Linking childhood trauma and cytokine levels in depressed adolescents.

BACKGROUND: Evidence supports raised circulating levels of inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor (TNFα), among clinically depressed adults, although preliminary findings in adolescents are mixed. Independently, meta-analyses identify correlations between childhood trauma and elevated cytokine levels in adulthood. Here, we examine the possible role of individual differences in exposure to childhood trauma in contributing to variability in cytokine levels in depressed adolescents. METHODS: 52 depressed adolescents and 20 healthy adolescents completed measures of childhood trauma and provided blood for the assessment of plasma IL-6 and TNFα. Cross-sectional associations of childhood trauma and cytokine measures were assessed in both depressed and healthy adolescents, along with exploratory analysis of childhood trauma subtypes. Longitudinal relationships between childhood trauma and cytokine measures were also studied in an exploratory fashion within a subset of depressed participants (n = 36). RESULTS: Higher childhood trauma (particularly emotional abuse) was positively associated with TNFα in depressed adolescents. Childhood trauma was not linked to longitudinal changes in cytokine levels. DISCUSSION: In depressed adolescents, childhood trauma may relate to higher levels of the proinflammatory cytokine TNFα and contribute to heterogeneity in cytokine elevation among depressed adolescents. Such findings may ultimately help guide more effective individualized treatments for adolescents with depression.

What's in a Face? Amygdalar Sensitivity to an Emotional Threatening Faces Task and Transdiagnostic Internalizing Disorder Symptoms in Participants Receiving Attention Bias Modification Training.

BACKGROUND: Altered amygdala activation in response to the emotional matching faces (EMF) task, a task thought to reflect implicit emotion detection and reactivity, has been found in some patients with internalizing disorders; mixed findings from the EMF suggest individual differences (within and/or across diagnoses) that may be important to consider. Attention Bias Modification (ABM), a mechanistic attention-targeting intervention, has demonstrated efficacy in treatment of internalizing disorders. Individual differences in neural activation to a relatively attention-independent task, such as the EMF, could reveal novel neural substrates relevant in ABM's transdiagnostic effects, such as the brain's generalized threat reactivity capacity. METHODS: In a sample of clinically anxious patients randomized to ABM (n = 43) or sham training (n = 18), we measured fMRI activation patterns during the EMF and related them to measures of transdiagnostic internalizing symptoms (i.e., anxious arousal, general distress, anhedonic depression, and general depressive symptoms). RESULTS: Lower baseline right amygdala activation to negative (fearful/angry) faces, relative to shapes, predicted greater pre-to-post reduction in general depression symptoms in ABM-randomized patients. Greater increases in bilateral amygdalae activation from pre-to-post ABM were associated with greater reductions in general distress, anhedonic depression, and general depression symptoms. CONCLUSIONS: ABM may lead to greater improvement in depressive symptoms in individuals exhibiting blunted baseline amygdalar responses to the EMF task, potentially by enhancing neural-level discrimination between negative and unambiguously neutral stimuli. Convergently, longitudinal increases in amygdala reactivity from pre-to-post-ABM may be associated with greater improvement in depression, possibly secondary to improved neural discrimination of threat and/or decreased neurophysiological threat avoidance in these specific patients.

A chicken and egg scenario in psychoneuroimmunology: Bidirectional mechanisms linking cytokines and depression.

Background: Cytokines are an important part of the immune system. Certain cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), have well-described associations with depression. Various mechanisms exist that may explain bidirectional effects of cytokines on depression and vice versa. No recent reviews to our knowledge have comprehensively characterized both these mechanisms and the interaction of these mechanisms using evidence from the molecular level to the clinical level. The goal of this review is to both evaluate the present knowledge base and identify knowledge gaps to help guide future research. Methods: We conducted an extensive bibliographic search across multiple databases, using both general (e.g. "cytokine") and topic-specific (e.g. "kynurenine") keywords. Results: We describe the most recent evidence outlining these mechanisms, including the role of the hypothalamic pituitary axis, the kynurenine pathway, and neural circuitry. For relevant topics, we outline the pathways by which cytokine activation may lead to depressive symptoms, and how depressive symptomology may lead to elevations in cytokines. We also identify key areas for future research, including the need for longitudinal clinical studies to examine causality in pertinent mechanisms and modulating factors in the cytokine-depression interaction. Limitations: Given the numerous potential mechanisms associating cytokines and depressions, this review paper solely focuses on the most commonly described mechanisms at a basic level. Conclusions: Bidirectional evidence exists for several mechanisms in the relationship between cytokines and depression. However, more work is required to further elucidate the role of these mechanisms in specific clinical populations.

Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents.

BACKGROUND: Depression has been associated with low-grade elevation of plasma cytokines (e.g. interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) in both cross-sectional and longitudinal studies in adults. Preclinical and clinical studies also suggest that IL-6 and TNFα elevation are associated with anhedonia. However, few studies have examined longitudinal relationships between cytokines and depression/anhedonia in clinically depressed samples, particularly adolescents. METHODS: Thirty-six adolescents with a depressive disorder receiving standard-of-care community treatment were assessed at a baseline and a follow-up timepoint. Self-report and clinical measures of depression and anhedonia, along with plasma IL-6 and TNFα levels, were obtained at both timepoints. Baseline cytokine measures were examined in association with baseline and follow-up clinical measures. On an exploratory basis, change in clinical measures over time was examined in relation to change in cytokine levels over time. RESULTS: Higher baseline TNFα levels predicted higher follow-up depression severity after approximately four months (controlling for baseline depression). Higher baseline TNFα levels also associated positively with baseline anhedonia and predicted higher anhedonia at follow-up (controlling for baseline anhedonia). No association was found between change in clinical measures and change in cytokine levels over time. CONCLUSIONS: Among adolescents receiving standard-of-care community treatment for depression, higher levels of TNFα predicted greater depressive symptoms at 4-month follow-up, suggesting this cytokine may be used to help identify patients in need of more intensive treatment. Elevated TNFα levels were also associated with concurrent and future anhedonia symptoms, suggesting a specific mechanism in which TNFα affects depression trajectories. Future studies should examine the relationships between cytokine levels and depression/anhedonia symptoms at multiple timepoints in larger cohorts of depressed adolescents.