Much ado about much: stress, dynamic biomarkers and HPA axis dysregulation along the trajectory to psychosis

Schizophr Res. 2015 Mar;162(1-3):253-60. doi: 10.1016/j.schres.2015.01.010. Epub 2015 Jan 22.


Objectives: In the context of a stress-vulnerability framework, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is thought contribute to the risk, onset and course of psychotic illness. However, recent reports regarding static and dynamic features of the HPA axis suggest a more complex set of phenomena at play in the early phases of psychosis.

Methods: We review literature regarding structural and functional aspects of the HPA axis in subjects at risk for or experiencing the first episode of psychosis, including evidence favoring as well as that which contradicts a model of HPA axis hyperactivation.

Results: Static measures of diurnal cortisol and hippocampal/pituitary volumes suggest that the HPA axis is in a hyperactivated state in early phases of psychosis. In contrast, the dynamic cortisol response to encountered or anticipated stress is blunted in the same populations. These incongruent findings need to be better understood.

Conclusions: We consider potential explanations for the seemingly contradictory elevation and blunting of HPA biomarkers in the early course of psychosis. Finally, we propose and explore implications of a conceptual model of tonic HPA hyperactivation and phasic HPA blunting that integrates and reconciles these data.

Keywords: Cortisol; Early psychosis; First episode; High-risk; Hippocampus; Hypothalamic–pituitary–adrenal axis; Pituitary; Stress; Stress–vulnerability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Hydrocortisone / metabolism
  • Hypothalamo-Hypophyseal System / pathology
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Pituitary-Adrenal System / pathology
  • Pituitary-Adrenal System / physiopathology*
  • Psychotic Disorders / pathology
  • Psychotic Disorders / physiopathology*
  • Stress, Psychological / pathology
  • Stress, Psychological / physiopathology*


  • Hydrocortisone