Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces

Alexandra J M Beunders; Sigfried N T M Schouws; Andrew T Olagunju; Vicent Balanzá-Martínez; Nicole C M Korten; Ralph W Kupka; Katherine E Burdick; Andre F Carvalho; Ariel G Gildengers; Lars V Kessing; Roger S McIntyre; Paula V Nunes; Ayal Schaffer; Ivan J Torres; Shang-Ying Tsai; Tamsyn E Van Rheenen; Eduard Vieta; Lakshmi N Yatham; Allan H Young; Lisa T Eyler; Kamilla W Miskowiak; Annemiek Dols

doi:10.1111/bdi.70109

Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces

Alexandra J M Beunders^*
, Sigfried N T M Schouws
, Andrew T Olagunju
, Vicent Balanzá-Martínez
, Nicole C M Korten
, Ralph W Kupka
, Katherine E Burdick
, Andre F Carvalho
, Ariel G Gildengers
, Lars V Kessing
, Roger S McIntyre
, Paula V Nunes
, Ayal Schaffer
, Ivan J Torres
, Shang-Ying Tsai
, Tamsyn E Van Rheenen
, Eduard Vieta
, Lakshmi N Yatham
, Allan H Young
, Lisa T Eyler

Kamilla W Miskowiak, Annemiek Dols

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

Abstract

BACKGROUND: Cognitive impairment is common in bipolar disorder (BD), but the underlying pathophysiology remains unclear. This systematic review aimed to (1) summarize all literature describing relationships of biofluid biomarkers and cognition in BD and (2) identify which biofluid biomarkers correlate most consistently with cognition in BD.

METHODS: This systematic review followed procedures of the PRISMA statement. PubMed, EMBASE, and PsycINFO were searched from inception until July 2023. Original studies assessing the relationships between biofluid biomarkers and cognitive functioning in adults with BD were included. Studies on neuroimaging markers and genetic biomarkers were excluded.

RESULTS: We identified 60 studies, together describing 184 biofluid biomarkers that were measured in relation to cognitive functioning in BD. Biomarkers were organized into ten categories: oxidative stress markers (n = 14); growth factors (n = 13); neurotransmitters (n = 14); neuropeptides and hormones (n = 14); neurodegenerative markers (n = 11); inflammatory/immune markers (n = 59); serostatus to infectious agents (n = 11); amino acids, vitamins, and minerals (n = 7); metabolic factors (n = 23); hemogram, coagulation, and fibrinolysis markers (n = 18). Preliminary evidence for a significant relationship with cognition appeared for HSV-1 IgG, CRP, and homocysteine (Hcy); higher biomarker levels were associated with worse cognition.

DISCUSSION: Included studies were heterogeneous and many were deemed to be of low quality following risk of bias assessment. The identified three biofluid biomarkers represent history of previous infections, current inflammation, and/or physical or psychological stress. Poor physical health, possibly represented by a broad range of biomarker aberrations, may play a role in the pathophysiology of cognitive impairment in BD.

TRIAL REGISTRATION: PROSPERO registration number: CRD42021224226.

Original language	English
Article number	e70109
Journal	Bipolar Disorders
Volume	28
Issue number	5
Early online date	1 Jul 2026
DOIs	https://doi.org/10.1111/bdi.70109
Publication status	E-pub ahead of print - 1 Jul 2026

Keywords

Humans
Bipolar Disorder/complications
Biomarkers/metabolism
Cognitive Dysfunction/metabolism

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Bipolar Disorders - 2026 - Beunders - Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder A Systematic ReviewFinal published version, 1.08 MBLicence: CC BY

Cite this

Beunders, A. J. M., Schouws, S. N. T. M., Olagunju, A. T., Balanzá-Martínez, V., Korten, N. C. M., Kupka, R. W., Burdick, K. E., Carvalho, A. F., Gildengers, A. G., Kessing, L. V., McIntyre, R. S., Nunes, P. V., Schaffer, A., Torres, I. J., Tsai, S.-Y., Van Rheenen, T. E., Vieta, E., Yatham, L. N., Young, A. H., ... Dols, A. (2026). Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces. Bipolar Disorders, 28(5), Article e70109. Advance online publication. https://doi.org/10.1111/bdi.70109

