Summary: A gene expression study shows it is possible to distinguish people with treatment-resistant depression from those with major depressive disorder who respond to antidepressants by measuring inflammation levels and the molecular pathways that activate inflammation.
Source: King’s College London
These findings may help guide the development of personalised depression treatments that incorporate anti-inflammatory approaches.
Led by King’s College London, the research team included collaborators from IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Italy), University of Milan, University of Cambridge, University of Oxford, University of Glasgow, Cardiff University and Janssen Pharmaceutica.
Published in Translational Psychiatry, the study analysed blood samples from 130 patients with major depressive disorder (MDD) and 40 healthy volunteers to determine whether whole-blood gene expression patterns could separate people with treatment-resistant depression (TRD) from those who respond to antidepressant medication. Participants were recruited through the Biomarkers in Depression (BIODEP) Study.
Depression affects roughly one in five people in the UK, and up to one third of those with depression do not respond adequately to standard antidepressant treatments. For these individuals, effective treatment options are limited and often harder to find.
Dr Annamaria Cattaneo from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, lead author of the study, said: “Although increased inflammation in depression is well documented, the biochemical mechanisms behind it are not fully understood. In this study we demonstrate that patients who do not respond to antidepressants can be distinguished from those who do respond based on established inflammatory markers and the molecular machinery that activates inflammation. Identifying these biological signatures could help clinicians select therapies that are more likely to benefit each patient from the start.”
The researchers found stronger molecular signals of inflammation and biological stress in both treatment-resistant patients and those not currently taking medication, compared with antidepressant-responsive patients and healthy controls. These results add to growing evidence that untreated depression and antidepressant-resistant depression are associated with higher levels of inflammation.
Consistent with prior work, the study observed elevated blood levels of C-reactive protein (CRP) in treatment-resistant and medication-free patients compared with responsive patients and controls. In addition, expression of several inflammation-related genes—such as IL-1-beta, IL-6, TNF-alpha and P2RX7—was higher in the treatment-resistant and drug-free groups. Some of the 16 genes assessed in this analysis had not previously been measured in human blood.
Beyond inflammatory markers, the team assessed stress-related molecular indicators and found that both treatment-resistant and drug-free patients had reduced levels of glucocorticoid receptor mRNA. These receptors play a central role in the body’s hormonal response to stress—by binding cortisol and related hormones—which helps regulate inflammation and stress reactivity. Fewer receptors can weaken this buffering system and may increase vulnerability to more severe depressive symptoms.
Professor Carmine Pariante, senior author and member of IoPPN at King’s College London, commented: “This study clarifies mechanisms linking inflammation and depression and points toward more personalised psychiatry. Rather than relying on trial-and-error prescribing, we should be aiming to identify biologically distinct subgroups—such as patients with inflammation-driven, treatment-resistant depression—so clinicians can choose the most appropriate treatment strategies earlier.”
Funding: The research was supported by the Wellcome Trust Strategic Award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, which includes funding from Janssen Pharmaceutica, Lundbeck, GSK and Pfizer. Additional support came from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR Cambridge Biomedical Research Centre (Mental Health), and the Cambridge NIHR BRC Cell Phenotyping Hub. Professor Pariante is a NIHR Senior Investigator.
About this genetics research article
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King’s College London
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Franca Davenport – King’s College London
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Original research: Open access. Citation: “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.” Annamaria Cattaneo et al., Translational Psychiatry. DOI: 10.1038/s41398-020-00874-7
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 molecular mRNA signatures that characterise the pro-inflammatory subtype of depression—and how these signatures differ across depression subtypes and respond to antidepressants—remain incompletely defined. In this study, the authors examined 130 patients with depression (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy control participants from the BIODEP cohort. Using whole-blood quantitative PCR, they measured expression of 16 candidate mRNAs, including interleukins IL-1-beta and IL-6, TNF-alpha, macrophage migration inhibitory factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, chemokines CCL2 and CXCL12, C-reactive protein (CRP), alpha-2-macroglobulin (A2M), aquaporin-4 (AQP4), ISG15, STAT1 and USP-18.
Most genes measured were differentially regulated among groups. Treatment-resistant and drug-free patients displayed a clear pro-inflammatory profile with higher expression of P2RX7 and several pro-inflammatory cytokine and chemokine mRNAs, alongside evidence of glucocorticoid resistance—lower GR and higher FKBP5 expression. Responsive patients showed an intermediate profile and additionally had lower CXCL12 expression. Using binomial logistic models, the researchers identified a six-mRNA signature (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) that reliably distinguished treatment-resistant from responsive patients, even after accounting for other differing factors such as anxiety, childhood maltreatment history and serum CRP. The authors recommend replication in larger, longitudinal cohorts and testing whether this mRNA profile can predict which patients might benefit from adjunctive anti-inflammatory treatment strategies for treatment-resistant depression.