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, 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, Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, Carmine M Pariante, 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, Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, Carmine M Pariante

Abstract

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Correlations (Spearman’s rho) between significantly-different…
Fig. 1. Correlations (Spearman’s rho) between significantly-different genes and immune measures.
Coloured coefficients are statistically different from zero at level P < 0.05; red = negative correlations, blue = positive correlations.
Fig. 2. Partial least squares discriminant analysis…
Fig. 2. Partial least squares discriminant analysis outputs: loading plots.
The partial least square discriminant analysis (PLSDA) was conducted to define which genes contribute to discriminate between each of the four groups. The plots depict the loadings of each gene: the larger the loading, the better the gene discriminates the study group from the others. Loadings summarise how the genes are related to each other as well as discriminate between the groups: all genes with positive loadings are positive correlated with each other and negatively correlated with genes with negative loadings; colours indicate the group for which the genes have a maximal median value. Panel A (on the three depressed groups only) shows that P2RX7, and, less, CXCL12 and IL-1-beta (all in red), best discriminate TRD vs. the other depressed groups; CCL2, and, less, FKBP5 and MIF (all in green), best discriminate drug-free vs the other depressed groups; and GR, and, less, IL-6 and A2M (all in blue), best discriminate responsive vs. the other depressed groups. Panel B (on the four groups) shows GR (in black) is the gene that best discriminates controls from all the other depressed groups.

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