Depression Induced by Interferon Therapy

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

Joerg F. Schlaak^1#*, Martin Trippler^1#, Carolina Hoyo-Becerra¹, Yesim Erim², Bernhard Kis³, Bo Wang¹, Norbert Scherbaum⁴, Guido Gerken¹

1 Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany, 2 Department of Psychosomatics, Rheinische Kliniken, Essen, Germany, 3 Department of Psychiatry and Psychotherapy, LVR-Klinikum, Essen, Germany, 4 Addiction Research Group at the Department of Psychiatry and Psychotherapy, LVR-Klinikum, Essen, Germany

Abstract

Background

Though 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.

Methods

50 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.

Results

IFN-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.

Conclusions

Our 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.

Citation: Schlaak JF, Trippler M, Hoyo-Becerra C, Erim Y, Kis B, et al. (2012) Selective Hyper-responsiveness of the Interferon System in Major Depressive Disorders and Depression Induced by Interferon Therapy. PLoS ONE 7(6): e38668. doi:10.1371/journal.pone.0038668

Editor: Taro Yamashita, Kanazawa University, Japan

Received: December 13, 2011; Accepted: May 14, 2012; Published: June 6, 2012

Discussion Only
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Determining the role of genetic vulnerability to harmful side effects is becoming a crucial issue in order to progress toward individualized drug therapy with successful outcome. A major obstacle of IFN therapy for chronic hepatitis C is that about a quarter of these patients will develop depressive side effects that can even lead to suicide in some cases [2], [3]. The pathophysiology of IFN-induced depression, however, is not well understood. Most of the molecular dysregulations observed in IFN-related depression are similar to those described for idiopathic depression, suggesting the existence of common pathways to both disorders. In fact, the monocyte-T-lymphocyte hypothesis of mayor depression predicts an immune system activation subjacent to the pathophysiology of major depressive disorder [40], and the association of the depressive symptoms with an increased production of pro-inflammatory cytokines [5]–[8] may indicate that they are the result of a maladaptive response to immune activation. Pegylated IFN-α and ribavirin therapy, as source of an artificial pro-inflammatory cytokine, has been related to the risk of develop depressive behavior by affecting the monoamine and cytokine balance, but a common genetic background with idiopathic depression is not yet elucidated. Our data suggest that the development of depressive side effects during therapy with pegylated IFN-α and ribavirin for chronic hepatitis C is associated with a selective hyper-responsiveness of the IFN system. This leads to the disproportional upregulation of 15 genes including 6 genes that were previously reported to be relevant for recurrent major depression or neuronal development in the brain. The relevance of these genes was validated in a separate cohort of psychiatric patients hospitalized for a severe depressive episode by analyzing the in vitro induction of these ISGs by pegylated IFN-α. In these cohorts, we were also able to demonstrate enhanced basal production of endogenous IFNs, which may contribute to the cytokine levels dysregulation. The 15 target genes include DYNLT1, GCH1, TOR1B, DISC1, MEF2A and ST3GAL5 that to date were never related to an IFN-α regulation while all of them have been described in association with brain development or depression. TOR1B, which shows immunoreactivity in all subfields of the hippocampus [41], is homologue to TOR1A (alternative name: DYT1), is associated with early-onset recurrent major depression and is involved in the regulation of dopamine release [42]. DYNLT1 (alternative name: TCTEL1) plays a key role in multiple steps of hippocampal neuron development such as neurite sprouting, axon specification and dendritic elaboration [43]. MEF2A is also involved in neuronal differentiation and postsynaptic differentiation [44]–[46]. DISC1 plays a role in neurite outgrowth and cortical development and contributes to alterations of hippocampal structure and function [47], [48]. Furthermore, genetic analyses revealed an association with schizophrenia and major depression [49]–[52]. ST3GAL5 is involved in neuronal apoptotic cell death in mouse hippocampal cell lines [53]. Finally, GCH1 is the rate-limiting enzyme in BH4 biosynthesis, an essential cofactor required by the aromatic amino acid hydroxylase and nitric oxide synthase which are in turn the rate-limiting enzymes in dopamine and serotonin biosynthesis. Interestingly, it has already been shown that different IFN types, including pegylated-IFN forms, are able to induce GCH1 activation with the subsequent increase of BH4 and its precursor neopterin, released from monocytes and macrophages [54], [55], which has been widely used as a pharmacodynamic marker in the evaluation and optimization of IFN therapy [56], [57]. Even more, several authors have lately reported that IFN-α therapy impairs phenylalanine metabolism in HCV infected individuals [58], [59], suggesting that behavioural side effects may be associated with the modulation of BH4 levels, thus affecting dopamine, serotonin and noradrenaline biochemistry. Clinically, alterations of GCH1 activity has been associated with bipolar disorders, depression, anxiety, dystonia and deafness [60], [61]. The hippocampus is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Recently, it has been suggested that depression may have a neurogenic origin as loss of neurons in the adult hippocampus is observed and neurogenesis is required for the actions of antidepressants [62], [63]. Furthermore, it has been demonstrated that exogenous administration of IFN-α suppressed neuronal proliferation via proinflammatory cytokines IL-1β and TNF-α in the hippocampus of adult rats [64]. Previous studies revealed that the exposition to these cytokines induce depressive symptoms in humans and depression-like behavior in animals. Latter findings even related specifically increased plasma levels of the mentioned cytokines to the cause of severe depressive symptoms in HCV patients [65]. Our data suggest that IFN-α may interfere with these processes through modulation of the target genes identified in this study.

