Analysis of Neuroinflammatory Biomarkers Associated with Treatment Resistance in Depression

Abstract

Introduction: Treatment-resistant depression (TRD) is a condition characterized by the absence of response to at least two adequate antidepressants, associated with neuroinflammatory alterations and dysfunctions in the hypothalamic-pituitary-adrenal (HPA) axis. Inflammatory biomarkers, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP), play a relevant role in the pathophysiology of this condition. Objective: To perform an integrative analysis on neuroinflammatory biomarkers associated with TRD, discussing biological mechanisms, therapeutic interventions and their clinical implications. Methodology: An integrative review was conducted using the PubMed and BVS databases, with the descriptors "Biomarkers", "Depressive Disorder" and "Treatment-Resistant". The inclusion criteria considered complete and free articles, published between 2000 and 2025, in Portuguese, English or Spanish. After screening, 15 articles were selected for analysis. Results and Discussion: Studies have highlighted elevated levels of IL-6, TNF-α, and CRP in patients with ESRD, associated with HPA dysfunction and persistent symptoms. Ketamine has shown efficacy in modulating synaptic plasticity and rapidly reducing depressive symptoms, although the effects are transient. Furthermore, electrophysiological biomarkers, such as neural connectivity patterns, offer additional insights for the management of ESRD. Methodological heterogeneity, however, makes it difficult to standardize results. Conclusion: Neuroinflammatory biomarkers are fundamental to understanding ESRD, but methodological limitations prevent their widespread clinical application. Future studies should prioritize personalized approaches, combining biological, psychosocial, and behavioral therapies to optimize outcomes in patients with ESRD.