Incorporating cortisol into the NAPLS2 individualized risk calculator for prediction of psychosis

Schizophr Res. 2021 Jan;227:95-100. doi: 10.1016/j.schres.2020.09.022. Epub 2020 Oct 9.


Background: Risk calculators are useful tools that can help clinicians and researchers better understand an individual's risk of conversion to psychosis. The North American Prodrome Longitudinal Study (NAPLS2) Individualized Risk Calculator has good predictive accuracy but could be potentially improved by the inclusion of a biomarker. Baseline cortisol, a measure of hypothalamic-pituitary-adrenal (HPA) axis functioning that is impacted by biological vulnerability to stress and exposure to environmental stressors, has been shown to be higher among individuals at clinical high-risk for psychosis (CHRP) who eventually convert to psychosis than those who do not. We sought to determine whether the addition of baseline cortisol to the NAPLS2 risk calculator improved the performance of the risk calculator.

Methods: Participants were drawn from the NAPLS2 study. A subset of NAPLS2 participants provided salivary cortisol samples. A multivariate Cox proportional hazards regression evaluated the likelihood of an individual's eventual conversion to psychosis based on demographic and clinical variables in addition to baseline cortisol levels.

Results: A total of 417 NAPLS2 participants provided salivary cortisol and were included in the analysis. Higher levels of cortisol were predictive of conversion to psychosis in a univariate model (C-index = 0.59, HR = 21.5, p-value = 0.004). The inclusion of cortisol in the risk calculator model resulted in a statistically significant improvement in performance from the original risk calculator model (C-index = 0.78, SE = 0.028).

Conclusions: Salivary cortisol is an inexpensive and non-invasive biomarker that could improve individual predictions about conversion to psychosis and treatment decisions for CHR-P individuals.

Keywords: Clinical high-risk; Cortisol; Prediction; Psychosis; Risk calculator; Survival analysis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Humans
  • Hydrocortisone*
  • Hypothalamo-Hypophyseal System
  • Longitudinal Studies
  • Prodromal Symptoms
  • Psychotic Disorders*


  • Hydrocortisone