While depression has long been associated with social factors, such as bereavement or trauma, scientists are beginning to unravel the role of our body’s defence system in this debilitating condition.
As we reported previously, peripheral markers of the immune response, broadly termed ‘pro-inflammatory cytokines,’ have been found in patients with major depressive disorder (MDD), as well as those who go on to develop the condition. Inflammatory markers even predict reduced treatment response to antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). As such, the addition of anti-inflammatory drugs to existing treatment protocols may further ameliorate depressive symptoms in some patients.
In addition to elevated pro-inflammatory cytokines, several genes related to immune functioning are overexpressed in those with depression relative to healthy adults. Within our DNA, genes encode for different proteins, including cytokines, and the process of reading and rewriting genetic codes into proteins is facilitated by ribonucleic acid (RNA). To measure the expression of specific genes, researchers collect tissue samples, which are then analysed for a specific type of RNA, messenger RNA, across various locations in the genome. Thus, gene expression studies lend insight into the functional properties of our genes and how these may vary across tissues or disease states.
Importantly, in depression, altered gene expression may represent a biomarker of the depressed state over and above depressive traits. This hypothesis has been supported by longitudinal follow-up of patients with MDD over two years, which showed that alterations in expression normalise with recovery.
Compelled by this emerging evidence, researchers at the University of Cambridge and their collaborators in the MICA Immuno-psychiatry consortium sought to test whether the expression of genes related to innate and adaptive immunity varied across individuals with and without MDD. Moreover, the researchers examined whether these differences were likely to replicate across two, case-control studies.
Dr. Gwenaël Leday of the Medical Research Council Biostatistics Unit, Dr. Petra Vértes of the Department of Psychiatry and the team identified sets of genes that were differentially expressed in whole blood samples collected from patients with MDD and healthy adults from two cohorts: the GlaxoSmithKline-High-Throughput Disease-specific Identification Program (GSK-HiTDiP) study and the Janssen Brain Resource Company (Janssen-BRC) study. Both studies balanced the MDD groups, so they contained roughly equal numbers of patients with and without comorbid generalised anxiety disorder.
Results of the study, published last month in Biological Psychiatry, identified 165 genes with significantly different expression across MDD and healthy control groups. Critically, these same 165 genes showed altered expression in both the GSK-HiTDiP cohort and the Janssen-BRC study, suggesting high replicability—a key step toward generalisability to others with MDD.
Further work will be needed to determine the contributions of genetic and environmental factors, as well as the role of altered cell counts, in the gene expression changes observed in the study. As a first step, whole blood gene expression from the GSK-HiTDiP and Janssen-BRC studies was compared to cell-type specific gene expression from an independent dataset. Interestingly, coexpression of the ninety innate immunity genes was clustered in monocytes and neutrophils—cells involved in the innate immune response. Coexpression of the seventy-five adaptive immunity genes was greatest in T cells and erythroblasts.
Since the MDD groups showed both over- and under-expression of immune genes, the authors determined the degree to which these changes were coupled across participants. They found a strong coupling between the two effects, meaning that individual patients may be located by a single number—or “score”—on a spectrum of coupled change in innate and adaptive immune function. The most inflamed MDD patients were identified by this score, suggesting that it may be a useful biomarker for defining an abnormally inflamed subgroup of MDD patients.
Overall, findings provide replicable evidence for immune gene markers of MDD, which can be measured readily in whole blood samples. The authors note that the use of pre-existing data limited their ability to fully assess participants’ immune function. Vértes emphasised the importance of measuring this in future work. “It would be important to know whether the transcriptomic changes we see in depression are also related to other immune markers such as [C-reactive protein], or various cytokines, or changes in specific immune cell counts. We hope our results will highlight the need for including immune markers in future studies in mental health research.”
Leday and Vértes hope their results pave the way for blood-based biomarkers of treatment response, which could be used to evaluate the efficacy of novel immune therapies within individual patients.
“The ultimate aim is to identify subsets of patients that might respond better when treated with anti-inflammatory drugs rather than conventional anti-depressants alone. Given the high incidence of depression and the fact that around 30% of patients are unresponsive to standard treatments this could be truly transformative for mental health,” said Vértes.
They point out that the brain and immune system have traditionally been studied separately, but a growing number of studies, including two consortia led by senior author Professor Ed Bullmore, are now turning the tide. These results and others have laid the foundation for additional studies, such as the BIODEP consortium, which will collect both brain and immune data from the same individuals.
BIODEP will give us access, for the first time, to […] detailed immune profiles and high-quality neuroimaging in a well-characterized sample on major depression. The study includes [four groups:] healthy volunteers and untreated patients with depression, as well as a group of patients that responded well to standard treatment and an unresponsive group.
The authors note that future work is this area rests upon strong collaborations between academia and industry. Two pharmaceutical companies, GSK and Janssen-BRC, shared data for this project, and the Cambridge researchers benefitted greatly from the expertise of co-author Dr. Gayle Wittenberg of Janssen.
Written by Maggie Westwater
Cover image: “DNA lab” by University of Michigan School for Environment and Sustainability. Licensed under CC BY 2.0.