Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression

Abstract

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...

Depression- and anxiety-like behaviour is related to BDNF/TrkB signalling in a mouse model of psoriasis

“…We also confirmed that fluoxetine treatment is able to attenuate pathological lesions in K5.Stat3C mice. Many studies have shown that there is an interaction between the 5-HT system and BDNF/TrkB signalling, 3 and this interaction is likely to be the mechanism by which BDNF affects depression or anxiety behaviours. 3,18 Therefore, it appears that fluoxetine ameliorated skin lesions through BDNF/TrkB signalling in K5.Stat3C mice, and this improvement is unlikely to be a consequence of an antiproliferative effect in this model of psoriasis.…”

“…In recent years, there has been growing evidence to show that the brain-derived neurotrophic factor (BDNF)/TrKB pathway can modulate serotonin (5-hydroxytryptamine; 5-HT) and other neurotransmitters, and this pathway has been implicated in the pathophysiology and treatment of depression and anxiety. 3 Clinical data have also revealed epigenetic changes in the BDNF gene in adult male patients with anxiety and depression, 4 and increases in BDNF levels following treatment with fluoxetine, an antidepression drug. 4 Thus, increasing BDNF in the brain can be a potential therapeutic means for the treatment of psychocutaneous disorders, such as psoriasis, which accompany depression-and anxiety-like behaviours.…”

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

“…74 In contrast, the COMT Val158Met rs4680 genotype oppositely altered the rs6295 association with interferon-induced depression. 75 Perhaps most intriguing is an interaction of the HTR1A rs6295 genotype with the phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) gene in major depression, seen in Utah and Ashkenazi populations. Subsequently, LHPP was identified in a genome-wide association study of female melancholic depression 76 and a Mexican-American major depression cohort.…”

Biological and psychological components of depression in patients receiving IFN-alpha therapy for hepatitis C

“…[3][4][5][6] Cytokines activity is associated with: 1) significant alterations in diurnal HPA axis activity including the flattening of the adrenocorticotropin (ACTH) and cortisol diurnal fluctuations, and an increase in evening ACTH and cortisol concentrations 4 ; 2) increased activity of the metabolic enzyme indoleamine 2,3-dioxygenase responsible for degrading tryptophan to kynurenine which is then metabolized to quinolinic acid interfering with CNS activity 7 ; 3) decreased brainderived neurotrophic factor (BDNF) levels 8 , and 4) altered function of the glucocorticoid receptors. 9 The effect of IFN-α seems to be purely biological rather than psychological, but patients during an antiviral treatment are going through a difficult phase in their life caused by neuropsychiatric symptoms such as emotional lability, cognitive decline and insomnia, as well as somatic symptoms including fever, nausea, lack of appetite, and weakness. In vulnerable individuals, this stressful situation may cause depression.…”