The Science Behind Inflammation’s Hidden Role in Depression

New research underscores the role of the immune system in depression, linking inflammation to poor response to standard antidepressants and highlighting the importance of personalized medicine in addressing different biological patterns in depressed individuals.

A collaborative study between researchers from the UK and Italy has uncovered new insights into the biological mechanisms of major depressive disorder (MDD), with a particular focus on the role of the immune system.

The researchers examined “gene expression,” which refers to the process by which the instructions in our genes are activated, influencing bodily functions.

The Link Between Inflammation and Depression

About one in three people with depression show elevated levels of inflammation, which is the body’s immune response to potential threats, 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.

People with both depression and inflammation are less likely to respond to standard antidepressants and may benefit from additional treatments that target the immune system, such as anti-inflammatory therapies. Understanding the biological processes behind this inflammation could help improve treatment options for individuals who do not respond to traditional antidepressants.

“In depression, as in almost every medical condition, one size does not fit all. Understanding the diversity of people with depression means also recognising the different biological patterns in action. As the field of precision medicine advances, psychiatry must keep pace.”

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 the metabolic activity.

Gene Expression Profiles and Antidepressant Response

The study found that that even with moderately increased inflammation, there is a significant activation of immune-related genes, while people with depression and very high levels of increased inflammation there is 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.”

Professor Annamaria Cattaneo, King’s IoPPN

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 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 personalised approaches.”

Professor Carmine Pariante, King’s IoPPN

Reference: “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, Moira Marizzoni, Chiara Bottanelli, Veronika Kunšteková, Valentina Zonca, Samantha Saleri, Melisa Kose, Giulia Lombardo, Nicole Mariani, Maria A. Nettis, Naghmeh Nikkheslat, Courtney Worrell, Zuzanna Zajkowska, Linda Pointon, Philip J. Cowen, Jonathan Cavanagh, Neil A. Harrison, Marco A. Riva, Valeria Mondelli, Edward T. Bullmore, the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, Annamaria Cattaneo and Carmine M. Pariante, 13 September 2024, Molecular Psychiatry.DOI: 10.1038/s41380-024-02736-w