New research focusing on immune alterations in major depressive disorder finds suite of changes, beyond just C-reactive protein.
15 July 2024
By Emma Young
The idea that immune changes are linked to major depressive disorder (MDD) has been discussed for many years now. In fact, there's "compelling" evidence for this, write the authors of a recent paper in Translational Psychiatry. However, their work suggests that the nature of the immune changes has not been fully appreciated, with possible implications both for diagnosis and treatment.
Most research to date on altered immune function in people with MDD has focused on raised blood levels of one particular marker of inflammation: C-reactive protein (CRP). Between 20 and 30% of people with MDD have levels of CRP above 3mg/litre, which is suggestive of at least low grade inflammation. Recent research also suggests that raised CRP is a marker for MDD even when a suite of other variables, including age, sex, BMI, smoking, and exposure to childhood trauma are taken account. This has led to the argument that raised CRP should be considered a 'core' biological feature of depression.
However, raised levels of several other biomarkers of inflammation have been identified in patients with MDD, and other studies have found differences in the expression of a variety of genes between patients and healthy people. This work inspired Luca Sforzini at King's College London and colleagues to run what they believe is the first study to analyse the expression of known immune-related genes in people with a diagnosis of MDD and with varying levels of blood CRP, compared with a group of healthy controls.
The team analysed data on 128 UK-based adults with MDD, plus a group of 40 healthy controls. The participants with MDD were divided into three CRP sub-groups: less than 1 mg/L, suggestive of no inflammation; 1-3 mg/L, which indicated increased inflammation; and above 3 mg/L, suggestive of at least low grade inflammation. The healthy controls all had low levels of CRP.
To explore gene expression, the team analysed mRNA relating to a set of 16 immune-related genes in blood samples from the participants. This analysis revealed that nine were differently expressed in the patients compared with the controls, but with no differences between the CRP sub-groups. For example, five known pro-inflammatory genes (including TNF-alpha and IL-6), were up-regulated (in other words, there was more production of mRNA) in all three MDD sub-groups, compared with controls.
The team then ran a further analysis, comparing only the low, 'normal' CRP MDD sub-group and healthy controls. Despite the fact that both groups had similar, low CRP levels, there were still differences in the activation of other immune-related genes in people with and without MDD. As before, they found up-regulation of pro-inflammatory genes and also glucocorticoid-related genes in patients with MDD compared with controls.
"These findings corroborate the presence of an immune-related molecular signature in many individuals with MDD," the researchers write. The findings also suggest that a CRP measure alone does not fully capture the nature of immune-related changes in people with MDD.
There are a few limitations to the study, such as a small sample size. But some other recent findings (for example, that levels of another inflammatory marker, IL-6, are better than CRP levels for predicting whether the antibiotic minocycline will help to treat a patient's MDD) support the idea that a focus on CRP levels alone is too limited. The team therefore advocates moving away from the concept of a single immunological marker — whether that's CRP, or another protein related to immune function — to a broader approach to evaluating and understanding immune changes in people with MDD.
Ultimately, a better understanding of the precise nature of immune-related changes in patients with MDD, and of any individual differences in the causes, should lead to more personalised, and so hopefully more effective, strategies for treatment.
Read the paper in full:
Sforzini, L., Cattaneo, A., Ferrari, C., Turner, L., Mariani, N., Enache, D., Hastings, C., Lombardo, G., Nettis, M. A., Nikkheslat, N., Worrell, C., Zajkowska, Z., Kose, M., Cattane, N., Lopizzo, N., Mazzelli, M., Pointon, L., Cowen, P. J., Cavanagh, J., & Harrison, N. A. (2023). Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study. Translational Psychiatry, 13(1), 185. https://doi.org/10.1038/s41398-023-02438-x
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