HPA Axis Mechanisms in Mood Disorders
Summary
The hypothalamic–pituitary–adrenal (HPA) axis is the principal neuroendocrine system governing the response to stress and maintaining homeostasis. Activation begins with the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates adrenocorticotropic hormone (ACTH) secretion by the pituitary; in turn, ACTH drives glucocorticoid release from the adrenal cortex. Glucocorticoids exert widespread effects on energy metabolism, immune regulation and neuronal plasticity, and they provide negative feedback to the hypothalamus and pituitary. In mood disorders such as major depressive disorder and bipolar disorder, this feedback loop is often impaired, leading to sustained hypercortisolaemia or, in some cases, hypocortisolaemia. Dysregulation of the HPA axis alters hippocampal and prefrontal circuitry, perturbs neurogenesis and compromises resilience to stress. Interactions with the immune system and alterations in barrier integrity of the blood–brain and blood–cerebrospinal fluid interfaces further amplify vulnerability. Individual variations in glucocorticoid receptor sensitivity, genetic predisposition and early-life exposure to elevated glucocorticoids can programme the set point of the HPA axis, predisposing to chronic mood disturbances. Understanding these mechanisms illuminates opportunities for novel diagnostic biomarkers and targeted interventions aimed at restoring neuroendocrine balance.
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Technical terms
HPA axis: The regulatory system comprising the hypothalamus, pituitary gland and adrenal cortex that orchestrates stress responses via hormone release.
Corticotropin-releasing hormone (CRH): A hypothalamic peptide that initiates the HPA axis cascade by stimulating ACTH secretion.
Adrenocorticotropic hormone (ACTH): A pituitary hormone that promotes glucocorticoid synthesis and release from the adrenal glands.
Glucocorticoids: Steroid hormones (e.g. cortisol) released by the adrenal cortex that modulate metabolism, immunity and central nervous system function.
Negative feedback: A regulatory mechanism in which rising levels of glucocorticoids inhibit further CRH and ACTH release to maintain hormonal balance.
Glucocorticoid receptor (GR): A nuclear receptor that mediates the genomic and non-genomic actions of glucocorticoids in target tissues.
References
- Inflammation in the pathogenesis of depression: a disorder of neuroimmune origin. Neuronal Signaling (2023).
- HPA Axis in the Pathomechanism of Depression and Schizophrenia: New Therapeutic Strategies Based on Its Participation. Brain Sciences (2021).
- Cortisol and Major Depressive Disorder—Translating Findings From Humans to Animal Models and Back. Frontiers in Psychiatry (2020).
- Relative Hypo- and Hypercortisolism Are Both Associated with Depression and Lower Quality of Life in Bipolar Disorder: A Cross-Sectional Study. PLOS ONE (2014).
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