Gene Activity in Depression Linked to Immune System and Inflammation

Summary: A new study reveals that inflammation and immune system activation are closely linked to major depressive disorder (MDD), particularly in those resistant to standard antidepressants. Researchers analyzed gene expression in people with depression, finding increased immune-related gene activity, especially in those with higher inflammation.

These findings suggest that targeting the immune system may be a potential treatment for those who don’t respond to traditional antidepressants. The study emphasizes the need for personalized medicine approaches in treating depression, based on individual biological differences.

Key Facts:

  1. About 1 in 3 people with depression have high levels of inflammation.
  2. Immune-related genes are more active in individuals with inflammation and depression.
  3. Targeting inflammation could help patients who don’t respond to standard antidepressants.

Source: King’s College London

A new study, conducted in a shared effort between U.K. and Italian researchers offers novel insights about the biological mechanisms behind major depressive disorder (MDD), and especially on the role of the immune system.

The study specifically analyzed “gene expression,” the process by which the instructions that are held in our genes are expressed, influencing bodily functions.

The work is published in the journal Molecular Psychiatry.

The study found that individuals with depression who had increased levels of inflammation showed increased activity of genes linked with the immune system and with metabolic activity. Credit: Neuroscience News

Approximately 1 in 3 people with depression have high levels of inflammation, an activation of the immune system, our body’s defense against potentially harmful stimuli, such as infections.

During stress, inflammation is activated to effectively fight threats, and it is likely the reason that the immune system is activated in depression, which is a condition of chronic stress.

Individuals with depression and inflammation present a greater risk of not responding to standard antidepressants, and they might benefit from additional treatments targeting the immune system, such as anti-inflammatories.

Thus, understanding the biological mechanisms underpinning this increased inflammation could also shed light on ways to help people with depression, especially those who do not respond to standard antidepressants.

“In depression, as in almost every medical condition, one size does not fit all. Understanding the diversity of people with depression means also recognizing the different biological patterns in action. As the field of precision medicine advances, psychiatry must keep pace,” says Dr. Luca Sforzini, King’s IoPPN.

Researchers used a technology called “mRNA sequencing” to measure the activity of all the genes expressed in the blood. The study found that individuals with depression who had increased levels of inflammation showed increased activity of genes linked with the immune system and with metabolic activity.

The study found that even with moderately increased inflammation, there is a significant activation of immune-related genes. People with depression and very high levels of increased inflammation have additional activation of genes involved in metabolic processes, that is, related to how we produce, consume and store energy, relevant, for example, to fat and sugar functions in the body.

“With gene expression, we might capture something different from what is clinically observable, something ‘intermediate’ between what’s encoded in our genes and what is ultimately manifested. Such research might therefore help to fully understand the biology of depression,” says Professor Annamaria Cattaneo.

In the study, the researchers also identified a specific gene expression profile in individuals who had effectively responded to an antidepressant, with changes in biological mechanisms relevant not only to inhibition of the immune function but also to the protection of the brain, suggesting that these biological processes may play a role in these people’s recovery from depression and in the way antidepressants work.

Overall, the present study demonstrates the importance of gene expression in understanding the biology of depression and of antidepressant actions.

Our genes and their associated biological patterns might explain the differences between different types of depression, such as those who do or do not respond to standard antidepressants, or those who do or do not develop medical comorbidities like diabetes and cardiovascular problems.

“Our research highlights the need to understand the biological basis of different types of depression, shifting away from the traditional approach, towards more targeted and personalized approaches,” says Professor Carmine Pariante.

About this genetics and depression research news

Author: Luca Sforzini
Source: King’s College London
Contact: Luca Sforzini – King’s College London
Image: The image is credited to Neuroscience News

Original Research: Open access.
Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation” by Luca Sforzini et al. Molecular Psychiatry


Abstract

Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation

Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression.

We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls.

We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 ‘not inflamed’ (CRP < 1 mg/L), n = 31 with ‘elevated CRP’ (1–3 mg/L), and n = 35 with ‘low-grade inflammation’ (>3 mg/L).

We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1–3 group showed stronger immune activation than the CRP > 3 group.

The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this ‘non-inflamed’ depressed group.

We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response.

In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders.

The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual’s trajectory toward immunometabolic depression and/or treatment-non-responsive depression.

The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.