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title = "Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces",

abstract = "BACKGROUND: Cognitive impairment is common in bipolar disorder (BD), but the underlying pathophysiology remains unclear. This systematic review aimed to (1) summarize all literature describing relationships of biofluid biomarkers and cognition in BD and (2) identify which biofluid biomarkers correlate most consistently with cognition in BD.METHODS: This systematic review followed procedures of the PRISMA statement. PubMed, EMBASE, and PsycINFO were searched from inception until July 2023. Original studies assessing the relationships between biofluid biomarkers and cognitive functioning in adults with BD were included. Studies on neuroimaging markers and genetic biomarkers were excluded.RESULTS: We identified 60 studies, together describing 184 biofluid biomarkers that were measured in relation to cognitive functioning in BD. Biomarkers were organized into ten categories: oxidative stress markers (n = 14); growth factors (n = 13); neurotransmitters (n = 14); neuropeptides and hormones (n = 14); neurodegenerative markers (n = 11); inflammatory/immune markers (n = 59); serostatus to infectious agents (n = 11); amino acids, vitamins, and minerals (n = 7); metabolic factors (n = 23); hemogram, coagulation, and fibrinolysis markers (n = 18). Preliminary evidence for a significant relationship with cognition appeared for HSV-1 IgG, CRP, and homocysteine (Hcy); higher biomarker levels were associated with worse cognition.DISCUSSION: Included studies were heterogeneous and many were deemed to be of low quality following risk of bias assessment. The identified three biofluid biomarkers represent history of previous infections, current inflammation, and/or physical or psychological stress. Poor physical health, possibly represented by a broad range of biomarker aberrations, may play a role in the pathophysiology of cognitive impairment in BD.TRIAL REGISTRATION: PROSPERO registration number: CRD42021224226.",

keywords = "Humans, Bipolar Disorder/complications, Biomarkers/metabolism, Cognitive Dysfunction/metabolism",

author = "Beunders, \{Alexandra J M\} and Schouws, \{Sigfried N T M\} and Olagunju, \{Andrew T\} and Vicent Balanz{\'a}-Mart{\'i}nez and Korten, \{Nicole C M\} and Kupka, \{Ralph W\} and Burdick, \{Katherine E\} and Carvalho, \{Andre F\} and Gildengers, \{Ariel G\} and Kessing, \{Lars V\} and McIntyre, \{Roger S\} and Nunes, \{Paula V\} and Ayal Schaffer and Torres, \{Ivan J\} and Shang-Ying Tsai and \{Van Rheenen\}, \{Tamsyn E\} and Eduard Vieta and Yatham, \{Lakshmi N\} and Young, \{Allan H\} and Eyler, \{Lisa T\} and Miskowiak, \{Kamilla W\} and Annemiek Dols",

note = "{\textcopyright} 2026 The Author(s). Bipolar Disorders published by John Wiley \& Sons Ltd.",

year = "2026",

month = jul,

day = "1",

doi = "10.1111/bdi.70109",

language = "English",

volume = "28",

journal = "Bipolar Disorders",

issn = "1398-5647",

publisher = "Blackwell Munksgaard",

number = "5",

}

Beunders, AJM, Schouws, SNTM, Olagunju, AT, Balanzá-Martínez, V, Korten, NCM, Kupka, RW, Burdick, KE, Carvalho, AF, Gildengers, AG, Kessing, LV, McIntyre, RS, Nunes, PV, Schaffer, A, Torres, IJ, Tsai, S-Y, Van Rheenen, TE, Vieta, E, Yatham, LN, Young, AH, Eyler, LT, Miskowiak, KW & Dols, A 2026, 'Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces', Bipolar Disorders, vol. 28, no. 5, e70109. https://doi.org/10.1111/bdi.70109

Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces. / Beunders, Alexandra J M; Schouws, Sigfried N T M; Olagunju, Andrew T et al.
In: Bipolar Disorders, Vol. 28, No. 5, e70109, 08.2026.

