Background: Bipolar disorders (BD) are chronic, debilitating disorders. Our understanding of the pathogenesis and functional biomarkers in BD remains limited. The blood-brain barrier (BBB), a highly selective, protective physical barrier which separates the central nervous system from the peripheral circulation, has been increasingly investigated in the BD. This systematic review aimed to assess the relationship between BD and markers of BBB dysfunction. Methods: Studies were identified in PubMed and Medline databases in January 2021. Articles were limited to full-length peer-reviewed journal publications with no date restrictions. Included studies compared blood, CSF, post-mortem, genetic and imaging measures of BBB function in people with BD compared to healthy controls. Results: 49 studies were identified, 34 of which found an association between BD and markers of BBB dysfunction. Blood QAlb, S100B and MMP levels were found to be increased in BD participants compared to controls in 57% of the studies. In post-mortem BD studies, ICAM, neurexin, claudin-5, and chondroitin sulphate proteoglycans were increased in the anterior cingulate cortex (ACC), prefrontal grey matter, occipital cortex and cerebellum, and lateral nucleus of the entorhinal cortex respectively compared to controls. Additionally, a study of BBB leakage measured by MRI found that nearly 30% of BD participants had extensive BBB leakage compared to controls. The mood state of BD participants was also associated with markers of BBB dysfunction, with participants experiencing mania generally having increased BBB marker levels compared to participants who were depressed or in remission. Conclusions: This review suggests an association between BD and markers of BBB dysfunction. Further research is needed to control for a number of confounding factors, and to clarify whether this association provides a pathogenic mechanism, or is an epiphenomenon of BD.

TP has received a speaking honorarium from Janssen for an educational lecture on an unrelated topic. PRAS reports non-financial support from Janssen Research and Development LLC, personal fees and non-financial support from Frontiers in Psychiatry, personal fees from Allergan and a grant from H Lundbeck, outside the submitted work.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=228324

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors