Researchers have analyzed gene expression in people with major depressive disorder (MDD), finding increased gene activity related to the immune system, especially in those with higher levels of inflammation. This study reveals that inflammation and immune system activation are closely linked. These findings suggest that targeting the immune system could be a potential treatment for those who do not respond to traditional antidepressants.
The molecular mechanisms that may underlie major depressive disorder (MDD) are being explored by analyzing transcriptomic profiles, or gene expression, which may indicate how certain biological pathways are activated or inhibited in people with depression.
A new study, conducted in a joint effort between researchers in the United Kingdom and Italy, offers new insights into the biological mechanisms behind major depressive disorder (MDD) and, in particular, the role of the immune system.
The study specifically looked at “gene expression,” the process by which the instructions contained in our genes are expressed, influencing bodily functions. The work was published in the journal Molecular Psychiatry.
The research focuses specifically on a type of depression known as “immunometabolic depression,” which is linked to inflammation and changes in metabolism. 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 off threats, and it is likely the reason why the immune system is activated in depression, which is a condition of chronic stress.
Individuals with depression and inflammation are at increased risk of not responding to standard antidepressants and may benefit from additional treatments that target the immune system, such as anti-inflammatories.
Thus, understanding the biological mechanisms that underlie this increased inflammation may also shed light on ways to help people with depression, especially those who do not respond to standard antidepressants.
The researchers conducted a study of 139 participants, 105 of whom had MDD, and 34 were healthy controls. The researchers used a technology called “mRNA sequencing” to measure the activity of all genes expressed in the blood.
The participants with MDD were divided into three groups based on the levels of inflammation in their bodies, as measured by the amount of C-reactive protein (CRP) in their blood:
Non-inflamed group (CRP < 1 mg/L)
High-CRP group (1–3 mg/L)
Low-grade inflammation group (CRP > 3 mg/L)
CRP is a protein that indicates the presence of inflammation. The goal was to understand how inflammation impacts gene activity in people with MDD and whether this is related to the severity or type of depression.
Key Findings:
Immunometabolic pathways: People with higher levels of CRP (above 1 mg/L) had activation of pathways related to the immune system and metabolism. Interestingly, those with moderate CRP levels (between 1–3 mg/L) showed even greater activation of these pathways than the group with higher CRP levels.
Cell cycle protection: In the “non-inflamed” group (CRP < 1 mg/L), pathways linked to the cell cycle were more active, which may be a protective factor against immunometabolic abnormalities, which are observed in the inflamed groups.
Response to antidepressants: In addition, the study compared people with MDD based on their response to antidepressants: “responders”, “non-responders” and “unmedicated”. Those who responded to treatment showed an activation of immunomodulatory and neuroprotective pathways, which did not appear to depend on CRP levels. This suggests that the response to antidepressants may be associated with biological processes other than inflammation.
Treatment effects: In those who were still depressed and had low CRP levels, an inhibition of cell cycle pathways was observed. However, this inhibition was not seen in people who had responded to antidepressants.
What This Means?
The study identifies clear biological differences in MDD, related to both inflammation and response to treatment. It suggests that depression may have different subtypes based on how the body deals with inflammation and metabolism. Understanding these differences could help develop more personalized and effective treatments that target specific mechanisms that affect each person.
“Our research highlights the need to understand the biological basis of different types of depression, moving away from the traditional approach towards more targeted and personalized approaches,” says Professor Carmine Pariante, one of the study’s authors.
This precision medicine approach, which takes into account the unique molecular characteristics of each individual, could improve the chances of successful treatment of depression. In addition, the study offers new insights into immunometabolic and cell cycle pathways that may prevent or facilitate the progression to immunometabolic and/or treatment-resistant depression.
READ MORE:
Transcriptomic profiles in major depressive disorder: the role of immunometabolic and cell-cycle-related pathways in depression with different levels of inflammation.
Sforzini L, Marizzoni, M, Bottanelli C. et al.
Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02736-w
Abstract:
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.
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