Review
Cytokines in bipolar disorder: A systematic review and meta-analysis

https://doi.org/10.1016/j.jad.2012.06.010Get rights and content

Abstract

Background

Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state.

Methods

We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement.

Results

Thirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p<0.01 for each). Levels of sTNF-R1 and TNF-α were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p<0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels.

Limitations

Stratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies.

Conclusions

This meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended.

Introduction

Multiple lines of evidence indicate that bipolar disorder is a systemic disease, with widespread biochemical alterations occurring in and beyond the central nervous system (Berk et al., 2010, Kapczinski et al., 2008). Current hypotheses regarding the neurobiological background for bipolar disorder point towards defects in both cellular energy regulation, the immune system and expression of neurotrophic factors along with epigenetic alterations as core elements in the pathophysiology of the disorder (Gardner and Boles, 2010, Grande et al., 2011). These components, along with epigenetic alterations, have accordingly been proposed to be central to the neuroprogressive changes observed in bipolar disorder (Berk, 2009, Berk et al., 2010).

Several areas of research have pointed to immune system dysregulation and inflammation in bipolar disorder (Goldstein et al., 2009). More specifically, immune system aberrations have been demonstrated in both in-vitro studies (Kim et al., 2007, Knijff et al., 2007) and in clinical studies showing both alterations of peripheral markers of inflammation (Brietzke et al., 2009b, Cunha et al., 2008, Dickerson et al., 2007) and alterations of inflammation related gene signatures (Drexhage et al., 2010b, Padmos et al., 2008). In addition, preclinical studies have indicated anti-inflammatory properties as a possible role of action for mood stabilizers (Bosetti et al., 2002, Lee et al., 2008, Maes et al., 1999, Rapaport and Manji, 2001).

Cytokines are key signalling molecules in inflammation, exerting a regulatory effect in both the innate and the adaptive immunological response. They are produced by immune cells as well as non-immune cells and exert their effects beyond strictly the immune system. Cytokines bind to either specific cellular receptors or soluble receptors capable of modulating the immunological effect of cytokines. The immune response is further moderated by cytokine receptor antagonists, also binding to cytokine receptors (Drexhage et al., 2010a). Importantly, the role of cytokines in metabolism extend beyond the inflammatory system, impacting also on neurotransmitter metabolism, neurogenesis and the neuroendocrine system (Haroon et al., 2012).

Alterations of the inflammatory system appear to be related to disease state. Peripheral markers related to inflammation, oxidative stress and neurotrophins have been proposed as mediators of systemic toxicity, specifially related to mood episodes and illness activity (Grande et al., 2011, Kapczinski et al., 2010a, 2010b). In unipolar depression, inflammatory markers elevated in depressed patients have been demonstrated to normalize after successful treatment (Miller et al., 2009) and in schizophrenia some cytokines have been indicated to be state markers for acute exacerbations (Miller et al., 2011). While mood-state related inflammatory system alterations have been demonstrated in individual clinical studies in bipolar disorder, mainly indicating elevated levels of pro-inflammatory markers during manic and depressive episodes, results have been inconsistent and the association between altered cytokine levels and mood state remains unclear for a number of cytokines (Goldstein et al., 2009).

Taken together, current evidence suggests that core pathological processes underlying bipolar disorder and the possible detrimental effects resulting from mood episodes are closely related to illness activity and alterations between affective states.

Meta-analysis has the potential to bring further clarity to an area of research where single studies are generally of low power and to improve the strength of evidence while also examining sources of heterogeneity among studies and whether this influences the observed effects.

The purpose of the present study was therefore to perform a meta-analysis of peripheral blood cytokine-, cytokine receptor and cytokine antagonist levels in bipolar disorder according to clinical state. First, we examined alterations of endogenous immune activity in bipolar disorder patients according to clinical state (i.e., manic, depressive and euthymic state) in comparison to healthy controls. Comparisons between bipolar patients in different clinical states and evaluation of intra-individual alterations of immune activity were also performed. Second, we performed a qualitative assessment of the effect of symptom severity, medication status and clinical characteristics (i.e., smoking status and body mass index) on cytokine-, cytokine receptor and cytokine antagonist levels.

We specifically refrained from including a global analysis of cytokine levels in bipolar patients compared with healthy controls, as this does not inform on cytokine levels according to mood state and illness activity.

This is the first meta-analysis of cytokines in bipolar disorder.

Section snippets

Methods and materials

The meta-analysis was conducted and reported according to the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) (Moher et al., 2009). A protocol for the review was prepared and is available by contact to the first author.

Study selection

Fig. 1 shows the PRISMA flow chart describing the study selection process. The initial literature search identified 195 articles from Medline, 400 articles from Embase, 92 articles from PsycINFO after limiting the search strategy to human studies published in English and one article was additionally identified by hand search. After eliminating duplicates, 58 potential studies were eligible for meta-analysis (Barbosa et al., 2011, Bellani et al., 2010, Boufidou et al., 2004, Breunis et al., 2003

Discussion

This systematic review and meta-analysis of cytokine-, cytokine receptor and cytokine antagonist levels in bipolar disorder during different affective phases of the illness included 13 studies, comprising 556 bipolar disorder patients and 767 healthy control subjects. It is the first meta-analysis of cytokine levels in bipolar disorder according to affective state.

