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Inflammation might be one of the keys to unlock depression

Our new research shows that more people with depression than previously estimated could have increased activation of their immune system

What are we looking at?

If you are familiar with Inspire the Mind, you will probably know that depression is a complex mental health condition that in a significant proportion of people is associated with increased levels of inflammation.

As a psychiatrist and a researcher at King’s College London, I am particularly interested in understanding the biological mechanisms involved in this intricate relationship, as they might help identify a subgroup of individuals with depression who could benefit from specific interventions targeting inflammation, for both treatment and prevention.

In our recently published research, we tried to broaden our understanding of the relationship between depression and inflammation.

We analysed specific markers (mRNAs) in the blood of people with and without depression and we showed that more depressed patients than previously thought have an increased activation of their immune system. Notably, this immune activation is present not only in people classically considered as having inflammation, such patients who do not respond to routinely-available antidepressants, but also in other groups of depressed patients, opening novel paths to understanding the biology of depression.

Let’s take a step back.

What do we mean by inflammation and why is it so important?

Inflammation is the activation of the immune system and the natural response of our body to anything that is perceived as damage, such as an injury or an infection. It is therefore clearly a useful mechanism (especially in the short term) that helps us in maintaining our well-being.

However, just like many things in medicine (and life), what is good in some circumstances and/or in an adequate amount may become harmful when in excess.

Under certain conditions, indeed, inflammation can become chronic (sustained over time), or it can be triggered without an external threat. In these cases, inflammation is associated with – and can contribute to – a wide range of health problems, including mental health disorders such as depression.

What do we know about the relationship between depression and inflammation?

There is strong and consistent evidence of clinically-significant, "low grade" inflammation in around 20-30% of people with depression. However, the exact mechanisms behind the relationship between depression and inflammation remain a topic of ongoing research, and disentangling this evidence is indeed the keystone of my studies.

Notably, people with depression and inflammation are also less likely to respond to conventional antidepressant treatments, further highlighting the need for tailored research in this field.

What are we measuring when measuring inflammation? The importance of gene expression.

Most of the published research on inflammation in mental health uses the levels of a protein in the blood, called C-reactive protein (or CRP).

CRP is a protein produced by the liver in response to immune signals secreted by blood immune cells (the “white cells”) during inflammation. It is therefore widely used as a marker of inflammation (by measuring CRP levels in the blood) in clinical and research settings.

However, when we are measuring CRP (or any other protein) we are looking at the final product of a complex process called “translation” - translation of gene expression (mRNAs) into proteins.

In a nutshell, genes are segments of the DNA (deoxyribonucleic acid – the molecule that carries all the essential information to our lives). Genes are present in all our cells, but they can be “switched on or off” based on different circumstances, such as during inflammation. Once a gene is “switched on” (or activated), it sets a series of actions within a cell before we see its end product – protein. As such, first it is transcribed into a molecule called mRNA (messenger ribonucleic acid) and then translated into a protein.

With gene expression, the information encoded in our genes (what we broadly call the genotype) is translated into functional products, such as proteins, ultimately producing the entirety of our observable traits (what we call the phenotype), such as the colour of our eyes or our height.

Therefore, while the genotype can be considered like a file with all our information in it, the phenotype is how this information is interpreted and adapted to external circumstances.

By applying this to our research, the measurement of mRNA levels can tell us about this process in reverse, that is, if protein levels provide a reliable snapshot of what happened “behind the scenes”, at a gene level.

Usually, mRNA levels are the markers used to measure gene expression.

We all recently became familiar with the concept of mRNAs and their therapeutic potential. For example, mRNA vaccines have been developed for COVID-19 and other clinical conditions. In all these cases, a specific mRNA is used to produce the correspondent protein, that will help the body in exerting a clinical response.

Our new study

Here comes our new study, which we recently published in Translational Psychiatry.

We investigated whether some mRNA profiles, specifically those related to the immune system, can provide a broader understanding of the connection between depression and inflammation.

Interestingly, we found a higher mRNA expression of genes which encode for immune-related proteins in individuals with depression, independently of CRP levels. In fact, even depressed people with CRP levels that are normal, showing no evidence of inflammation, have increased levels of immune-related mRNAs.

This evidence suggests that the immune dysregulation in depression is not limited to the inflammation seen in elevated CRP levels alone, highlighting the complexity of immune processes and suggesting the involvement of additional biological mechanisms at play in the gene expression process.

The evidence we provide is an important piece of the puzzle, but we need to do more research to understand the exact mechanisms through which these immune-related gene expression patterns translate into inflammation at the protein level, like CRP.

By understanding this process, we can be more accurate in our diagnoses and effective treatments for depression, ultimately improving the lives of individuals living with this challenging mental health condition.

Professor Carmine M. Pariante, senior author of the study and Editor in Chief of Inspire the Mind, commented:

“These important findings will allow us to identify the molecular pathways involved in depression and also help to more accurately identify those who have different types of immune responses which could pave the way for more personalised approaches to treatment.”

Snapshot of the article in Translational Psychiatry

On the path to precision psychiatry

Summing up, inflammation is relevant to a large subgroup of people with depression, probably larger than we thought, but it is also complex, and we can see that in the many ways it can be measured.

To add to the complexity, it is important to highlight that not everyone with depression is inflamed. Just like not every person with depression will have the same clinical response to a specific treatment. Therefore, as researchers and clinicians, we should always remember this when treating people and when doing research.

Embracing the diversity and recognising shared biological alterations producing a disease, is not an easy task but one that could finally improve the way we manage the condition and truly advance the field towards a precision psychiatry.

“Lives can be meaningfully transformed. Real progress can be made, but only when we identify and test specific biological mechanisms known to affect symptoms — and then develop drugs that treat those symptoms”

Professor Andrew H. Miller and Doctor Charles L. Raison on Inspire the Mind.

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