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Neurotrophins, cytokines, oxidative stress mediators and mood state in bipolar disorder: systematic review and meta-analyses

  • Tobias Rowland (a1), Benjamin I. Perry (a2), Rachel Upthegrove (a3), Nicholas Barnes (a4), Jayanta Chatterjee (a5), Daniel Gallacher (a6) and Steven Marwaha (a7)...



A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.


To synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness.


Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses.


In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified.


Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.

Declaration of interest


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This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (, which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

Correspondence: Steven Marwaha, Mental Health and Wellbeing, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK. Email:


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These authors contributed equally to the work.



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