Patients with chronic HCV infection often report fatigue, depressive mood, impaired cognitive functions, and reduced quality of life [66]–[68]. As these symptoms do not correlate with severity of liver disease, hepatic encephalopathy, or history of intravenous drug use [66], it has been speculated that HCV itself may cause these alterations. This is supported by the fact that HCV RNA is detectable in the brain [69] or in cerebrospinal fluid leading to the hypothesis that HCV may cross the blood brain barrier by infected monocytes which could result in secondary infection of microglial cells [70]. It is well known that HCV can activate the production of IFN-β through activation of the Toll-like receptor system [71], [72], which explains the strong upregulation of IFN-β in the peripheral blood of HCV patients in our study. Microarray studies have indicated that increased type I IFN production occurs also in the livers of HCV-infected chimpanzees and humans [73], [74]. Therefore, we hypothesize that this endogenous IFN production may, at least in part, explain the depressive and cognitive disorders that are frequently seen in these patients.

Only little is known about the relevance of the IFN system for depressive episodes in the course of affective disorders. In accordance with our mRNA data, it has been shown that plasma levels of IFN-γ are higher in patients with depression [75]. Though the role of type I IFNs is still not well understood, it has been reported that they may help sustain the chronic inflammatory response promoting the recruitment of inflammatory monocytes [76] which may be involved in the pathophysiology of the depressive symptoms. In this context, our findings may point to a direct implication of monocyte/macrophage activation by IFN-α with an alteration of the tryptophan metabolism and the subsequent neurotransmitter dysregulation through GCH1 modulation.

According to our results, this study may have major implications regarding a) the pathophysiology of IFN-induced depression, b) the pathophysiology of depressive disorders and cognitive dysfunctions in HCV patients and c) the relevance of the IFN system for severe depressive episodes in psychiatric diseases. Still, possible limitations regarding the relative small sample size, the different medical treatment taken by some HCV and psychiatric patients or comparison of related but not identical psychiatric disorders must be considered. Our study design does not allow to clearly differentiate the alterations solely related to interferon therapy from another medication, drug or altered physiological condition. This would be possible to resolve by studying only patients without any previous psychiatric history and treatment, but such a group would be too difficult to obtain due to the demographic characteristics of HCV and psychiatric patients. Thus, the conclusions presented here need to be confirmed in independent larger cohorts. Nevertheless, this work provides valuable information about the possible mechanisms underlying depression and other cognitive dysfunctions affecting HCV patients treated with the current standard therapy and, as a last resort, giving the likelihood to try to prevent, mitigate or avoid such side effects. Collectively, our results extend across two completely different clinical scenarios to generate convergent data that bridge the phenomenon of IFN-induced depression and major depression and thereby provide a pathophysiologic mechanism of depressive disorders focused on the role of inflammatory cytokines.

In conclusion, these data suggest that selective hyper-responsiveness to exogenous or endogenous type I IFNs may lead to the development of depressive symptoms. This sheds new light on the pathogenesis of IFN-induced and depressive episodes and could ultimately lead to the discovery of novel therapeutic approaches to treat these conditions.

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