Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue.

Cytokine-induced stimulation of p38 mitogen activated protein kinase (MAPK) has been shown to influence behaviorally-relevant pathophysiologic pathways including monoamine neurotransmission and neuroendocrine function and thus may contribute to behavioral changes that occur during chronic administration of the innate immune cytokine, interferon (IFN)-alpha. Accordingly, in the current study, phosphorylation (activation) of intracellular p38 MAPK in peripheral blood lymphocytes was analyzed by flow cytometry every 2 h for 12 h following the initial injection of IFN-alpha in eleven patients with chronic hepatitis C. Hourly assessments of plasma concentrations of adrenocorticotropic hormone, cortisol and interleukin-6 were also obtained. Symptoms of depression and fatigue were measured at baseline and after 4 and 12 weeks of IFN-alpha treatment. Acute administration of IFN-alpha significantly increased the percentage of lymphocytes staining positive for intracellular phosphorylated p38 (p-p38). IFN-alpha-induced increases in p-p38 were significantly greater in patients that developed clinically significant depressive symptoms [Montgomery-Asberg Depression Rating Scale (MADRS) score≥15] during the first 12 weeks of IFN-alpha treatment. Increases in the percentage of p-p38-positive lymphocytes following the first IFN-alpha injection also highly correlated with depression severity at weeks 4 (r=0.85, p=0.001) and 12 (r=0.70, p=0.018). Similar relationships were observed for fatigue. Examination of relationships between p-p38 induction and factors previously reported to predict IFN-alpha-induced depressive symptoms revealed strong associations of p-p38 with baseline MADRS (r=0.82, p=0.002) and cortisol responses to the initial injection of IFN-alpha (r=0.91, p=0.000). Taken together, these findings indicate that sensitivity of p38 MAPK signaling pathways to immune stimulation is associated with depressive symptoms during chronic IFN-alpha treatment.

Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression.

BACKGROUND: Interferon (IFN)-alpha is an innate immune cytokine that causes high rates of depression in humans and therefore has been used to study the impact of cytokines on the brain and behavior. To establish a nonhuman primate model of cytokine-induced depression, we examined the effects of IFN-alpha on rhesus monkeys. METHODS: Eight rhesus monkeys were administered recombinant human (rHu)-IFN-alpha (20 MIU/m(2)) or saline for 4 weeks in counterbalanced fashion, and videotaped behavior, as well as plasma and cerebrospinal fluid (CSF), were obtained at regular intervals to assess behavioral, neuroendocrine, immune, and neurotransmitter parameters. Additionally, expression and activity of IFN-alpha/beta receptors in monkey peripheral blood mononuclear cells (PBMCs) were assessed. RESULTS: Compared with saline treatment, IFN-alpha administration was associated with persistent increases in anxiety-like behaviors and decreases in environmental exploration. In addition, IFN-alpha induced significant increases in plasma concentrations of corticotropin (ACTH), cortisol, and interleukin-6 that tended to diminish after chronic administration, especially in dominant animals. Interestingly, in three animals, depressive-like, huddling behavior was observed. Monkeys that displayed huddling behavior exhibited significantly higher plasma concentrations of ACTH and lower CSF concentrations of the dopamine metabolite homovanillic acid. Rhesus monkey PBMCs were found to express mRNA and protein for the IFN-alpha/beta receptor. Moreover, treatment of PBMCs with rHu-IFN-alpha led to induction of STAT1, one of the primary IFN-alpha-induced signaling molecules. CONCLUSIONS: IFN-alpha evoked behavioral, neuroendocrine, and immune responses in rhesus monkeys that are similar to humans. Moreover, alterations in hypothalamic-pituitary-adrenal axis responses and dopamine metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.

Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress.

OBJECTIVE: The authors sought to determine innate immune system activation following psychosocial stress in patients with major depression and increased early life stress. METHOD: Plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells were compared in medically healthy male subjects with current major depression and increased early life stress (N=14) versus nondepressed male comparison subjects (N=14) before and after completion of the Trier Social Stress Test. RESULTS: Trier Social Stress Test-induced increases in IL-6 and NF-kappaB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity, but not early life stress. Natural killer (NK) cell percentages also increased following stress. However, there were no differences between groups and no correlation between NK cell percentage and stress-induced NF-kappaB DNA-binding or IL-6. CONCLUSIONS: Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.

Promoter polymorphisms of the interferon-alpha receptor gene and development of Interferon-induced depressive symptoms in patients with chronic hepatitis C: preliminary findings.

BACKGROUND: Interferon (IFN)-alpha treatment frequently induces depression, which can impair quality of life and reduce treatment adherence. Defining relevant risk factors for IFN-alpha-induced depression is essential for designing preventative treatment strategies. OBJECTIVE: The purpose of the present study was to determine whether promoter polymorphisms of -408C/T, -3C/T and GT repeat dinucleotide microsatellite in the IFN-alpha/beta receptor 1 (IFNAR1) gene are associated with the development of IFN-induced depression. METHOD: Fifty patients with chronic hepatitis C were treated with pegylated IFN alpha-2b plus a standard or weight-based dose of ribavirin. Severity of depression was assessed using the Zung Self-Rating Depression Scale (SDS) at baseline and at 4, 8, 12 and 24 weeks of treatment. RESULT: The baseline to maximum difference in the SDS index score of neurovegetative/somatic symptoms was higher in patients with the 5/14 genotype of the GT repeat dinucleotide microsatellite polymorphism than in those patients with other genotypes (p = 0.0084). CONCLUSION: This preliminary result suggests that the promoter GT repeat dinucleotide microsatellite polymorphism of the IFNAR1 gene may represent a risk factor for the development of depressive symptoms during IFN-alpha therapy for hepatitis C and other conditions.