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.

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.

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 hours for 12 hours 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). IFNalpha-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 IFNalpha (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.

These data accord with earlier studies demonstrating regulation of RGS4 expression by dopamine 4 and specifically by COMT genotype. 8 Lipska and colleagues showed significantly decreased RGS4 mRNA expression in the DLPFC of Val/Val subjects, relative to Met-carriers. These changes suggest that variation in cortical dopamine may alter RGS4-dependent signaling by regulating its transcription. Alternatively or in addition, genetic variation in RGS4 may become more manifest in COMT Val/Val subjects, whose cortical synaptic dopamine levels are lower. Our findings support earlier statistical genetic and neuropathological evidence for epistasis between COMT and RGS4 by demonstrating an interaction between these two putative risk genes on an in vivo measure of prefrontal function. These results bolster the notion that COMT val158met genetic background mediates the impact of other schizophrenia susceptibility genes. Recent data indicate that activation of the p38 mitogen-activated protein kinase (MAPK) signaling cascade by cytokines including interleukin (IL)-1 and tumor necrosis factor (TNF)-a increases the expression and activity of the serotonin transporter (SERT). Herein, we report that increased p38 activity, as manifested by an increased percentage of peripheral blood monocytes staining positive for intracellular phosphorylated p38 (p-p38), was associated with decreased cerebrospinal fluid (CSF) concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and increased maternal rejection in 17 rhesus monkeys, 8 of whom were exposed to poor maternal care as infants. These data provide the first evidence of an in vivo relationship between p38 MAPK activation and brain serotonin metabolism in an animal model of early life stress and indicate that activation of p38 MAPK signaling pathways may participate in the contribution of early life stress to psychiatric morbidity. Early life stress including physical/sexual abuse as well as neglect has been associated with a number of adverse health outcomes including increased anxiety and depression. 1 We recently reported that adolescent rhesus monkeys (Macaca mulatta) exposed to physical abuse and high levels of maternal rejection as infants exhibit increased distress and anxiety, delayed social development and reduced exploration, compared to non-abused animals. 2,3 This early exposure to poor maternal care was also associated with reduced brain serotonergic function as reflected by decreased CSF concentrations of serotonin (5-HT) and the serotonin metabolite, 5-HIAA, that were in turn correlated with increased anxiety-like behavior during adolescence. 4 Data indicate that stress, including early life stress, also can be associated with activation of innate immune responses including release of proinflammatory cytokines and activation of proinflammatory cytokine signaling cascades. 5,6 Relevant to the impact of early life stress on serotonin metabolism, the cytokine signaling pathway, p38 MAPK, has been found to increase expression and activity of the SERT...

Background: Interferon (IFN)-α treatment frequently induces depression, which can impair quality of life and reduce treatment adherence. Defining relevant risk factors for IFN-α-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-α/β 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 α-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-α therapy for hepatitis C and other conditions.