diagnostic test: the Montgomery-Åsberg Depression Rating Scale; to measure severity of depressive symptoms; Other: questionnaire prepared by the researchers; 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; 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.; to determine cognitive dysfunction; Diagnostic test: Venous blood samples; to measure levels of cytokines, endotoxin, and genetic markers.; Diagnostic test: brain MRI; to evaluate BBB permeability to water, brain structure volumes, white matter integrity, cerebral perfusion, and neurometabolite concentrations; Diagnostic test: the Montgomery-Åsberg Depression Rating Scale; to measure severity of depressive symptoms; Other: questionnaire prepared by the researchers; collecting sociodemographic data and information about smoking status, BMI, data on the course of MDD, past treatment, comorbid diseases, and current use of medications.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain MRI	Perform a multiparametric brain MRI assessment of depressed patients and a control group. We hypothesize that, among patients with MDD, there are changes in blood-brain barrier permeability to water, levels of neuroinflammation and perfusion, and structural neurodegenerative changes that are associated with blood plasma endotoxin and cytokine concentrations.	Day 1
Cognitive dysfunction	Evaluate cognitive functions. We hypothesize that low-grade neuroinflammation negatively affects cognitive performance among patients with MDD.	Day 1
Covariates	Perform a subgroup analysis on neuroinflammation markers based on individuals' BMI and smoking status.	Day 1
Genetic markers	Determine possible genetic markers among MDD subjects in relation to blood plasma endotoxin and inflammatory cytokines concentrations that could predict a genetic predisposition to neuroinflammation, neurodegeneration and the development of MDD.	Day 1

Collaborators and Investigators

• Sponsor: Lithuanian University of Health Sciences
• Investigators: Principal Investigator: Vesta Steibliene, PhD, MD, Proffesor, Lithuanian University of Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: January 2, 2024
• First Submitted That Met QC Criteria: January 11, 2024
• First Posted (Actual): January 12, 2024

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Endotoxin; Major depressive disorder; Genetic polymorphisms; Multiparametric Magnetic Resonance Imaging; Cognitive dysfunction; Blood Brain Barrier
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Infections; Mood Disorders; Systemic Inflammatory Response Syndrome; Neurocognitive Disorders; Disease Attributes; Sepsis; Cognition Disorders; Bacteremia; Toxemia; Disease Susceptibility; Depression; Depressive Disorder; Inflammation; Cognitive Dysfunction; Endotoxemia; Depressive Disorder, Major; Genetic Predisposition to Disease
• Other Study ID Numbers: DEPRINFLAMATION-Versija 3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No