Association between cortisol levels and psychosis in at-risk and diagnosed individuals: protocol for a systematic review

Introduction Psychosis poses a significant global health challenge, with growing evidence linking dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and altered cortisol levels to its onset and progression. This systematic review protocol aims to synthesise case-control and cohort studies to achieve two main objectives: to evaluate the association between cortisol levels and psychosis, and to examine cortisol levels in individuals at risk of developing psychosis. The review will consolidate existing empirical evidence on the relationship between cortisol levels and psychosis in both at-risk populations and diagnosed patients. Methods and analysis Electronic searches will be conducted in academic databases, including Web of Science, PubMed, Scopus, Embase and PsycINFO, using a PECO (Population, Exposure, Comparator, Outcome) framework. A search strategy will be developed in Web of Science and adapted for other databases. Additionally, a search will be performed on Google Scholar, reviewing the first 1000 publications to crosscheck findings. The initial PECO-derived search will use Medical Subject Headings terms: (‘Cortisol’ OR ‘Hydrocortisone’) AND (‘Psychosis’ OR ‘Psychotic disorders’ OR ‘Schizophrenia’) AND (‘HPA axis’ OR ‘Stress response’) AND (‘Clinical high risk’ OR ‘Prodromal’ OR ‘Ultra-high risk’), along with phrases identified from related literature. The review will focus on case-control and cohort studies reporting original research on individuals at risk of psychosis or with confirmed psychotic disorders, with no restrictions on publication year or language. Exclusion criteria will include randomised controlled trials, pilot studies, reviews, meta-analyses, case reports, conference abstracts, animal studies and studies lacking cortisol measurements, as well as editorials and commentaries. The risk of bias will be assessed using the Joanna Briggs Institute methodology, and the Grading of Recommendations Assessment, Development, and Evaluation will be used to assess the certainty of the evidence. The review is ongoing. Ethics and dissemination No ethical approval is required. Findings will be disseminated via a peer-reviewed journal. Study registration PROSPERO, CRD420251136994 (registered 6 October 2025)