Selective Hyper-responsiveness of the Interferon System in Major Depressive Disorders and Depression Induced by Interferon Therapy

Abstract

BackgroundThough an important percentage of patients with chronic hepatitis C virus (HCV) undergoing interferon (IFN) therapy develop depressive symptoms, the role of the IFN system in the pathogenesis of depressive disorders is not well understood.Methods50 patients with HCV infection were treated with standard combination therapy (pegylated IFN-α2a/ribavirin). IFN-induced gene expression was analyzed to identify genes which are differentially regulated in patients with or without IFN-induced depression. For validation, PBMC from 22 psychiatric patients with a severe depressive episode (SDE) and 11 controls were cultivated in vitro with pegylated IFN-α2a and gene expression was analyzed.ResultsIFN-induced depression in HCV patients was associated with selective upregulation of 15 genes, including 6 genes that were previously described to be relevant for major depressive disorders or neuronal development. In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients.ConclusionsOur data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms. These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders.

Comparison of the prevalence of psychiatric co-morbidities in hepatitis C patients and hepatitis B patients in Saudi Arabia

“…[44] That this mechanistic evidence links HCV, but not HBV, with depression corroborates our findings.…”

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

“…For example, one study that examined early (initial injection) changes in the response to IFN-alpha administration reported differential expression of IFN stimulated genes and genes that have been related to depression or neural development in patients that subsequently developed depression (Schlaak et al, 2012). Some of these genes were also found to be up-regulated following in vitro stimulation with IFN-alpha (GCH1, TOR1B, DYNLT1, DISC1) in leukocytes isolated from subjects with depression compared to controls in this same study, and numerous genes encoding IFNs, IFN-regulated genes and toll-like receptors were also up-regulated at baseline in depressed subjects compared to controls.…”

The Poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery

“…Involvement of the TLR3 and TLR4 signaling pathways in neuropsychiatric disorders. Several components and processes of the Toll-like receptor (TLR) 3 and TLR4 pathways have been implicated in the etiology of neuropsychiatric diseases as illustrated by selected reports from literature: 1,2 -TLR (Muller et al, 2012;Hoyo-Becerra et al, 2013;Keri et al, 2014;Pandey et al, 2014); 3 -SARM1 ; 4 -NF-kB (Koo et al, 2010;Keri et al, 2014); 5 -proinflammatory cytokines (Dunn et al, 2005;Dowlati et al, 2010;Hannestad et al, 2011;Hiles et al, 2012aHiles et al, , 2012bValkanova et al, 2013); 6 -DRIIs (Schlaak et al, 2012;Hoyo-Becerra et al, 2013); 7 -MAPK (Wefers et al, 2012;Mitic et al, 2014;Reus et al, 2014). Abbreviations: AP-1 (=activator protein 1), DRIIs (=depression-related interferon-induced genes), FADD (=Fas-associated protein with death domain), IKKs (=inhibitors of NF-kB kinase), IRAKs (=interleukin-1 receptor-associated kinase) 1 and 4, IRF3 (=interferon regulatory factor 3), MAL (=MyD88 adaptorlike), MAPK (=mitogen-activated protein kinase), MyD88 (=myeloid differentiation primary response gene 88), NF-kB (=nuclear factor kappa-light-chain-enhancer of activated B cells), PKCε (=protein kinase C epsilon), SARM1 (=sterile alpha and TIR motif containing 1), TAK1 (=transforming growth factor beta activated kinase-1), TAB (=TAK binding protein) 1 and 3, TLR (Toll-like receptor) 3 and 4; TRAF3 (=TNF receptor-associated factor 3), TRAF6/RIP1 (=TNF receptor-associated factor 6/receptor interacting protein 1), TRAM (=TRIF-related adaptor molecule), TRIF (=TIR-domain-containing adapter-inducing interferon-β).…”