Early-Life Stress in the HPA Axis and MR/GR Receptors in the Development of Depression

Depression remains a leading cause of global disability, with early-life stress (ELS) representing one of its most potent and well-replicated risk factors. This chapter synthesizes evidence linking childhood adversity-including abuse, neglect, and loss-to persistent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. A key mechanism is the imbalance between mineralocorticoid (MR) and glucocorticoid receptors (GR), resulting in altered cortisol rhythms, impaired stress recovery, and increased susceptibility to recurrent and treatment-resistant depression. Converging neuroimaging, molecular, and epigenetic data reveals that ELS induces lasting changes in MR/GR signaling, including methylation and HSD11B1 polymorphisms, which biologically embed risk across the lifespan. Translational tools such as the prednisolone suppression test (PST) and cortisol awakening response (CAR) have emerged as promising biomarkers for patient stratification, treatment prediction, and suicide risk assessment. Future directions highlight the potential of biomarker-guided psychiatry, integrating endocrine, genetic, epigenetic, neuroimaging, and immune data to inform mechanism-based interventions-such as MR/GR agonists and antagonists, including an epigenetic approach-aimed at mitigating the enduring impact of childhood adversity and advancing precision mental health care.