Genes Related to Inflammation and Stress May Help Tailor Treatments for Depression

Summary: Gene expression study reveals it is possible to distinguish between those with treatment-resistant depression and those with major depressive disorder who respond to antidepressants based on levels of inflammation and the presence of molecular mechanisms that spark inflammation into action.

Source: King’s College London

In addition, these findings could potentially help towards developing personalised treatments for depression that involve the use of anti-inflammatories.

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.

Published in Translational Psychiatry, the study examined the blood from 130 patients with major depressive disorder (MDD) and 40 healthy controls to understand how gene expression – the process which signals the production of new molecules – could be used to distinguish those patients with treatment-resistant depression (TRD) from those who are responsive to medication. The participants were recruited as part of the Biomarkers in Depression (BIODEP) Study.

About 1 in 5 people suffer from depression in the UK and up to one third of these are considered resistant to treatment, which means that medication has no measurable effect and they have fewer options for managing their depression.

Lead author on the paper, Dr Annamaria Cattaneo from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) King’s College London said: ‘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. In this study we show for the first time that it is possible to distinguish patients with depression who do not respond to medication from those who are responding to the antidepressant medication, based on the levels of well-known measures of inflammation and the presence of molecular mechanisms that put this inflammation into action. This could potentially provide a means to assess which treatment options may be more beneficial from the outset.’

The researchers observed notably stronger molecular signs of inflammation and stress in both the patients who were not responding to antidepressant treatment and patients who were medication-free, compared with patients with depression who were responsive to medication and healthy controls. These findings support the growing evidence that patients that do not respond to antidepressants or have untreated depression have heightened inflammation compared with controls.

Previous research has shown that high levels of C-reactive protein (CRP) in the blood indicate some degree of inflammation in the body and, in the present study, researchers found higher levels of blood CRP in both patients that were resistant to treatment and medication-free patients compared with patients with depression who were responsive to medication as well as healthy controls. Likewise, researchers 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.

Some of the 16 genes measured in this paper had never before been measured in human blood.

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This shows a depressed woman
About 1 in 5 people suffer from depression in the UK and up to one third of these are considered resistant to treatment, which means that medication has no measurable effect and they have fewer options for managing their depression. Image is in the public domain.

Researchers 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 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.

Senior author of the study, Professor Carmine Pariante from the IoPPN, King’s College London said: ‘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. While much of drug-based intervention currently relies on a ‘trial and error’ approach, studies such as this implore investigation into identifying sub-groups of patients with depression – such as treatment resistant patients with inflammation – so that patients may be guided directly to treatment strategies which work best for them.’

Funding: This work was supported by the Wellcome Trust Strategic Award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium; this Consortium includes funding from Janssen Pharmaceutica, Lundbeck, GSK and Pfizer. Further support to the work was obtained from the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR Cambridge BRC (Mental Health) and the Cambridge NIHR BRC Cell Phenotyping Hub. Professor Pariante is a NIHR Senior Investigator.

About this genetics research article

Source:
King’s College London
Media Contacts:
Franca Davenport – King’s College London
Image Source:
The image is in the public domain.

Original Research: Open access
“Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study”. by Annamaria Cattaneo, Clarissa Ferrari, Lorinda Turner, Nicole Mariani, Daniela Enache, Caitlin Hastings, Melisa Kose, Giulia Lombardo, Anna P. McLaughlin, Maria A. Nettis, Naghmeh Nikkheslat, Luca Sforzini, Courtney Worrell, Zuzanna Zajkowska, Nadia Cattane, Nicola Lopizzo, Monica Mazzelli, Linda Pointon, Philip J. Cowen, Jonathan Cavanagh, Neil A. Harrison, Peter de Boer, Declan Jones, Wayne C. Drevets, Valeria Mondelli, Edward T. Bullmore, the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium & Carmine M. Pariante. Translational Psychiatry.


Abstract

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study

The mRNA expression signatures associated with the ‘pro-inflammatory’ phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.

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