HPA Axis Dysregulation in Major Depressive Disorder

The hypothalamic-pituitary-adrenal (HPA) axis orchestrates the body’s response to stress by regulating the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and ultimately cortisol. In major depressive disorder (MDD), this system frequently exhibits hyperactivity, leading to elevated basal and post-stress cortisol levels. Impaired negative feedback at the level of glucocorticoid receptors in the pituitary and hippocampus exacerbates hypercortisolaemia, which in turn alters neurotransmitter balance, neuronal plasticity and inflammatory pathways. Chronic cortisol elevation can damage hippocampal neurons, reduce neurogenesis and promote systemic inflammation—processes linked to persistent depressive symptoms. Early life stress, genetic variability in HPA axis components and comorbid medical conditions further modulate axis sensitivity, contributing to heterogeneity in clinical presentation and treatment response. Recognition of HPA axis dysregulation as both a vulnerability factor and a potential biomarker offers avenues for personalised interventions, including receptor-targeted agents and stress-modulating behavioural therapies. Understanding these mechanisms has global significance, informing strategies for early identification of at-risk individuals and refining therapeutic approaches in diverse healthcare settings.

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Technical terms

HPA axis: The network comprising the hypothalamus, pituitary gland and adrenal cortex that regulates stress responses via hormonal signalling.

Cortisol awakening response (CAR): The rapid rise in cortisol levels within the first hour after waking, reflecting HPA axis reactivity.

Glucocorticoid receptor (GR) resistance: Reduced sensitivity of GRs to cortisol feedback, leading to impaired suppression of the HPA axis.

Hypercortisolaemia: A state of chronically elevated cortisol concentrations in blood or saliva, often linked to stress-related disorders.

References

1. Childhood trauma associated with increased post-awakening cortisol in major depressive disorder. Psychological Medicine (2023).
2. Cortisol and development of depression in adolescence and young adulthood – a systematic review and meta-analysis. Psychoneuroendocrinology (2021).
3. An integrated approach to understand biological stress system dysregulation across depressive and anxiety disorders. Journal of Affective Disorders (2021).