A Dual-Stage Model of Hypothalamic Pituitary-Adrenal (HPA) Axis Dysregulation in Anxiety Disorders: A Systematic Review
A Dual-Stage Model of Hypothalamic Pituitary-Adrenal (HPA) Axis Dysregulation in Anxiety Disorders: A Systematic Review

Summary/Abstract: Anxiety disorders are associated with substantial morbidity and disability. Dysregulation of the hypothalamic pituitary-adrenal (HPA) axis remains a prominent biological hypothesis, but findings across disorders and methods are heterogeneous. We updated the structured review published in 2014 to include studies from April 2014 to November 2025 using the same methodological approach. Sixty-two records were screened; twenty-four full texts were assessed and fifteen studies met inclusion criteria for qualitative synthesis. The post-2014 literature preserves the principal conclusion of the earlier review, substantial inter-study heterogeneity, while adding disorder-specific advances: (a) randomised and experimental evidence that pre-exposure glucocorticoid administration can facilitate exposure therapy in specific (simple) phobia; (b) increasing use of hair cortisol concentration (HCC) and longitudinal HCC assessments in generalised anxiety disorder (GAD) producing evidence for temporally dynamic HPA patterns; and (c) growing data that acute in-session cortisol elevations in social anxiety disorder (SAD) may predict poorer exposure outcomes. Overall, the updated evidence provides convergent support for a dual-phase model in which acute anxiety states are commonly accompanied by transient HPA hyperactivation and elevated cortisol, while chronic or recurrent illness may be characterised by HPA downregulation or blunted responses leading to reduced cortisol output or normalised HCC.

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