The relationship between total tau protein, phosphorylated tau protein, schizophrenia and bipolar disorder: a systematic review and meta-analysis

Introduction: Neurodevelopmental disorders, notably schizophrenia, continue to pose major challenges in mental health and clinical practice. Numerous studies have posited potential associations between tau proteins and schizophrenia or bipolar disorder (BD), yet these associations have not been systematically described or quantitatively examined. This study aims to compare total tau and phosphorylated tau levels in plasma, serum (collectively referred to as peripheral blood), and cerebrospinal fluid (CSF) between individuals with schizophrenia and healthy controls, and to further examine total tau levels in BD. Methods: Employing a meticulous search strategy across PubMed, Embase, Medline and Web of Science, this study adheres to PRISMA guidelines. Eligible studies were non-randomized controlled trials investigating associations between tau proteins, schizophrenia or BD. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. This study protocol has been registered on PROSPERO (CRD420251123530). Results: 10 studies were included in the meta-analysis. Total tau levels were significantly lower in patients with schizophrenia compared to controls in CSF (SMD = -0.33, 95% CI: [-0.59, -0.08]) and peripheral blood samples (SMD = -0.88, 95% CI: [-1.61, -0.15]). Combining both samples, the overall SMD was -0.48 (95% CI: [-0.66, -0.31]), indicating a significant reduction in total tau levels. The pooled analysis for phosphorylated tau group yielded an SMD of -1.07 (95% CI: [-1.55, -0.59]), with consistent findings in CSF samples (SMD = -0.76, 95% CI:[-1.17, -0.35]). In contrast, total tau levels did not differ significantly between patients with BD and healthy controls (SMD = -0.07, 95% CI: [-0.26, 0.12]), Data were insufficient to support a meta-analysis of the relationship between phosphorylated tau and BD. Conclusion: T-tau and p-tau protein levels are lower in schizophrenia patients compared with healthy controls, whereas no significant difference was observed in BD patients. These findings may have potential for clinical diagnostics. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251123530.