ReviewCytokines in bipolar disorder: A systematic review and meta-analysis
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)
S02-02 mitochondrial dysfunction and oxidative stress in bipolar disorder
European Psychiatry
(2009)- et al.
Serum S100B and antioxidant enzymes in bipolar patients
Journal of Psychiatric Research
(2007) - et al.
Altered mRNA levels of chemokines and cytokines in schizophrenia and bipolar disorder
Schizophrenia Research
(2010) - et al.
Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells
Molecular and Cellular Neurosciences
(2003) - et al.
Cytokine production in bipolar affective disorder patients under lithium treatment
Journal of Affective Disorders
(2004) - et al.
High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder
Biological Psychiatry
(2003) - et al.
Abnormalities in serum chemokine levels in euthymic patients with bipolar disorder
Brain, Behavior, and Immunity
(2009) - et al.
Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder
Journal of Affective Disorders
(2009) - et al.
Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus
Neuroscience
(1994) - et al.
Hypothalamic-pituitary-adrenal axis and bipolar disorder
Psychiatric Clinics of North America
(2005)
Immunologic abnormalities associated with mania
Brain, Behavior, and Immunity
Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder
Progress in Neuro-Psychopharmacology & Biological PsychiatryisBiological Psychiatry
The activation of monocyte and T cell networks in patients with bipolar disorder
Brain, Behavior, and Immunity
A neurotrophic model for stress-related mood disorders
Biological Psychiatry
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
Cytokine levels in euthymic bipolar patients
Journal of Affective Disorders
Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia
Journal of Psychiatric Research
Positive and negative acute phase proteins in affective subtypes
Journal of Affective Disorders
High-sensitivity C-reactive protein levels in patients with major depressive disorder and bipolar mania
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis
Journal of Psychiatric Research
Effect of alcohol consumption on systemic markers of inflammation
Lancet
Peripheral biomarkers and illness activity in bipolar disorder
Journal of Psychiatric Research
The potential use of biomarkers as an adjunctive tool for staging bipolar disorder
Progress in Neuro-Psychopharmacology & Biological Psychiatry
Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder
Journal of Affective Disorders
T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients
Psychiatry Research
The immune system, depression and the action of antidepressants
Progress in Neuro-Psychopharmacology & Biological Psychiatry
State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study
Neuroscience Letters
Immunologic variables in acute mania of bipolar disorder
Journal of Neuroimmunology
Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture
Brain Research
Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects
Neuroscience Letters
Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers
Journal of Psychiatric Research
Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs
Psychiatry Research
Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression
Biological Psychiatry
Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects
Biological Psychiatry
Cytokine profiles in bipolar affective disorder: focus on acutely ill patients
Journal of Affective Disorders
To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers
Brain, Behavior, and Immunity
Effects of antipsychotic drugs on cytokine networks
Journal of Psychiatric Research
Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein to a high-fat dietary load
Nutrition
IL-6 is associated with metabolic syndrome in bipolar disorder
Brain, Behavior, and Immunity
Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells
Biological Psychiatry
Immune parameters in euthymic bipolar patients and normal volunteers
Journal of Affective Disorders
Oxidative stress markers in bipolar disorder: a meta-analysis
Journal of Affective Disorders
Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder
European Archives of Psychiatry and Clinical Neuroscience
Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia
Journal of Neuroscience
Neuroprogression: pathways to progressive brain changes in bipolar disorder
International Journal of Neuropsychopharmacology
Pathways underlying neuroprogression in bipolar disorder: focus on inflammation; oxidative stress and neurotrophic factors
Neuroscience & Biobehavioral Reviews
Immune system-central nervous system interactions: effect and immunomodulatory consequences of immune system mediators on the brain
Antimicrobial Agents and Chemotherapy
Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain
Molecular Psychiatry
Cytokines in bipolar disorder: recent findings, deleterious effects but promise for future therapeutics
CNS Spectrums
Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor
Bipolar Disorder
Cited by (224)
A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives
2024, Brain, Behavior, and ImmunityHigh unrecognized SARS-CoV-2 exposure of newly admitted and hospitalized psychiatric patients
2023, Brain, Behavior, and ImmunityFerritin as a potential disease marker in patients with bipolar disorder
2023, Journal of Affective DisordersHeightened inflammation in bipolar disorder occurs independent of symptom severity and is explained by body mass index
2023, Brain, Behavior, and Immunity - Health