Interferon-Induced Depression in Chronic Hepatitis C: A Review of Its Prevalence, Risk Factors, Biology, and Treatment Approaches

Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Montefiore Medical Center, Anxiety and Depression Program, Klau Basement, 111 E. 210th Street, Bronx, New York 10467, USA.
Journal of Clinical Gastroenterology (Impact Factor: 3.5). 05/2006; 40(4):322-35. DOI: 10.1097/01.mcg.0000210099.36500.fe
Source: PubMed


Hepatitis C viral infection is a global health problem that affects approximately 4 million people in the United States. Combination treatment with pegylated interferon (IFN)-alpha plus ribavirin has been shown to be most effective in treating patients with chronic hepatitis C (CHC). Despite its efficacy, one of the most common side effects of this regimen is depression. Whereas IFN-alpha has been found to induce depression in chronic myelogenous leukemia, melanoma, and renal cell carcinoma, CHC patients may be especially prone to develop IFN-induced depression. This review includes a summary of differences between IFN-alpha and IFN-beta and addresses whether pegylation of IFN (versus nonpegylated IFN) gives rise to a treatment with reduced potential to induce depressive symptoms. Consideration is also given to evidence showing that treatment with ribavirin may contribute to IFN-induced depression. Thyroid disorders and anemia (as well as other medical conditions) have also been associated with IFN exposure and may account for some incidences of depression in CHC patients. Evidence is reviewed indicating that prior psychiatric and mood disorders (especially previous episodes of major depressive disorder), just prior to IFN treatment, contribute to the propensity to develop depression during treatment. In addition, a brief description is provided of potential biological mechanisms of IFN-induced depression (ie, monoamines, hypothalamic-pituitary-adrenocortical [HPA] axis, proinflammatory cytokines, peptidases, intercellular adhesion molecule-1, and nitric oxide). Finally, a discussion is provided on the use of antidepressants as a preventative versus restorative treatment, including a commentary on risks of using antidepressants in this patient population.

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Available from: Richard De La Garza, Jan 28, 2015
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    • "Although it was reported that citalopram could be safely used during IFN treatment in patients with CHC [44], there were risks of using SSRIs during IFN treatment, because CHC may alter the pharmacokinetics of SSRIs. Therefore, SSRI dose may require adjustment to optimize the treatment [40]. "
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    ABSTRACT: Antidepressants are effective in treating interferon-α/ribavirin (IFN-α/RBV)-associated depression during or after treatment of chronic hepatitis C (CHC). Whether antidepressant prophylaxis is necessary in this population remains under debate. Comprehensive searches were performed in Medline, Embase, Cochrane Controlled Trials Register and PubMed. Reference lists were searched manually. The methodology was in accordance with the 2009 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement. We identified six randomized, double-blind, placebo-controlled trials involving 522 CHC patients treated with pegylated (PEG)-IFN-α plus RBV. The antidepressants used were escitalopram, citalopram, and paroxetine, which are selective serotonin reuptake inhibitors (SSRIs). The rates of depression (17.9% vs. 31.0%, P = 0.0005), and rescue therapy (27.4% vs. 42.7%, P<0.0001) in the SSRI group were significantly lower than those in the placebo group. The rate of sustained virological response (SVR) (56.8% vs. 50.0%, P = 0.60) and drug discontinuation (18.7% vs. 21.1%, P = 0.63) in the SSRI group did not differ significantly to those in the placebo group. In terms of safety, the incidence of muscle and joint pain (40.8% vs. 52.4%, P = 0.03) and respiratory problems (29.3% vs. 40.1%, P = 0.03) were lower, but the incidence of dizziness was significantly higher (22.3% vs. 10.2%, P = 0.001) in the SSRI group. Prophylactic SSRI antidepressants can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression in patients with CHC, with good safety and tolerability, without reduction of SVR.
    Preview · Article · Oct 2013 · PLoS ONE
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    • "Supporting these observations, (i) immune activation with lipopolysaccharide (LPS) is known to produce a set of behavioral and cognitive alterations (anhedonia, anorexia, memory deficits , among others) that resemble depression both in animals and in humans (Yirmiya et al., 2000; Reichenberg et al., 2010); (ii) depression is commonly accompanied by an inflammatory response expressed as an increase in serum levels of TNF-a, IFN-g, IL-6, IL-1b and C-reactive protein (Maes et al., 1997; Mikova et al., 2001; Howren et al., 2009). These cytokines are known to cause behavioral changes (Asnis and De La Garza, 2006; Kaster et al., 2012), affect neurotransmitter metabolism (Guillemin et al., 2001; Sakash et al., 2002; Barrientos et al., 2004) and decrease neuroplasticity (Barrientos et al., 2004; Ben Menachem-Zidon et al., 2008; Goshen et al., 2008; Koo and Duman, 2008). Of note, patients who suffer from refractory depression (30—40%) show higher levels of acute phase response markers (IL-6, reactive C protein, etc.) (Sluzewska et al., 1995; Maes et al., 1997), therefore inflammation could become a new therapeutic target for this particular subset of patients. "
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    ABSTRACT: A causative relationship between inflammation and depression is gradually gaining consistency. Because Nrf2 participates in inflammation, we hypothesized that Nrf2 could play a role in depressive disorders. In this study, we have observed that Nrf2 deletion in mice results in: (i) a depressive-like behavior evaluated as an increase in the immobility time in the tail-suspension test and by a decrease in the grooming time in the splash test, (ii) reduced levels of dopamine and serotonin and increased levels of glutamate in the prefrontal cortex, (iii) altered levels of proteins associated to depression such as VEGF and synaptophysin and (iv) microgliosis. Furthermore, treatment of Nrf2 knockout mice with the anti-inflammatory drug rofecoxib reversed their depressive-like behavior, while induction of Nrf2 by sulforaphane, in an inflammatory model of depression elicited by LPS, afforded antidepressant-like effects. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf2 can lead to a depressive-like phenotype while induction of Nrf2 could become a new and interesting target to develop novel antidepressive drugs.
    Full-text · Article · Apr 2013 · Psychoneuroendocrinology
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    • "Indeed, the experimental or clinical administration of cytokines or endotoxins results in a range of symptoms of depression [21]. For example, clinical administration of the pro-inflammatory cytokine interferon (IFN)-α in the treatment of cancer or chronic infection induces symptoms of major depressive disorder in 23% to 45% of all patients, with the degree of depression being positively related to dose and duration of treatment [22]. Epidemiologic evidence also shows that systemic inflammation predicts future risk for depressive symptoms and clinical episodes of depression in some [23-25], but not all longitudinal studies [26,27]. "
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    ABSTRACT: Consistent evidence links major depression and its affective components to negative health outcomes. Although the pathways of these effects are likely complex and multifactorial, recent evidence suggests that innate inflammatory processes may play a role. An overview of current literature suggests that pathways between negative moods and inflammation are bi-directional. Indeed, negative moods activate peripheral physiologic mechanisms that result in an up regulation of systemic levels of inflammation. Conversely, peripheral inflammatory mediators signal the brain to affect behavioral, affective and cognitive changes that are consistent with symptoms of major depressive disorder. It is likely that these pathways are part of a complex feedback loop that involves the nervous, endocrine, and immune systems and plays a role in the modulation of peripheral inflammatory responses to central and peripheral stimuli, in central responses to peripheral immune activation and in the maintenance of homeostatic balance. Further research is warranted to fully understand the role of central processes in this feedback loop, which likely contributes to the pathophysiology of mental and physical health.
    Full-text · Article · Feb 2012 · Biology of Mood and Anxiety Disorders
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