How our genes can help us to treat depression and an exciting new development
Most of us know what depression is, but how many of us know that it is not only affecting the brain, but is a disorder of the body?
It is believed that depression is a combination of genetic, environmental (such as economic status and education), and psychological (such as stressful and traumatic events) factors. Those factors not only can affect the biological system in the brain but also parts of the entire body.
While pharmacological therapy with antidepressants is an important treatment for depression, there is still a significant number of patients who do not respond to it (called ‘treatment-resistant’), or experience serious side effects such as gastrointestinal disruptions, anxiety, agitation, and insomnia. Various research has been conducted to date in order to recognise and verify biomarkers involved in the response to antidepressant treatment that could be targeted in order to improve the treatment effectiveness and reduce side effects. A biomarker is a molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified.
Among others, gene expression is being used as an approach to understand the molecular mechanisms underlying depression… wait, too scientific, let’s take a step back for a second — what is gene expression and why it is important?
As we all know, our traits (such as the colour of our eyes, our height or our risk for certain diseases) are determined by the genetic information contained in our DNA (DeoxyriboNucleic Acid). Genes are parts of the DNA that spell out specific instructions — much like in a cookbook recipe — for making proteins. Proteins are the building blocks for everything in your body. Bones and teeth, hair and earlobes, muscles and blood, are all made up of proteins. This “protein-making” process is called gene expression.
Although every cell has two copies of each gene, each cell needs only certain genes to be switched on in order to perform its particular functions. The unnecessary genes are switched off. However, sometimes, a gene contains a change that disrupts the gene’s instructions. A change in a gene can occur spontaneously (no known cause), or it can be inherited. Changes in the coding that makes a gene function can lead to a wide range of conditions and diseases.
It has now been a few years that we, and other researchers, have been trying to understand how the expression of genes can influence depression and how it can help to improve the way we treat it.
In our recent review, we have presented several studies that looked at the expression levels of various genes in patients with depression. Altogether, these studies have discovered a pattern of altered expression in many genes related to different biological systems including inflammation.
Does this mean that those who have certain genes that are less/more expressed could be less/more likely to respond to antidepressant therapy?
To try to answer this question, our group has carried out the BIODEP study. This is the largest non-interventional study (meaning that, apart from their usual ongoing treatment, no drug was given to participants) conducted so far to investigate candidate gene expression in depressed patients, characterised by their current depressive symptoms and by their response to antidepressant treatment. Interestingly, what we have found is that there are similarities in the expression of some genes (most of which are related to inflammation) between treatment-resistant depressed patients and depressed patients that were not taking any medication, whereas the expression of the same genes in patients that were responding to the treatment (meaning that they saw an improvement in their symptoms), was alike participants without depression. You can find more details about this study in a previous blog written by Melisa Kose “Genes related to inflammation and stress may help tailor treatments for depression”.
Knowing this, what can we do to improve the response to the antidepressant?
I previously mentioned that some of the genes that are more expressed in patients with depression are related to inflammation. This confirms that there is a connection between inflammation and depression, as also previously discussed in a few of our blogs and papers.
But what is inflammation in this context?
There are two types of inflammation: acute and chronic.
People are most familiar with acute inflammation which is the one that gives redness, warmth, swelling, and pain around tissues and joints and that occurs in response to an injury, like when you cut yourself or you twist your ankle. When the body is injured, your immune system releases white blood cells to surround and protect the area. It is also the one that helps fight infections, helps speed up the healing process.
In contrast, when inflammation gets turned up too high and lingers for a long time, and the immune system continues to pump out white blood cells and chemical messengers that prolong the process, that’s known as chronic inflammation and this is what I will refer to as inflammation in this blog.
This means that we could target inflammation and try to reduce it to improve the response to antidepressants. Our group, as part of the NIMA consortium founded by the Wellcome Trust, is running a clinical trial (ATP trial) that aims to test whether a new anti-inflammatory drug has the potential to treat patients suffering from depression and whose symptoms remain despite current medications.
In particular, this trial (ATP) is based on the founding from the BIODEP study showing that one of the genes altered in depression is the P2X7 receptor (P2X7R). The P2X7 receptor is produced by immune cells in the brain. Laboratory experiments have shown that the P2X7 receptor can trigger inflammation and drugs that block the P2X7 receptor can reduce inflammatory activation of immune cells. We believe that inflammation of the brain can cause depression in some people and that a drug blocking this receptor may improve the response to the antidepressant by blocking the inflammatory response of immune cells in the brain.
So, how can our genes help us to treat depression?
The clinical practice continues to be a trial-and-error method that requires multiple treatment studies to reach adequate improvement of symptoms for a majority of MDD patients. Thus, there is an urgent need to personalize antidepressant treatment by maximizing the likelihood of improvement. The use of the measurement of gene expression levels could be particularly helpful in the clinical setting, for an early prediction of treatment response in depressed patients. In fact, it could help to develop personalized antidepressant treatment, maximizing the likelihood of improvement and minimizing the risk of adverse events.