Meta-analysis finds decreased GDNF levels in bipolar disorder but high heterogeneity limits conclusions

BACKGROUND: Bipolar disorder (BD) is a chronic and debilitating mental illness characterized by alternating episodes of mania and depression, affecting approximately 5-6% of the global population. Despite extensive research, the underlying pathophysiology of BD remains poorly understood, necessitating further exploration of potential biomarkers. This meta-analysis investigates peripheral levels of glial cell line-derived neurotrophic factor (GDNF) to evaluate its utility as a biomarker in individuals with BD. METHODS: We systematically searched four international databases, identifying 13 case-control studies (825 patients with BD vs. 885 healthy controls) and 4 clinical trials encompassing 153 patients with BD. The study adhered to PRISMA guidelines and employed rigorous quality assessment tools, including the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias tool for clinical trials. RESULTS: The analysis revealed a pooled standardized mean difference of d = -0.81 [CI: 1.41 to -0.22], p = 0.007. However, extreme heterogeneity (I > 96%) and publication bias preclude reliable interpretation of this estimate. Furthermore, the meta-regression analyses were significant for illness duration, YMRS score, and year of study. Subgroup analysis showed significant estimates for blood sample, mania episode, and Asian region. Although treatment interventions increased GDNF levels, these changes were not statistically significant (d = 0.12, [95% CI: 0.20 to 0.44], p = 0.463). High heterogeneity was observed across studies, indicating substantial variability in study designs and participant characteristics. CONCLUSION: The literature provides preliminary, highly heterogeneous evidence suggestive of altered GDNF levels in BD, primarily within serum during mania. The plasma-serum discrepancy highlights a major methodological confounder (platelet GDNF release), and the significant heterogeneity and publication bias preclude a reliable estimate of the true effect size. GDNF cannot be considered a disorder-specific biomarker for BD, as similar alterations are reported in major depression and schizophrenia. Future research must prioritize plasma measurements, standardized protocols, and longitudinal designs in medication-naïve cohorts to clarify whether GDNF acts as a state-dependent marker of acute mood episodes within a transdiagnostic framework.