Activation of CNS Inflammatory Pathways by Interferon-alpha: Relationship to Monoamines and Depression (original) (raw)
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Neuropsychiatric side-effects of interferon-alpha treatment: pathophysiology and therapeutic options
2014
Interferon alpha (IFN-α) is the approved standard of care for chronic hepatitis C and B. Unfortunately, it has neuropsychiatric side-effects that have a major impact upon the quality of life and the drug adherence. The mechanism of IFN-α-induced behavioral changes is complex, involving interactions between the immune system, the endocrine system, the monoaminergic systems and the opioid receptors. Recent studies support the neurodegeneration hypothesis as a possible mechanism of IFN-α-induced depressive behavior. Although a meta-analysis showed that antidepressant pretreatment effectively reduces the incidence and severity of depressive symptoms, irrespective of pre-existing psychiatric disorders, it is not approved for prophylactic use. The "on demand" treatment strategy is justified as the majority of patients have only mild depressive symptoms. Patients with risk factors for depression undergoing IFN-α therapy need to be regularly screened and followed-up by a psychiatr...
Journal of Psychosomatic Research, 2007
Objective: Proinflammatory cytokines have the potential to activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and HPA axis hyperactivity is also encountered in depression. Therefore, the induction of depressive symptoms by interferon-a (IFNa) may be mediated by changes in the cytokine network and the HPA axis. Methods: In 17 hepatitis C patients undergoing IFN-a treatment, depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). In addition, serum cytokine concentrations were measured. Saliva was collected five times over the course of a day in order to assess daily average cortisol (DAC) and awakening response. Assessments were carried out at baseline and six later time points after starting treatment. Results: During treatment, the increases in the MADRS were significantly and positively correlated with soluble interleukin (IL)-2 receptor, tumor necrosis factor a (TNF-a), and IL-6. There were no significant associations between the DAC or cortisol awakening response with the MADRS score. Conclusion: Results suggest a clear connection between IFN-a-induced depressive symptoms and cytokine concentrations, but not cortisol. D
Physiology & behavior, 2015
Major medical illnesses are associated with increased risk for depression and alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Pathophysiological processes such as inflammation that occur as a part of medical illnesses and their treatments have been shown to cause depressive symptoms, and may also affect the HPA axis. We previously reported that patients with hepatitis C virus chronically administered interferon (IFN)-alpha develop increased evening plasma cortisol concentrations and a flattened diurnal cortisol slope, which correlated with increased tumor necrosis factor (TNF) and its soluble receptor 2 (sTNFR2). Increased TNF and sTNFR2 were further correlated with depression and fatigue scores. The current study examined whether flattened cortisol slope might be secondary to reduced glucocorticoid receptor (GR) sensitivity, by measuring glucocorticoid negative feedback to dexamethasone (DEX) administration followed by corticotropin releasing hormone (CRH) challe...
Interferon therapy and its association with depressive disorders – A review
Frontiers in Immunology
Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body’s inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates mem...
Interferon-Induced Depression in Chronic Hepatitis C
The Journal of Clinical Psychiatry, 2012
Background: Chronic hepatitis C (CHC) infection represents a serious public health problem. The approved treatment for CHC, the combination of interferon-alpha (IFN) and Ribavirin (RBV), often presents side effects such as depressive symptoms and even Major Depressive Episode (MDD). The incidence of depression identified by researchers varies widely, probably due to the differences in the methodological approaches applied.
Neuropsychopharmacology, 2012
In patients at high risk for recurrence of malignant melanoma, interferon-a (IFN-a), a stimulator of innate immunity, appears to induce distinct neurobehavioral symptom dimensions: a mood and anxiety syndrome, and a neurovegetative syndrome, of which the former is responsive to prophylactic administration of paroxetine. We sought to determine whether symptom dimensions (and treatment responsiveness) arise in patients with hepatitis C administered IFN-a and ribavirin. In a randomized, double-blind, 6-month study, 61 patients with hepatitis C eligible for therapy with IFN-a and ribavirin received the antidepressant paroxetine (n ¼ 28) or a placebo (n ¼ 33). Study medication began 2 weeks before IFN-a/ribavirin therapy. Neuropsychiatric assessments included the 10-item Montgomery-Asberg Depression Rating Scale (MADRS). The items of the MADRS were grouped into depression, anxiety, cognitive dysfunction, and neurovegetative symptom dimensions, and analyzed using a mixed model. By 2 weeks of IFN-a/ribavirin therapy, all four dimensions increased, with the symptom dimensions of anxiety and cognitive dysfunction fluctuating and worsening, respectively, in both groups over time. The depression symptom dimension was significantly lower in the paroxetine treatment group (p ¼ 0.04); severity of the neurovegetative symptom dimension was similar in both groups. Similar to patients with malignant melanoma receiving high-dose IFN-a, the depression symptom dimension is more responsive to paroxetine treatment in individuals undergoing concomitant IFN-a/ribavirin therapy. However, the anxiety, cognitive dysfunction, and neurovegetative symptom dimensions appear less responsive to prophylactic paroxetine administration. Different neurobiologic pathways may contribute to the responsiveness of IFN-a-induced symptom dimensions to antidepressant treatment, requiring relevant psychopharmacologic strategies.
International Journal of Neuropsychopharmacology, 2011
Interferon-a (IFN-a) therapy for the treatment of hepatitis C is known to induce depressive symptoms and major depression in a substantial proportion of patients. While immune activation and disturbances in peripheral tryptophan catabolism have been implicated, the exact underlying mechanism remains unknown. A role for brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders has recently emerged. This study examined whether depressive symptoms over time are associated with changes in serum BDNF concentration in hepatitis C patients treated with IFN-a, and whether BDNF mediates the effects of IFN-a-induced immune activation on depressive symptoms. For this purpose, 17 hepatitis C patients received IFN-a treatment with ribavirin. Patients were assessed before and at 1, 2, 4, 8, 12 and 24 wk after start of treatment. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). In addition, cytokine concentrations and serum BDNF levels were measured at all time-points. Serum levels of BDNF decreased during the course of treatment, and were significantly and inversely associated with total MADRS score. Furthermore, pro-inflammatory cytokine levels predicted lower subsequent BDNF levels, whereas low BDNF levels, as well as increased cytokine levels, were independently associated with the development of depressive symptoms during IFN-a treatment. These findings suggest that the effect of IFN-a-induced immune activation on depression may be explained in part by alterations in neuroprotective capacity, reflected by decreases in serum BDNF following IFN-a treatment.
Journal of Clinical Gastroenterology, 2006
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)-a plus ribavirin has been shown to be 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 IFNa 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-a and IFN-b 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.