The Role of Brain-Derived Neurotrophic Factor in the Neurobiology of Borderline Personality Disorder: A Systematic Review and Meta-Analysis

<span style="font-weight: 400;">Borderline Personality Disorder (BPD) is a severe psychiatric condition rooted in dysfunctional neuroplasticity within key fronto-limbic circuits. Brain-Derived Neurotrophic Factor (BDNF), a master regulator of neuronal growth and synaptic function, is a critical molecular candidate for understanding the pathophysiology of BPD. This systematic review and meta-analysis synthesizes the complete body of literature examining the multifaceted role of BDNF in BPD, encompassing peripheral protein levels, genetic polymorphisms, and epigenetic regulation. Our analysis reveals a field characterized by significant yet interpretable heterogeneity. Studies on circulating BDNF levels have yielded conflicting results, with reports of both decreased and increased concentrations in BPD patients. A qualitative meta-analysis demonstrates that these discrepancies are largely attributable to methodological inconsistencies, particularly the failure to control for comorbid major depressive disorder, antidepressant medication status, and the type of biological sample assayed (serum vs. plasma). Genetic association studies find no consistent link between the common BDNF Val66Met polymorphism (rs6265) and a direct risk for BPD diagnosis. However, evidence strongly indicates that this polymorphism functions as a key modulator of gene-environment interactions and BPD-related endophenotypes; the Val/Val genotype appears to confer vulnerability to trauma-induced impulsive aggression, while the Met allele is associated with deficits in amygdala habituation, a neural correlate of emotional dysregulation. The most compelling evidence emerges from epigenetic studies. A consistent body of research demonstrates that BPD is associated with hypermethylation of the </span><em><span style="font-weight: 400;">BDNF</span></em><span style="font-weight: 400;"> gene promoter, and that the degree of this methylation is directly proportional to the severity of experienced childhood trauma. Critically, these epigenetic marks are dynamic, with successful psychotherapy correlating with a decrease in </span><em><span style="font-weight: 400;">BDNF</span></em><span style="font-weight: 400;"> methylation.m We conclude by outlining critical directions for future research, emphasizing the need for methodological rigor and the potential of BDNF-related mechanisms as novel therapeutic targets.</span>