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

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.