Cytokines in bipolar disorder: A systematic review and meta-analysis
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.
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Patients with MDD or BD have increased levels of different pro-inflammatory cytokines compared with healthy controls.
“Data from several meta-analyses outlines that patients suffering MDD or BD have increased different pro-inflammatory cytokines levels as compared with healthy controls [47,48,49,50].”
From Neutrophil-to-Lymphocyte Ratio, a Novel Inflammatory Marker, as a Predictor of Bipolar Type in Depressed Patients: A Quest for Biological Markers (2021) · cites this paper as [50]
sIL-2R and sTNF-R1 were significantly elevated consistently in BD.
“For example, sIL-2R and sTNF-R1 were significantly elevated consistently in BD32–34.”
From Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses (2019) · cites this paper as [34]
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- Authors
- Munkholm, K., Vinberg, M., & Vedel Kessing, L.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Munkholm, Klaus
- Venue
- Journal of Affective Disorders
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 144
- Issue
- 1-2
- Pages
- 16-27
- ISSN
- 0165-0327 (ISSN-L)
- OpenAlex
- W2028131345
- Cited by
- 256
- References
- 112
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 13 · 2023: 12 · 2022: 17 · 2021: 25 · 2020: 24 · 2019: 20 · 2018: 17 · 2017: 22 · 2016: 21 · 2015: 31 · 2014: 26 · 2013: 10 · 2012: 2
- FWCI
- 2.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Affective Disorders (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Lundbeck Foundation, Denmark (R34-A3696)
- Danish Council for Independent Research | Medical Sciences (09-073972)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- bipolar disorder, cytokines, immune dysregulation, TNF-α, soluble interleukin-2 receptor, manic state, euthymic state, affective states, cytokine receptors, cytokine antagonists
- MeSH terms
- Adult, Affect, Bipolar Disorder, Female, Humans, Male, Middle Aged, Tumor Necrosis Factor-alpha, Receptors, Interleukin-2, Cytokines, Receptors, Cytokine, Controlled Clinical Trials as Topic, Receptors, Tumor Necrosis Factor, Type I
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