Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment

Abstract

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1–4 (EGR1–4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

Oxidative stress, inflammation and treatment response in major depression

“…Differences in oxidative stress markers between MDD subjects and healthy controls remained highly statistically significant after controlling for these variables, suggesting that some factor intrinsic to depression or, alternatively, the psychological stress frequently associated with depression, may account for this significant group difference in oxidative stress markers. In support of the notion that increased oxidative stress is something intrinsic to MDD, we have previously reported that genes regulated by Nuclear factor erythroid-derived 2-like 2 (NRF-2), a transcription factor regulated by oxidative stress, are elevated in MDD and decrease after successful antidepressant treatment (Mellon et al, 2016). …”

“…To the best of our knowledge, only one study has investigated baseline oxidative stress markers (e.g., Vitamin C and glutathione peroxidase (GPx) among others) as predictors of antidepressant treatment response, and that study had negative results (Sarandol et al, 2007). There is, however, evidence that successful antidepressant treatment may improve oxidative stress status (Jimenez-Fernandez et al, 2015; Mellon et al, 2016), although F2-isoprostanes and 8-OHdG, the two oxidative stress markers most often elevated in MDD, have never been investigated in this regard.…”

Severity of anxiety– but not depression– is associated with oxidative stress in Major Depressive Disorder

“…The use of antidepressants may influence oxidative stress markers and may thus be a serious confounder (Black et al, 2016b and Mellon et al, 2016). Another strength is that we used several strategies to parse out anxiety and depression symptomatology in relation to oxidative stress.…”

“…Indeed, many studies have found evidence of increased oxidative stress in MDD, as well as increased gene expression regulated by oxidative stress, suggesting that this is an important contributor to depression pathophysiology (Lindqvist et al, 2017, Maes et al, 2011, Mellon et al, 2016 and Wolkowitz et al, 2011). …”

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges

“…At low oxidative stress levels, Nrf-2 is activated and stimulates the transcription of antioxidative genes, leading to the cytoprotective effects. Supporting the hypothesis that increased ROS plays a significant role in depression, Mellon et al reported that genes regulated by Nrf-2 were elevated in MDD patients and decreased after effective antidepressant treatment [158]. In addition, a recent preclinical study with rodents found that vulnerability to depression resulted from a persistent state of oxidative stress, mediated by Nrf-2 dysfunction, which was reversed by treatment with antioxidants [159].…”