Implication of HPA-axis Dysfunction in Depression: From Neurobiological Mechanisms to Future Treatment Strategies

Abstract: The Hypothalamic–Pituitary–Adrenal (HPA) axis dysfunction hypothesis of depression posits that maladaptive stress responsivity, sustained hypercortisolemia, and impaired Glucocorticoid Receptor (GR) signaling constitute core neurobiological mechanisms underlying depressive pathology. Dysregulation of this system, characterized by impaired glucocorticoid receptor feedback, sustained hypercortisolemia, and altered diurnal cortisol rhythms, contributes to neuronal vulnerability, maladaptive stress responsivity, and the progression of depressive pathology. This review synthesizes clinical and preclinical evidence linking HPA axis dysfunction to depression, with particular focus on key molecular targets including corticotropin-releasing hormone (CRH) receptors, glucocorticoid and mineralocorticoid receptors, and the arginine vasopressin system. In addition, we examine the emerging role of oxidative stress and inflammatory mediators in amplifying HPA dysregulation, and discuss the potential utility of biomarkers such as cortisol, ACTH, F2- isoprostanes, and 8-OHdG as diagnostic and treatment-responsive indicators. While current data provide compelling support for the HPA axis dysfunction hypothesis, methodological variability, reliance on peripheral measures, and limited longitudinal studies constrain causal inference. Future research should prioritize standardized biomarker panels, integration of multi-omics approaches, and validation of predictive signatures to enable precision medicine. Importantly, the review highlights novel therapeutic strategies, including CRH receptor antagonists, glucocorticoid receptor modulators, mineralocorticoid receptor agonists, and agents targeting oxidative and inflammatory pathways, as promising candidates for next-generation antidepressant development. By consolidating mechanistic, clinical, and translational evidence, this review highlights oxidative stress–HPA axis interactions as a pivotal determinant of depression vulnerability, underscores critical limitations in the current evidence base, and identifies future research priorities aimed at advancing biomarker-guided strategies for the prevention and treatment of depression.