The use of mRNA expression signatures can help to identify those patients with treatment-resistant major depressive disorder (MDD) who are more likely to respond to the use of adjuvant strategies, including combination therapies with anti-inflammatory agents. Study participants came from the noninterventional, case-control Biomarkers of Depression (BIODEP) study, which was part of the Wellcome Trust Consortium for Neuroimmunology of Mood Disorder and Alzheimer’s disease and was approved by the National Research Ethics Service East of England, Cambridge Central, UK. Results of the analysis were published in Translational Psychiatry.
Recognizing that patients with MDD have increased serum concentrations of such pro-inflammatory cytokines as interleukin 1 beta (IL-1-β), IL-6, and tumor necrosis factor alpha (TNF-α), the investigators sought to examine the mRNA signature foundation associated with the pro-inflammatory phenotype of depression, along with the differential signatures linked to depression subtypes and the impact of antidepressant agents in these situations.
They examined a total of 130 patients with MDD — 58 of whom were treatment-resistant, 36 of whom were antidepressant-responsive, and 36 of whom were currently untreated — as well as 40 healthy controls, all of whom had available gene expression data from the BIODEP study.
The researchers used whole-blood mRNA quantitative polymerase chain reaction to measure the expression of 16 candidate mRNAs, some of which had never before been quantified: IL-1-β, IL-6, TNF-α, macrophage migration inhibitory 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 of the genes other than AQP4, ISG15, and USP-18 were differentially regulated.
Results of the study demonstrated that patients with treatment-resistant depression and drug-free patients with depression have the strongest signatures of glucocorticoid resistance and inflammation. In these individuals, increased levels of CRP were reported. In particular, CRP levels were higher in patients with treatment-resistant depression compared with antidepressant-responsive individuals and healthy controls, as well as in drug-free patients compared with controls (P <.001).
Further, patients with treatment-resistant depression and those with drug-free MDD had both elevated inflammasome activation (ie, higher P2RX7 and pro-inflammatory cytokines/chemokines mRNA expression) and increased glucocorticoid resistance (ie, lower GR and higher FKBP5 mRNA expression). In contrast, those with antidepressant-responsive MDD exhibited an intermediate phenotype with lower CXCL12.
With the use of binomial logistic models, a signature of 6 mRNAs — P2RX7, IL-1-β,
IL-6, TNF-α, CXCL12, and GR — differentiated treatment-resistant from antidepressant-responsive patients, even following adjustment for history of childhood maltreatment, serum CRP levels, and trait- and state-anxiety.
Additional studies are warranted, in which the current findings are reproduced in larger, longitudinal patient cohorts. These analyses will need to explore whether new treatments work and whether patient responses to new therapies can be improved by selecting those individuals with abnormal concentrations of relevant mRNAs.
Cattaneo A, Ferrari C, Turner L, et al; on behalf of the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium. 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. Transl Psychiatry. 2020;10(1):232. doi: 10.1038/s41398-020-00874-7.