Decoding Depression
- Luca Sforzini
- 2 minutes ago
- 4 min read
Could the activity of our genes hold the clues to the biological secrets of depression and open new doors for treatment?
Depression is a complex condition. We know its symptoms well, but we still do not fully understand what happens in the body when someone is depressed. Also, not all individuals with depression are the same, and this diversity may arise from differences in biology – the many bodily processes that constantly shape the way we are and behave.
As both a psychiatrist and researcher, I find this question deeply fascinating.
If we could decode the biological changes behind depression, it could completely transform how we understand those who live with it and, most notably, how we treat it.
In two recently published studies, carried out through collaboration between UK and Italian researchers, we explored exactly these questions:
What are the biological mechanisms that underlie depression, particularly those linked to the immune system?
And can these biological markers help us predict who might benefit from anti-inflammatory treatment?
Depression and the immune connection
Around one in three people with depression show signs of inflammation, meaning their immune system is activated, as if fighting an infection. Normally, this response protects us against harm. But if chronically sustained, the immune system can stay switched on, potentially contributing to the symptoms of depression.
What’s more, people with depression and inflammation often respond less well to standard antidepressants. That’s why researchers are exploring whether anti-inflammatory medications might help this subgroup, for whom we clearly need new and alternative treatments. And this is exactly the main aim of a large study we are coordinating, called ASPIRE, together with many other research centres around the world, as we already covered in a recent blog article.
Understanding how inflammation affects our bodies and minds, and why it is activated in a relevant proportion of people with depression, could help us deepen our understanding of these individuals and to find more effective and more tailored treatments.
The role of gene expression
To study the relationship between depression and inflammation at its roots, we looked at gene expression, which is essentially how active our genes are. Think of it as seeing which “light switches” in our genetic code are turned on or off. This activity determines which biological functions are at work.
In particular, using a technology called RNA sequencing, we measured the activity of thousands of genes in blood samples from people with depression. By analysing these patterns, we can begin to map which biological processes are active – and which are quiet – in different types of depression, including the one associated with inflammation.
In our first study, published last year, we found that people with depression and higher inflammation showed greater activity in genes related to the immune system and metabolism, that is how our body creates and uses energy.
Of note, even people with low inflammation using clinical blood tests had evidence of immune activation, confirming that with gene expression we might observe a larger proportion of people with depression with activation of the immune system compared with standard inflammatory markers. On the other hand, high inflammation also affected genes involved in metabolism besides immune-related ones.
Meanwhile, people with depression but no inflammation showed a different biological signature: a reduced activity in genes related to cell growth and repair. This might reflect a kind of protective mechanism, shielding them from some of the damaging effects of inflammation.
We also identified unique gene expression patterns in people who responded well to antidepressants, showing changes linked to both reduced immune activity and enhanced brain protection. These biological clues could help explain why some treatments work for certain people but not others.
Can anti-inflammatory treatment help?
In our second study, published just a month ago, we focused on a clinical trial testing minocycline, an antibiotic with anti-inflammatory properties. All participants had depression that hadn’t improved with antidepressants and showed at least some signs of inflammation.
When we compared their gene activity, we found that, before treatment began, people who later responded to minocycline had distinct immune activity. Their immune system was “on the move”, showing markers of immune cell movement and activation.
Those who didn’t respond lacked these immune signatures.
Interestingly, by the end of the four-week treatment, these differences had disappeared, suggesting that it is the starting biological state (the activated immune state, in this case), and not just the medication, that determines who benefits most.
This could be a vital clue for future precision psychiatry: identifying who might respond to anti-inflammatory treatments before they start these medications.
Toward a more personalised future in psychiatry
Depression, like most medical conditions, is not one-size-fits-all. Understanding its biological diversity means recognising that not every patient’s depression looks – or behaves – the same.
The immune system is a crucial piece of that puzzle.
By uncovering how genes and immunity interact in depression, we move one step closer to precision psychiatry, where treatments are tailored to each individual’s biology.
Our findings offer hope that, one day, we’ll be able to match patients with the therapies most likely to help them, transforming depression care from a process of trial and error to one of true personalisation.
And perhaps, in doing so, we’ll come closer to understanding not just the science of depression, but the people who live with it every day.
