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

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

Interventions

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.

Sponsors & Collaborators

• Lithuanian University of Health Sciences

  lead OTHER

Principal Investigators

• Vesta Steibliene, PhD, MD · Proffesor, Lithuanian University of Health Sciences

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2022-06-01

Primary Completion

2024-06-01

Completion

2024-06-01

Countries

• Lithuania

Study Locations