Neurofilament light and glial fibrillary acidic protein in mood and anxiety disorders: A systematic review and meta-analysis

Background: Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal injury measurable in cerebrospinal fluid (CSF) and blood. Despite their potential as diagnostic tests for neurodegenerative disorders, it is unclear how they behave in mood and anxiety disorders. We conducted a systematic review and meta-analysis to investigate whether NfL and GFAP concentrations were altered in adults with mood and anxiety disorders compared to healthy controls. Methods: The study was prospectively registered on PROSPERO (CRD42023434617). We followed the PRISMA guidelines, searched PubMed, Web of Science, PsycINFO, MEDLINE and Embase up to the 31/05/2023, and assessed relevant studies and their risk of bias. The primary outcome was the standardised mean difference (SMD) and 95% confidence interval (95% CI) of NfL and GFAP concentrations, which was pooled using a random-effects model adopting the restricted maximum likelihood estimator. Results: Twenty-one studies met inclusion criteria, comprising of 2327 individuals (695 major depression, 502 bipolar disorder, and 1130 controls). When we compared people with major depression and controls, there was no difference in NfL (SMD = 0.29; 95% CI: -0.10, 0.68) nor GFAP (SMD = 0.47; 95% CI: -0.74, 1.68). In people with bipolar disorder, NfL was significantly elevated compared to controls (SMD = 0.58; 95% CI: 0.16, 0.99). However, the subgroup analysis including more sensitive assay kits (blood Simoa and CSF ELISA), found no significant difference (SMD = 0.40; 95% CI: -0.04, 0.85). Only one study studied GFAP in bipolar disorder. No studies explored NfL nor GFAP concentrations in anxiety disorders. Discussion: We found that NfL and GFAP concentrations were not elevated in depression. In bipolar disorder, NfL concentration was elevated, though not in the sensitivity analysis. Our study informs clinicians about how to interpret these emerging biomarkers in determining whether an undifferentiated clinical presentation is caused by a neurodegenerative or mood disorder. ### Competing Interest Statement PBM has received remuneration from Janssen (Australia) for advisory board membership and lectures in the last 3 years. ### Funding Statement Matthew Kang is supported by the Research Training Program Scholarship (stipend) from the Department of Psychiatry, University of Melbourne with contributions from the Australian Commonwealth Government and the Ramsay Health Research Foundation Translation Challenge. The funders had no role in the design or conduct of this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study used only openly available or de-identified human data. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data available at reasonable request