ReviewCytokines in bipolar disorder vs. healthy control subjects: A systematic review and meta-analysis
Introduction
Current hypotheses regarding the neurobiological background for bipolar disorder involves impairment in both cellular energy regulation, the immune system and defects in neuroprotective mechanisms along with epigenetic abberations (Gardner and Boles, 2011; Grande et al., 2012). These components have been suggested to be central to the neuroprogressive changes observed in bipolar disorder (Berk, 2009; Berk et al., 2011) and inflammatory system dysfunction could potentially be a key integrating element in the pathophysiological mechanism behind the disorder (Kapczinski et al., 2008; Stertz et al., 2013).
One theory behind the involvement of the inflammatory system in bipolar disorder, the macrophage-T-lymphocyte theory, was initially proposed for depression and schizophrenia (Leonard, 2001; Smith, 1991; Smith & Maes, 1995), and recently extended to bipolar disorder. This theory states a role for a chronically activated immune response system mediated by macrophages (and in the brain, microglia) and T-lymphocytes as a basis for the disease, in which their production of cytokines and inflammatory substances renders a vulnerability and destabilization of the brain function, resulting in susceptibility towards environmental stressors and, in turn, precipitating mood disturbances.
Another theory, the microglial hypothesis, postulates that activated microglia in the brain, with the release of proinflammatory cytokines, exerts negative effects on the neuroprotective system, thereby mediating further pathophysiological disturbances in bipolar disorder (Rajkowska, 2000; Schroeter et al., 2011).
Recently, evidence from clinical studies has emerged in support of these theories, indicating a role for immune system dysregulation and inflammation in bipolar disorder (Goldstein et al., 2009). Immune system abberations have been demonstrated in peripheral blood using both in-vitro techniques (Kim et al., 2007; Knijff et al., 2007) and in-vivo analysis, showing alterations of inflammatory markers (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). Additionally, evidence from preclinicial studies suggests that modulation of neuroinflammatory processes is among the mechanisms of action of mood stabilizers such as lithium (Kang et al., 2012; Nahman et al., 2012) and valproic acid (Xuan et al., 2012), further indicating a role for neuroinflammation in bipolar disorder. Along these lines, treatment augmentation with nonsteroidal anti-inflammatory drugs (NSAID) may be of potential (Torrey & Davis, 2012) but has yet been explored in only one randomized trial, showing some effect on depressive symptoms in depressive and mixed episodes in bipolar disorder patients (Nery et al., 2008).
Several lines of evidence pointing to dysregulation of cellular metabolism, impaired neuroprotection and inflammation as key pathophysiological processes in bipolar disorder indicate that peripheral markers of these pathways are related to illness activity (Kapczinski et al., 2011). Alterations of peripheral markers have most consistently been demonstrated during acute illness episodes. However, both functional deficits and biomarker abberations also appear to be present in euthymia, indicating a role for peripheral biomarkers as trait markers as well (Breunis et al., 2003; Hsiao et al., 2009; Jamrozinski et al., 2009; Kauer-Sant'Anna et al., 2009), possibly reflecting pathophysiological processes present during euthymic periods. Thus disturbances in the inflammatory system appear to be present in all phases of the illness.
While alterations related to the inflammatory system have been reported in individual studies, results have been inconsistent. In a recent systematic review and meta-analysis of state related alterations of cytokine-, cytokine receptor and cytokine antagonists in bipolar disorder by our group, we found support of elevated levels of some cytokines and cytokine receptors in both manic patients and euthymic patients (Munkholm et al., 2013), with overall findings limited by heterogeneity, small sample sizes and lack of control for confounding factors. Stratification of the analysis according to affective state allowed for assessment of state-related alterations of cytokines, but also resulted in low study numbers and a lack of replicability for a majority of the cytokines investigated. Because of our finding of a largely identical direction of cytokine alterations in bipolar disorder patients compared with healthy controls regardless of the affective state, it may be relevant and well justified to do a global analysis, integrating research results from both euthymic, depressive and manic bipolar patients, with the potential of increasing the number of include studies, the statistical power of the analyses and the strength of evidence in this important area of research, and in this way broadening conclusions beyond our initial work.
We therefore conducted a meta-analysis of peripheral blood cytokine-, cytokine receptor and cytokine antagonist levels in bipolar disorder, integrating results globally, across affective states. Our primary objective was to investigate peripheral alterations of endogenous immune activity in bipolar disorder patients in comparison with healthy control subjects. Second, we wished to assess the effect of symptom severity, medication status and various clinical characteristics on cytokine-, cytokine receptor and cytokine antagonist levels.
Section snippets
Methods and materials
A protocol for the review was prepared before commencing the data collection process. The meta-analysis was reported according to the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) (Moher et al., 2009).
Study selection
The database search yielded a total of 849 results (218 articles from Medline, 524 articles from Embase and 107 articles from PsycINFO) after limiting the search strategy to human studies published in English and three articles were additionally identified by hand search (Fig. 1). A total of 65 potential studies were eligible for meta-analysis after eliminating duplicates (Barbosa et al., 2011; Barbosa et al., 2012a, 2012b; Bellani et al., 2010; Boufidou et al., 2004; Breunis et al., 2003;
Discussion
This meta-analysis, using a global approach, incorporating findings from the euthymic, depressed and manic phases of the illness included 18 studies, totalling 761 bipolar disorder patients in various affective phases and 919 healthy control subjects.
Of the 17 different cytokine-, cytokine receptor and cytokine antagonists investigated, 14 were examined in multiple studies with overall significant findings for five cytokine parameters. Specifically, the meta-analysis demonstrated significantly
Conflicts 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.
Julie Vesergaard Braüner has no conflicts to disclose.
Contributors
Klaus Munkholm, Julie V. Braüner, Maj Vinberg and Lars V. Kessing designed the study. Klaus Munkholm wrote the study protocol and performed the initial literature search and data extraction. Julie V. Braüner, Maj Vinberg and Lars V. Kessing subsequently performed data extraction, confirming the results of the initial data extraction. Klaus Munkholm performed the statistical procedures and wrote first draft of the manuscript with assistance from Julie V. Braüner. All authors contributed to and
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).
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