Overall, the meta-analysis demonstrated elevated levels of sTNF-R1, TNF-α and sIL-2R in manic patients compared with healthy control

Role of funding source

The study was supported by grants from the Lundbeck Foundation, Denmark (R34-A3696) and the Danish Council for Independent Research | Medical Sciences (09-073972).

Conflict of interest

Maj Vinberg has been a consultant for Eli Lilly, AstraZeneca, Servier and Janssen-Cilag.

Lars Vedel Kessing has been a consultant for Bristol-Myers Squibb, Eli Lilly, Lundbeck, AstraZeneca, Pfizer, Wyeth, Servier and Janssen-Cilag.

Klaus Munkholm has no conflicts of interest to disclose.

Acknowledgments

This study was supported by grants from the Lundbeck Foundation, Denmark (R34-A3696) and the Danish Council for Independent Research | Medical Sciences (09-073972).

References (119)

  • F. Dickerson

    Immunologic abnormalities associated with mania

    Brain, Behavior, and Immunity

    (2010)
  • F. Dickerson et al.

    Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder

    Progress in Neuro-Psychopharmacology & Biological PsychiatryisBiological Psychiatry

    (2007)
  • R.C. Drexhage et al.

    The activation of monocyte and T cell networks in patients with bipolar disorder

    Brain, Behavior, and Immunity

    (2011)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biological Psychiatry

    (2006)
  • B.S. Fernandes et al.

    Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis

    Journal of Psychiatric Research

    (2011)
  • S. Guloksuz et al.

    Cytokine levels in euthymic bipolar patients

    Journal of Affective Disorders

    (2010)
  • S. Hope et al.

    Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia

    Journal of Psychiatric Research

    (2011)
  • M. Hornig et al.

    Positive and negative acute phase proteins in affective subtypes

    Journal of Affective Disorders

    (1998)
  • T.L. Huang et al.

    High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2007)
  • M. Haack et al.

    Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis

    Journal of Psychiatric Research

    (1999)
  • A. Imhof et al.

    Effect of alcohol consumption on systemic markers of inflammation

    Lancet

    (2001)
  • F. Kapczinski et al.

    Peripheral biomarkers and illness activity in bipolar disorder

    Journal of Psychiatric Research

    (2011)
  • F. Kapczinski et al.

    The potential use of biomarkers as an adjunctive tool for staging bipolar disorder

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2009)
  • Y.K. Kim et al.

    Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder

    Journal of Affective Disorders

    (2007)
  • Y.K. Kim et al.

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

    Psychiatry Research

    (2004)
  • B.E. Leonard

    The immune system, depression and the action of antidepressants

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2001)
  • P.Y. Lin

    State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study

    Neuroscience Letters

    (2009)
  • H.C. Liu et al.

    Immunologic variables in acute mania of bipolar disorder

    Journal of Neuroimmunology

    (2004)
  • Y.P. Liu et al.

    Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture

    Brain Research

    (2005)
  • R. Machado-Vieira et al.

    Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects

    Neuroscience Letters

    (2007)
  • M. Maes et al.

    Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers

    Journal of Psychiatric Research

    (1995)
  • M. Maes et al.

    Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs

    Psychiatry Research

    (1997)
  • A.H. Miller et al.

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

    Biological Psychiatry

    (2009)
  • B.J. Miller et al.

    Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects

    Biological Psychiatry

    (2011)
  • S.M. O'Brien et al.

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

    Journal of Affective Disorders

    (2006)
  • M.F. O'Connor et al.

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

    Brain, Behavior, and Immunity

    (2009)
  • T. Pollmacher et al.

    Effects of antipsychotic drugs on cytokine networks

    Journal of Psychiatric Research

    (2000)
  • S.D. Poppitt et al.

    Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein to a high-fat dietary load

    Nutrition

    (2008)
  • A. Prossin et al.

    IL-6 is associated with metabolic syndrome in bipolar disorder

    Brain, Behavior, and Immunity

    (2010)
  • G. Rajkowska

    Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells

    Biological Psychiatry

    (2000)
  • M.H. Rapaport

    Immune parameters in euthymic bipolar patients and normal volunteers

    Journal of Affective Disorders

    (1994)
  • A.C. Andreazza et al.

    Oxidative stress markers in bipolar disorder: a meta-analysis

    Journal of Affective Disorders

    (2008)
  • I.G. Barbosa et al.

    Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder

    European Archives of Psychiatry and Clinical Neuroscience

    (2011)
  • M.M. Behrens et al.

    Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia

    Journal of Neuroscience

    (2008)
  • M. Berk

    Neuroprogression: pathways to progressive brain changes in bipolar disorder

    International Journal of Neuropsychopharmacology

    (2009)
  • M. Berk et al.

    Pathways underlying neuroprogression in bipolar disorder: focus on inflammation; oxidative stress and neurotrophic factors

    Neuroscience & Biobehavioral Reviews

    (2010)
  • P.H. Black

    Immune system-central nervous system interactions: effect and immunomodulatory consequences of immune system mediators on the brain

    Antimicrobial Agents and Chemotherapy

    (1994)
  • F. Bosetti et al.

    Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain

    Molecular Psychiatry

    (2002)
  • E. Brietzke et al.

    Cytokines in bipolar disorder: recent findings, deleterious effects but promise for future therapeutics

    CNS Spectrums

    (2011)
  • E. Brietzke et al.

    Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor

    Bipolar Disorder

    (2010)
  • Cited by (224)

    View all citing articles on Scopus
    View full text