Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression

Abstract

Early-onset major depressive disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not optimally effective. Biological markers of early-onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early-onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. We carried out unbiased analyses of this combined set of 26 candidate blood transcriptomic markers in a sample of 15–19-year-old subjects with MDD (N=14) and subjects with no disorder (ND, N=14). A panel of 11 blood markers differentiated participants with early-onset MDD from the ND group. Additionally, a separate but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Four transcripts, discovered from the chronic stress animal model, correlated with maltreatment scores in youths. These pilot data suggest that our approach can lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies.

Translational identification of transcriptional signatures of major depression and antidepressant response

“…Recently, translational studies have been conducted to trigger the discovery of protein-coding transcriptional markers that would play a role in the balance between susceptibility and resilience to acute and chronic signals involved in depressive symptoms (Pajer et al, 2012;Malki et al, 2015;Bagot et al, 2016;Miyata et al, 2016a,b). In a series of experiments, Redei et al (2014) used genetic models of depression and chronic stress on different strains of rats to separately profile transcriptional signatures of depression in the brain and the blood, and test whether a subset of transcripts that differentiated depressed-like rats from non-depressed-like rats would also differentiate human patients with early-onset MDD from those without any disorder.…”

“…In a series of experiments, Redei et al (2014) used genetic models of depression and chronic stress on different strains of rats to separately profile transcriptional signatures of depression in the brain and the blood, and test whether a subset of transcripts that differentiated depressed-like rats from non-depressed-like rats would also differentiate human patients with early-onset MDD from those without any disorder. The same gene candidates were tested for their capacity to follow and predict response to a cognitive behavioral therapy Pajer et al, 2012;Redei et al, 2014;Redei and Mehta, 2015;Mehta-Raghavan et al, 2016). Although characteristics of the animal model we used and that of our human validation cohort were different, it turned out that some variations in transcriptional signatures were shared between the different animal models and the human cohorts.…”

“…Indeed, inaccessibility to brain tissues from living MDD patients constrained research to using blood and occasionally cerebrospinal fluid to study genetic alterations in depressive subjects (Wan et al, 2015;Hestad et al, 2016), making it almost impossible to draw any direct correlations between changes observed in the brain. To overcome this issue and to extend our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology of major depression, translational research has been established using animal models of depression (Joeyen-Waldorf et al, 2012;Pajer et al, 2012;Issler et al, 2014;Arloth et al, 2015;Qesseveur et al, 2016). Using this method, it is possible to test animal tissues from both central and peripheral locations, identify candidate biomarkers, and assess correlation of these marker variations of expression in accessible human MDD samples with etiological hypotheses of depression.…”

Core Modular Blood and Brain Biomarkers in Social Defeat Mouse Model for Post Traumatic Stress Disorder

“…In particular, the genes Abca4, Fech, Magoh, Ppp1r12b, and Uros were previously shown to be differentially expressed in a human PTSD signature discovered by Segman et al [8]. Seven of the 43 genes closely resemble genes from a blood signature for depression (Ahsp, Dhrs9, Map2k2, Slc13a2, Slc16a1, Slc39a3, U2af1) [39,40], while Hmbs, Pafah1b1, Sfrs2, and Yes1 were previously identified as bipolar disorder blood markers [41]. In addition, Ugt2b5 and Slc6a9 are also present in a blood signature for brain injury [42], while Dbh, Itgb1, Ltc4s, and Rhoa were reported to be relevant to mTBI [43].…”

The Promise of Biomarkers in Diagnosing Major Depression in Primary Care: the Present and Future

“…We identified a prospective panel of blood transcriptomic biomarkers by genome-wide expression analysis of both a genetic and a chronic stress-induced animal model of depression. These biomarkers were tested in human patients, and a subset of them was able to differentiate adolescents with depression from their nondepressed controls [41]. This study was followed up in adult primary care patients with MDD and their controls.…”