Translational Identification of Transcriptional Signatures of Major Depression and Antidepressant Response

Abstract

Major depressive disorder (MDD) is a highly prevalent mental illness whose therapy management remains uncertain, with more than 20% of patients who do not achieve response to antidepressants. Therefore, identification of reliable biomarkers to predict response to treatment will greatly improve MDD patient medical care. Due to the inaccessibility and lack of brain tissues from living MDD patients to study depression, researches using animal models have been useful in improving sensitivity and specificity of identifying biomarkers. In the current study, we used the unpredictable chronic mild stress (UCMS) model and correlated stress-induced depressive-like behavior (n = 8 unstressed vs. 8 stressed mice) as well as the fluoxetine-induced recovery (n = 8 stressed and fluoxetine-treated mice vs. 8 unstressed and fluoxetine-treated mice) with transcriptional signatures obtained by genome-wide microarray profiling from whole blood, dentate gyrus (DG), and the anterior cingulate cortex (ACC). Hierarchical clustering and rank-rank hypergeometric overlap (RRHO) procedures allowed us to identify gene transcripts with variations that correlate with behavioral profiles. As a translational validation, some of those transcripts were assayed by RT-qPCR with blood samples from 10 severe major depressive episode (MDE) patients and 10 healthy controls over the course of 30 weeks and four visits. Repeated-measures ANOVAs revealed candidate trait biomarkers (ARHGEF1, CMAS, IGHMBP2, PABPN1 and TBC1D10C), whereas univariate linear regression analyses uncovered candidates state biomarkers (CENPO, FUS and NUBP1), as well as prediction biomarkers predictive of antidepressant response (CENPO, NUBP1). These data suggest that such a translational approach may offer new leads for clinically valid panels of biomarkers for MDD.

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

“…Transcriptome changes, assessed by differential expression, were relatively small, which is consistent with previous reports despite the different methodologies employed in the various studies (21,22). Also in line with previous reports, most changes were observed in the hippocampus (21,22,56), confirming its sensitivity to stress (57). Our data highlight that despite the tissue-specific differential expression of genes, in particular in the hypothalamus compared to the hippocampus and prefrontal cortex, many enriched biological processes were shared across brain regions.…”

“…Transcripts and associated processes affected by 9-week exposure to chronic mild stress. Transcriptome changes, assessed by differential expression, were relatively small, which is consistent with previous reports despite the different methodologies employed in the various studies (21,22). Also in line with previous reports, most changes were observed in the hippocampus (21,22,56), confirming its sensitivity to stress (57).…”

“…These data highlight the value of using the blood transcriptome in animal studies to identify biomarkers in response to challenges and draw comparison with patient populations (22). Several DEGs encoding neuropeptides (Pmch, Vip, Avp) may provide a link at the neuroendocrine level between the stress-induced REMS alterations and the HPA axis dysregulation.…”

“…Most studies have focused on the hippocampus and prefrontal cortex, identifying differential gene expression in processes related to inflammation, immune response and neurogenesis (19)(20)(21). While transcriptomic changes underlying neuroplastic adaptation to chronic stress have been extensively studied, very few animal studies investigated the transcriptome response to stress in blood (22,23). This is of particular interest in the context of translational studies since blood transcriptomic signatures of depression and treatment response have been identified in humans (24)(25)(26).…”

Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression

“…Since MDD is heterogeneous, it has been suggested that different animal models may help to identify both the diversity of the causes and the shared mechanisms underlying common symptoms of the human disease [11]. This approach has allowed the identification of common transcriptional dysregulations between rodent models and MDD patients [12][13][14].…”