Candidate Genes Expression Profile Associated with Antidepressants Response in the GENDEP Study: Differentiating between Baseline ‘Predictors’ and Longitudinal ‘Targets’

Abstract

To improve the ‘personalized-medicine' approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants (‘predictors'), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment (‘targets'). In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-α), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study. Non-responders had higher baseline mRNA levels of IL-1β (+33%), MIF (+48%), and TNF-α (+39%). Antidepressants reduced the levels of IL-1β (−6%) and MIF (−24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (−9%) and of FKBP5 (−11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)—that is, response was associated with changes in genes that did not predict, at the baseline, the response. Our findings indicate a dissociation between ‘predictors' and ‘targets' of antidepressant responders. Indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect.

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

“…Moreover, we correlated SGK1 expression with the expression of GR-relevant genes that we had previously analyzed in the same individuals (17). Consistent with our in vitro data showing decreased GR in the presence of increased SGK1 expression, SGK1 mRNA levels correlated negatively with GR levels in our clinical sample (r = −0.32, P = 0.046).…”

“…We selected 25 depressed patients (10 females, 15 males) from the Genome-based Therapeutic Drugs for Depression (GENDEP) study who were drug-naïve or had been drug-free for at least 2 wk before assessment (17,36). Controls (7 females, 7 males) were recruited in London through local advertisement and volunteer databases, as part of the GENDEP study.…”

“…To corroborate the clinical relevance of our cellular and molecular findings, we measured SGK1 mRNA expression in peripheral blood of patients with major depression, a condition in which both hypercortisolemia and reduced neurogenesis are considered relevant pathophysiological mechanisms. We have previously described candidate gene expression profiles associated with GR function and neuroplasticity in the Genome-based Therapeutic Drugs for Depression (GENDEP) study (17). Here we analyzed SGK1 expression in a subpopulation of this cohort.…”

New hypothesis and treatment targets of depression: an integrated view of key findings

“…Evidence from clinical trials has shown that the MIF expression in leukocytes from patients with severe depression is 40% higher than that in patients with moderate depression [76] , while in patients who are insensitive to antidepressants, the MIF mRNA levels are 48% higher [77] . In addition, depressed patients have reduced glucocorticoid sensitivity during and after stress events [76] , which is likely related to the upregulation of MIF induced by glucocorticoids.…”

“…In addition, depressed patients have reduced glucocorticoid sensitivity during and after stress events [76] , which is likely related to the upregulation of MIF induced by glucocorticoids. After treatment with antidepressants, the infl ammatory levels in the peripheral circulation as well as MIF expression levels in macrophages and lymphocytes are reduced [77] . Although MIF expressed by infl ammatory cells (such as macrophages) in the peripheral circulation can act against glucocorticoids and infl ammation, inhibition of MIF cannot stop depression; instead, it induces anxiety-and depression-like phenotypes in laboratory animals, leading to a decline in hippocampus-dependent learning and memory [78] .…”