HPA Axis Dysregulation in Psychotic Disorders

The hypothalamic–pituitary–adrenal (HPA) axis orchestrates the physiological response to stress via a cascade of neuroendocrine signals culminating in the release of cortisol. In psychotic disorders, mounting evidence indicates that this system becomes dysregulated, manifesting as elevated basal cortisol levels, impaired diurnal variations and altered feedback sensitivity. Disruptions in HPA function have been observed across the psychosis spectrum—ranging from clinical high‐risk states to first‐episode and chronic illness—and are linked to symptom severity, cognitive deficits and metabolic comorbidities. Blunted responses to acute stressors and reduced suppression following dexamethasone challenge suggest a loss of regulatory control, which may contribute to neural circuit alterations in regions rich in glucocorticoid receptors, such as the hippocampus and prefrontal cortex. Such maladaptive HPA activity interacts with immune and metabolic pathways, potentially exacerbating brain structural changes and functional connectivity deficits. Antipsychotic treatment appears to modulate cortisol levels, though responses vary by agent and illness stage. Understanding HPA axis abnormalities in psychosis holds global relevance for early identification of at‐risk populations, refinement of treatment strategies and the development of novel interventions aimed at restoring neuroendocrine balance.

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HPA Axis Dysregulation in Psychotic Disorders publication trend

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Technical terms

HPA axis: Integrated system involving the hypothalamus, pituitary gland and adrenal cortex that regulates stress responses through hormone secretion.

Cortisol: Primary glucocorticoid hormone released by the adrenal cortex in response to stress, modulating metabolism and immune function.

Dexamethasone suppression test: Clinical assessment measuring feedback sensitivity of the HPA axis by administering a synthetic glucocorticoid and monitoring subsequent cortisol levels.

Cortisol awakening response: Rapid increase in cortisol concentration occurring within the first hour after awakening, reflecting HPA axis reactivity.

Clinical high-risk (CHR): Population identified as at elevated risk for developing psychosis based on attenuated symptoms and functional decline.

References

1. Cortisol in schizophrenia spectrum disorders: A comprehensive meta-analysis. Frontiers in Neuroendocrinology (2025).
2. A meta-analysis of blood and salivary cortisol levels in first-episode psychosis and high-risk individuals. Frontiers in Neuroendocrinology (2021).
3. Stressor-Cortisol Concordance Among Individuals at Clinical High-Risk for Psychosis: Novel Findings from the NAPLS Cohort. Psychoneuroendocrinology (2020).
4. Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Molecular Psychiatry (2018).
5. HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis. Translational Psychiatry (2016).
6. Effects of Antipsychotics on the Hypothalamus–Pituitary–Adrenal Axis in a Phencyclidine Animal Model of Schizophrenia. Cells (2024).
7. Cortisol Responses to Naturally Occurring Psychosocial Stressors Across the Psychosis Spectrum: A Systematic Review and Meta-Analysis. Frontiers in Psychiatry (2020).