The HPA axis and kynurenine pathway: exploring the role of stress and neuroinflammation in treatment-resistant depression

Abstract Treatment-resistant depression (TRD) continues to pose a major challenge in clinical practice, as a large proportion of patients fail to achieve remission despite multiple antidepressant drugs. Growing evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, together with epigenetic alterations, neuroinflammation, and kynurenine pathway metabolism, plays a central role in the pathophysiology of TRD. Particularly, prolonged stress-induced glucocorticoid receptor (GR) resistance, persistent hypercortisolaemia, and elevated pro-inflammatory cytokines contribute to neurotoxicity, hippocampal atrophy, and impaired neuroplasticity, aggravating depressive symptoms and reducing treatment response. Additionally, dysregulated tryptophan metabolism and the shift towards neurotoxic kynurenine metabolites further impair neuronal function and resulting in TRD. This review integrates recent findings on the complex interplay between HPA axis dysfunction, neuroimmune responses, and metabolic disturbances in TRD while highlighting novel therapeutic avenues such as ketamine, GR modulators, and anti-inflammatory agents. Further, disruption in the blood-brain barrier as one of the mechanisms of TRD was also reviewed. A deeper understanding of these mechanisms will enable the development of personalized treatment strategies to enhance clinical outcomes for TRD patients.