Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders
Introduction
Bipolar disorder (BD), one of the world's ten most disabling conditions, exerts a considerable toll on the psychological and physical health of the sufferer (Kupfer, 2005). The search for biological markers has yielded candidate endophenotypes including abnormal intracellular signaling cascades, inadequate cortical control over limbic activity when processing emotions, sleep and circadian rhythm dysregulation, heightened reward sensitivity, and low levels of brain-derived neurotrophic factor (Geddes and Miklowitz, 2013). Given the high rates of medical illness comorbidity in BD, the potential role of altered inflammatory activity as an illness mechanism has begun to receive attention (Goldstein et al., 2015a, Goldstein et al., 2015b).
It is well-established that inflammatory cytokines induce behaviors associated with depression, including changes in sleep, anhedonia, and decreased activity. As compared to healthy controls, adults with major depressive disorder (MDD) show increases in circulating levels of proinflammatory cytokines (Miller et al., 2009). Increases in systemic markers of inflammation are also found in patients with BD, especially among those in acutely depressed or manic states (Modabbernia et al., 2013, Brietzke et al., 2009, O’Brien et al., 2006, Guloksuz et al., 2010). These studies have focused almost exclusively on circulating levels of proinflammatory cytokines (e. g., IL-6) in adults with established MDD or BD. Fewer studies have examined upstream inflammatory signaling mechanisms such as nuclear factor kappa B (NF-κB), despite evidence that activation of these transcription factors plays a key role in the regulation of the inflammatory cascade and in responses to psychological stress (Keri et al., 2014, Pace et al., 2006, Slavich and Irwin, 2014, Wieck et al., 2013). Compared to healthy volunteers, higher levels of NF-κB activity have been found in adults with BD during depressed (Spiliotaki et al., 2006) and euthymic states (e.g., Amoruso et al., 2015). Barbosa et al. (2013) found a 7.2-fold increase in phosphorylated p65 NF-κB protein levels in euthymic bipolar I patients compared to healthy volunteers. These findings have been limited to the study of mixed peripheral blood mononuclear cell populations, despite evidence that activation of NF-κB in monocyte populations is key in initiating the inflammatory response in vivo.
Little is known about changes in the inflammatory biology of pediatric-onset major depression or BD. Limited cross-sectional data suggest that children with MDD show elevations in proinflammatory cytokines such as IL-1 beta (IL-1β) and IL-6 as compared to healthy controls (Henje Blom et al., 2012; Gabbay et al., 2009, Brambilla et al., 2004, Mitchell and Goldstein, 2014). No study has examined whether levels of the anti-inflammatory cytokine IL-10 are correspondingly lower in pediatric MDD or BD. Preliminary findings suggest increases in pro-inflammatory gene expression in adolescent offspring of adults with BD (Padmos et al., 2008) and increases in a systemic marker of inflammation, C-reactive protein (CRP) in adolescents with a bipolar spectrum disorder (i.e., bipolar disorder I,II, or not elsewhere classified) (Goldstein et al., 2011). In a within-group analysis of 123 bipolar adolescents and young adults (mean age 20.4), there was an association between high-sensitivity CRP levels (hs-CRP) and earlier age at illness onset, as well as the severity of depressive symptoms over 6 months (Goldstein et al., 2015a, Goldstein et al., 2015b). Importantly, mean levels of hs-CRP in this young sample were above the established threshold for increased risk for cardiovascular disease among adults.
The present study examined systemic and cellular markers of inflammation in adolescents who had lifetime BD spectrum disorders or MDD (currently in remission or with subsyndromal symptoms) compared to healthy controls. Our primary hypothesis was that adolescents with BD and MDD would show greater circulating concentrations of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) and/or lower levels of IL-10, as compared to healthy volunteers. Secondarily, given the key role of the NF-κB transcription control pathway in regulating cellular expression of proinflammatory genes and increases in inflammatory cytokines, we hypothesized that among adolescents with BD or MDD, levels of NF-κB activation would be higher in peripheral blood mononuclear cells, including monocyte and lymphocyte subpopulations, than among adolescents with no psychiatric history. We measured levels of NF-κB signaling in spontaneous (unstimulated) states (i.e., activation in cells in the peripheral blood) to provide an index of in vivo activation of NF-κB. Additionally, we evaluated the ability of peripheral blood mononuclear cells and lymphocyte and monocyte populations to respond to a TNF-α challenge, because this proinflammatory cytokine induces a rapid (i.e., within 15 min) activation of the NF-κB signaling pathway, regardless of cell type, as would occur in an inflammatory response. NF-κB signaling was expressed as the change in intensity between unstimulated and stimulated cells. Finally, we examined the current severity of depressive and manic symptoms, body mass index, and medication regimens as additional independent variables or covariates for these group comparisons.
Section snippets
Participants
All subjects were between age 12 and 18 yrs. Patient participants had to meet lifetime DSM-IV-TR (American Psychiatric Association, 2000) criteria for bipolar disorder (BD), type I (n=7), type II (n=5), or not otherwise specified (n=6); or major depressive disorder (MDD, n=13). Bipolar disorder not otherwise specified was operationalized as per the Course and Outcome of Bipolar Youth criteria (Birmaher et al., 2009): (1) a distinct period of abnormally elevated, expansive, or irritable mood
Sample Composition
Of 150 candidates screened by telephone or in person, 60 refused and 52 were deemed ineligible. Of the 52 ineligible candidates, 34 were outside the 12–18 year age range, and 10 had autism spectrum disorders, psychosis, or chronic medical illnesses. Six candidates for the control group were excluded because they had siblings who were being treated for depression or BD. Two reported being afraid of needles. The remaining 38 participants met the study's inclusionary criteria:18 had BD, 13 had
Discussion
Early onset of bipolar disorder (i.e., under age 18) is a consistent predictor of a poor course of illness over time, including an increased frequency of suicide attempts, more severe residual symptoms, higher rates of recurrence, and treatment resistance (Post et al., 2010). The present study examined whether adolescents with BD differed from adolescents with MDD or no psychiatric history on measures of inflammation. Examining a young sample reduces the role of illness burden or extensive
Conflict of interest
Dr. Miklowitz has received research funding from the National Institute of Mental Health, the UCLA Cousins Center for Psychoneuroimmunology, the Deutsch, Kayne, and Knapp Family Foundations, Danny Alberts Foundation, Attias Family Foundation, and the American Foundation for Suicide Prevention; and book royalties from Guilford Press and John Wiley and Sons. Dr. Irwin is supported by the NIMH, the UCLA Cousins Center for Psychoneuroimmunology; and the UCLA Claude D. Pepper Older Americans
Funding
This research was supported by National Institute of Mental Health grants R01MH093676 and R33MH097007 (DJM) and grants from the UCLA Clinical and Translational Sciences Institute, the Carl and Roberta Deutsch Foundation, the Kayne Family Foundation (DJM), and the UCLA Cousins Center for Psychoneuroimmunology (MRI). The funders had no role in the design or conduct of the study, in data collection, analysis or interpretation, or in writing the report.
Acknowledgments
The authors thank Marissa Caudill, Marc Weintraub, and Brittany Matkevich of the UCLA Semel Institute for their assistance with data collection, and Lisa Goehler of the University of Virginia for comments on an initial draft of this manuscript.
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