Research output: Contribution to journal › Review article › peer-review

TY - JOUR

T1 - Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder

T2 - A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces

AU - Beunders, Alexandra J M

AU - Schouws, Sigfried N T M

AU - Olagunju, Andrew T

AU - Balanzá-Martínez, Vicent

AU - Korten, Nicole C M

AU - Kupka, Ralph W

AU - Burdick, Katherine E

AU - Carvalho, Andre F

AU - Gildengers, Ariel G

AU - Kessing, Lars V

AU - McIntyre, Roger S

AU - Nunes, Paula V

AU - Schaffer, Ayal

AU - Torres, Ivan J

AU - Tsai, Shang-Ying

AU - Van Rheenen, Tamsyn E

AU - Vieta, Eduard

AU - Yatham, Lakshmi N

AU - Young, Allan H

AU - Eyler, Lisa T

AU - Miskowiak, Kamilla W

AU - Dols, Annemiek

PY - 2026/7/1

Y1 - 2026/7/1

N2 - BACKGROUND: Cognitive impairment is common in bipolar disorder (BD), but the underlying pathophysiology remains unclear. This systematic review aimed to (1) summarize all literature describing relationships of biofluid biomarkers and cognition in BD and (2) identify which biofluid biomarkers correlate most consistently with cognition in BD.METHODS: This systematic review followed procedures of the PRISMA statement. PubMed, EMBASE, and PsycINFO were searched from inception until July 2023. Original studies assessing the relationships between biofluid biomarkers and cognitive functioning in adults with BD were included. Studies on neuroimaging markers and genetic biomarkers were excluded.RESULTS: We identified 60 studies, together describing 184 biofluid biomarkers that were measured in relation to cognitive functioning in BD. Biomarkers were organized into ten categories: oxidative stress markers (n = 14); growth factors (n = 13); neurotransmitters (n = 14); neuropeptides and hormones (n = 14); neurodegenerative markers (n = 11); inflammatory/immune markers (n = 59); serostatus to infectious agents (n = 11); amino acids, vitamins, and minerals (n = 7); metabolic factors (n = 23); hemogram, coagulation, and fibrinolysis markers (n = 18). Preliminary evidence for a significant relationship with cognition appeared for HSV-1 IgG, CRP, and homocysteine (Hcy); higher biomarker levels were associated with worse cognition.DISCUSSION: Included studies were heterogeneous and many were deemed to be of low quality following risk of bias assessment. The identified three biofluid biomarkers represent history of previous infections, current inflammation, and/or physical or psychological stress. Poor physical health, possibly represented by a broad range of biomarker aberrations, may play a role in the pathophysiology of cognitive impairment in BD.TRIAL REGISTRATION: PROSPERO registration number: CRD42021224226.

AB - BACKGROUND: Cognitive impairment is common in bipolar disorder (BD), but the underlying pathophysiology remains unclear. This systematic review aimed to (1) summarize all literature describing relationships of biofluid biomarkers and cognition in BD and (2) identify which biofluid biomarkers correlate most consistently with cognition in BD.METHODS: This systematic review followed procedures of the PRISMA statement. PubMed, EMBASE, and PsycINFO were searched from inception until July 2023. Original studies assessing the relationships between biofluid biomarkers and cognitive functioning in adults with BD were included. Studies on neuroimaging markers and genetic biomarkers were excluded.RESULTS: We identified 60 studies, together describing 184 biofluid biomarkers that were measured in relation to cognitive functioning in BD. Biomarkers were organized into ten categories: oxidative stress markers (n = 14); growth factors (n = 13); neurotransmitters (n = 14); neuropeptides and hormones (n = 14); neurodegenerative markers (n = 11); inflammatory/immune markers (n = 59); serostatus to infectious agents (n = 11); amino acids, vitamins, and minerals (n = 7); metabolic factors (n = 23); hemogram, coagulation, and fibrinolysis markers (n = 18). Preliminary evidence for a significant relationship with cognition appeared for HSV-1 IgG, CRP, and homocysteine (Hcy); higher biomarker levels were associated with worse cognition.DISCUSSION: Included studies were heterogeneous and many were deemed to be of low quality following risk of bias assessment. The identified three biofluid biomarkers represent history of previous infections, current inflammation, and/or physical or psychological stress. Poor physical health, possibly represented by a broad range of biomarker aberrations, may play a role in the pathophysiology of cognitive impairment in BD.TRIAL REGISTRATION: PROSPERO registration number: CRD42021224226.

KW - Humans

KW - Bipolar Disorder/complications

KW - Biomarkers/metabolism

KW - Cognitive Dysfunction/metabolism

U2 - 10.1111/bdi.70109

DO - 10.1111/bdi.70109

M3 - Review article

C2 - 42387906

SN - 1398-5647

VL - 28

JO - Bipolar Disorders

JF - Bipolar Disorders

IS - 5

M1 - e70109

ER -

Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces

Abstract

Keywords

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