Elsevier

Psychiatry Research

Volume 241, 30 July 2016, Pages 315-322
Psychiatry Research

Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders

https://doi.org/10.1016/j.psychres.2016.04.120Get rights and content

Highlights

  • Few studies have examined immunological functioning in youths with bipolar disorder.

  • Bipolar, depressed, and healthy adolescents were compared on inflammatory measures.

  • Bipolar adolescents had higher levels of NF-κB and IL-1β than controls.

  • Immune dysregulation may be a target for early intervention in bipolar disorder.

Abstract

Adults with bipolar disorder (BD) and major depressive disorder (MDD) have higher circulating levels of proinflammatory cytokines than healthy controls. However, it is not known whether pediatric-onset patients with BD or MDD show increases in levels of inflammation or activation of nuclear factor kappa B (NF-κB), a key transcription factor in inflammatory signaling. Circulating levels of inflammatory cytokines, as well as spontaneous and stimulated levels of activated NF-κB in total peripheral blood mononuclear cells, monocytes and lymphocytes were measured in adolescents with BD (n=18), MDD (n=13), or no psychiatric history (n=20). Participants had a range of mood symptoms at time of testing. Adolescents with BD had significantly higher spontaneous levels of NF-κB in peripheral blood mononuclear cells, monocyte and lymphocyte populations, and higher plasma levels of IL-1β than healthy controls. Following stimulation with recombinant human TNF-α, participants with BD and MDD both had greater increases in NF-κB in monocytes than controls. Further, greater stimulated increases of NF-κB in monocytes were associated with the current severity of depressive symptoms. The results are limited by the small sample and cross-sectional design. Interventions that target early immunological dysregulation should be examined in relation to long-term outcomes in youth with bipolar and depressive disorders.

Clinical Trial registration information: Early Intervention for Youth at Risk for Bipolar Disorder, https://clinicaltrials.gov/ct2/show/NCT01483391.

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.

References (52)

  • M.R. Irwin et al.

    Sleep loss activates cellular inflammatory signaling

    Biol. Psychiatry

    (2008)
  • J. Kaufman et al.

    Schedule for Affective Disorders and Schizophrenia for school-age children - Present and Lifetime version (K-SADS-PL): initial reliability and validity data

    J. Am. Acad. Child Adolesc. Psychiatry

    (1997)
  • S. Keri et al.

    Blood biomarkers of depression track clinical changes during cognitive-behavioral therapy

    J. Affect. Disord.

    (2014)
  • Y.K. Kim et al.

    T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients

    Psychiatry Res.

    (2004)
  • A.H. Miller et al.

    Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression

    Biol. Psychiatry

    (2009)
  • R.H.B. Mitchell et al.

    Inflammation in children and adolescents with neuropsychiatric disorders: a systematic review

    J. Am. Acad. Child Adolesc. Psychiatry

    (2014)
  • A. Modabbernia et al.

    Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies

    Biol. Psychiatry

    (2013)
  • K.A. Muscatell et al.

    Greater amygdala activity and dorsomedial prefrontal-amygdala coupling are associated with enhanced inflammatory responses to stress

    Brain Behav. Immun.

    (2015)
  • S.M. O’Brien et al.

    Cytokine profiles in bipolar affective disorder: focus on acutely ill patients

    J. Affect. Disord.

    (2006)
  • M.F. O’Connor et al.

    To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers

    Brain Behav. Immun.

    (2009)
  • M. Spiliotaki et al.

    Altered glucocorticoid receptor signaling cascade in lymphocytes of bipolar disorder patients

    Psychoneuroendocrinology

    (2006)
  • A. Wieck et al.

    Differential neuroendocrine and immune responses to acute psychosocial stress in women with type 1 bipolar disorder

    Brain Behav. Immun.

    (2013)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • D. Axelson et al.

    A preliminary study of the kiddie schedule for affective disorders and schizophrenia for school-age children mania rating scale for children and adolescents

    J. Child Adolesc. Psychopharmacol.

    (2003)
  • A. Bierhaus et al.

    A mechanism converting psychosocial stress into mononuclear cell activation

    Proc. Natl. Acad. Sci. USA

    (2003)
  • B. Birmaher et al.

    Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the course and outcome of bipolar youth (COBY) study

    Am. J. Psychiatry

    (2009)
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