Genes related to inflammation and stress may help tailor treatments for depression

In the UK, roughly 1 in 5 people suffer from depression; while many find that they have some degree of response to antidepressant treatment methods, up to one-third of people living with depression are considered to be resistant to treatment. This means that, despite the use of traditional treatments, these medications appear to have no measurable effect on their depression.


Unsurprisingly, those with treatment-resistant depression (TRD) often find that they have fewer options — especially pharmaceutically — available to them for managing their mental wellbeing. Though treatment-resistant, this doesn’t mean that they are untreatable, as Dr Etta Nettis explains perfectly in an earlier blog.


With this in mind, mental health research has shown increasing interest in finding ways that medicine can support those who are otherwise unsupported by conventional treatment strategies. There are quite a few approaches and angles that researchers have looked at over the years. One such approach is to look at the body’s chemical responses to stress, and in particular at the activation of the inflammatory system.


 

On the path to personalised treatments


New research from our laboratory, and other collaborators in the UK and Italy, has found that measuring levels of inflammation and stress-response in the blood may provide useful information to show which patients with depression will or will not respond to treatment with antidepressants.


As previously discussed in another of our blogs, identifying subgroups of depressed patients based on how their bodies and immune systems respond to stress can help developing personalised treatment plans for patients, in turn allowing patients to bypass the delay in getting the most helpful treatment for them. This may reduce time spent trying different antidepressants with little to no response.


Published in the scientific journal, Translational Psychiatry, our new study examines blood from 130 patients with major depressive disorder (MDD) and 40 healthy controls to understand how gene expression it the blood — the process which signals the production of new molecules such as those responsible for managing the immune system and stress response — could be used to distinguish those patients with TRD from those who are responsive to medication. The participants are part of the Biomarkers in Depression (BIODEP) Study, funded by the Wellcome Trust.


“While there is overwhelming evidence of increased inflammation in depression it is still unclear how exactly this occurs and what it looks like at the level of chemistry within the body.””

— DR ANNAMARIA CATTANEO, LEAD AUTHOR ON THE PAPER.


As also discussed in our blog, inflammation and stress-related responses in depression have been an area of great intrigue for quite some time now. Indeed, previous research has shown that high levels of C-reactive protein (CRP) in the blood indicate some degree of inflammation in the body.

Building on this framework, our research, led by Dr Cattaneo, finds higher levels of blood CRP in both patients that were resistant to treatment and medication-free patients, compared with patients with depression who are responsive to medication, as well as healthy controls.

Sixteen inflammation and stress-related genes have been measured in this study, some of which have never before been measured in human blood. As with CRP, researchers also reported that the expression of several inflammation-related genes (including IL-1-beta, IL-6, TNF-alpha, and P2RX7) was also increased in both treatment-resistant and medication-free patients.

 

So, what do these findings mean for patients with depression?

While inflammation is well-established as being linked to stress and MDD, it is also not a standard abnormality: not every person with depression will exhibit heightened inflammation.

The findings of this new research support the growing evidence that patients that do not respond to antidepressants or have untreated depression have heightened inflammation compared with controls.

Considering this link and the findings of this study, targeting inflammation appears to be a viable avenue for future clinical trials to examine the usefulness of anti-inflammatory medications to treat those with TRD.



We also examined indicators of stress and found that both the treatment-resistant and drug-free patients have reduced numbers of glucocorticoid receptors, which are involved in the body’s stress response. With reduced numbers of these receptors, the body’s ability to buffer stress through hormones such as cortisol is diminished, which increases the risk of more severe forms of depression.


“Our study has provided important insight into the mechanisms that can explain the link between inflammation and depression which will especially impact the future of personalised psychiatry.”

— PROFESSOR CARMINE PARIANTE, SENIOR AUTHOR OF THE PAPER.


As far as antidepressant treatments have come in the last 50 years, they still have quite a way to go. While much of the medication-based interventions for depression currently rely on a ‘trial and error’ approach, studies such as this highlight the importance of getting a more thorough and complex understanding of the individual patient so that they may be guided directly to treatment strategies which work best for them, through a personalised medicine based approach.


Yes, we still have a long road ahead of us, with unpredictable turns and bothersome bumps — but our group and other researchers in this field have, and continue to make fantastic strides, so that the future of mental health treatments can make the promise of effective medical support to all those who need it.


 

NOTE FROM THE EDITORS: The study was led by King’s College London and involved researchers from IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Italy), University of Milan (Italy), University of Cambridge, University of Oxford, University of Glasgow, Cardiff University, and Janssen Pharmaceutica. The sources of funding of the study, and any conflicts of interests, are detailed in the original paper.