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Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression., Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis., Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression., Conclusions: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Current treatments of depression include psychological, pharmacological and physical approaches. Pharmacological interventions to treat depression have previously focused on modifying dysfunctional neurotransmitter systems. Overall, these treatments have demonstrated an ability to manage major depression but otucomes continue to be poor in many patients, especially those with long term illness or with previous multiple relapses. This may be due to the fact that depression is a systemic and neuroprogressive illness involving multiple biological pathways such as immunological factors. There is substantial evidence that cytokine therapies induce depressive symptoms in clinical populations. The model of cytokine-induced depression has provided important information relative to the risk factors and biological pathways involved in the etiology of depressive symptoms and, most importantly, the identification and knowledge of these factors has allowed new treatment targets to be explored. When an exogenous cytokine such as interferon-alpha is administered, proinflammatory cytokines are activated, leading to alterations in neurotransmission and endocrine pathways and producing neurotoxicity. Several new treatments for depression acting through pathways other than amine neurotransmission have emerged in recent years. The regulation of the inflammatory response, the decrease in the activity of the hypothalamic-pituitary-adrenal axis and the prevention of neurotoxicity are potential targets for new drugs. Though these drugs are mostly at the proof-of-concept stage, some of them have already shown promising results for the treatment of depression.

Background: Cytokines and serotonin neurotransmission may play an important role on the development of psychopathological symptoms during interferon (IFN) treatment. The aim of the present study was to investigate the association between IFN-induced depression, anxiety and fatigue and functional genetic variants at the interleukin-6 gene (IL-6) and serotonin transporter gene (SERT)., Methods: 385 consecutive Caucasian outpatients with chronic hepatitis C initiating treatment with IFN-alpha and ribavirin were included. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV (SCID-I) and those with a current major depressive disorder or anxiety disorder before starting treatment were excluded. Depression and anxiety were assessed at baseline during the treatment (at 4, 12, 24 and 48 weeks) using the Hospital Anxiety and Depression Scale and fatigue was evaluated using a visual analogue scale. The 5-HTTLPR region of SERT gene and the functional polymorphism located at the promoter region of IL-6 gene (rs1800795) were genotyped., Results: Genotypic distribution was in the Hardy-Weinberg equilibrium for SERT (p=0.41) and for IL-6 (p=0.72) polymorphisms. At baseline we found only a significant effect of IL-6 polymorphism on fatigue symptoms. During antiviral treatment we reported that subjects with CC genotype (IL-6) presented significantly lower changes from baseline in IFN-induced depression (p=0.005) and IFN-induced anxiety (p=0.004). We did not find statistically significant differences on depression (p=0.21) or anxiety (p=0.15) between SS/SL and LL genotypes of SERT., Conclusions: Genetic variations in the IL-6 gene increase the risk of IFN-induced depression and anxiety. The IL-6 polymorphism was associated with fatigue rates in patients with chronic hepatitis C before treatment. Our study confirms the role of inflammatory mechanisms in IFN-induced psychopathological symptoms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Our objective was to study the clinical and management differences between primary and interferon (IFN)-induced depressive disorders in malignant melanoma patients visited by the consultation-liaison team during a two year period. This was a prospective study of 31 patients with malignant melanoma treated with IFN-alpha in a general teaching hospital. Clinical, psychiatric variables and DSM-IV-TR diagnosis were analyzed. The Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) of illness scales were administered at the time of consultation and at the end of hospitalization. The main diagnoses were depressive adjustment disorders in 14 patients (45.16%) followed by interferon-induced depressive disorders in 6 (19.36%). In patients with adjustment disorders, melanoma stage was significantly more advanced than in those with interferon-induced depressive disorder (p = 0.019). The latter scored higher in the CGI-S scale (p = 0.044) and in the CGI-I scale (p = 0.029). The interferon-induced depressive disorders, except one who required a reduction of IFN-alpha-2b dose, were successfully treated with antidepressant drugs. Clinical management and antidepressant treatment allowed the continuation of interferon therapy in malignant melanoma patients. Interferon-induced depression occurred in a few patients, which in turn were the most severe. Adjustment depressive disorder was the most common psychiatric diagnosis.