Cortisol response patterns to stress correlated to white matter integrity and duration of illness in patients with schizophrenia

Xinyu Jiang; Mengzhuang Gou; Yi Yin; Wenjin Chen; Yanli Li; Song Chen; Shujuan Pan; Xingguang Luo; Shuping Tan; Baopeng Tian; Wei Li; Jinghui Tong; Jue Wang; Hongna Li; Ting Yu; Zhiren Wang; Ping Zhang; Junchao Huang; Li Tian; Peter Kochunov; Chiang-Shan R Li; L Elliot Hong; Yunlong Tan

doi:10.1016/j.psyneuen.2025.107501

Cortisol response patterns to stress correlated to white matter integrity and duration of illness in patients with schizophrenia

Psychoneuroendocrinology. 2025 Jun 3:179:107501. doi: 10.1016/j.psyneuen.2025.107501. Online ahead of print.

Authors

Xinyu Jiang¹, Mengzhuang Gou¹, Yi Yin¹, Wenjin Chen¹, Yanli Li¹, Song Chen¹, Shujuan Pan¹, Xingguang Luo², Shuping Tan¹, Baopeng Tian¹, Wei Li¹, Jinghui Tong¹, Jue Wang¹, Hongna Li¹, Ting Yu¹, Zhiren Wang¹, Ping Zhang¹, Junchao Huang¹, Li Tian³, Peter Kochunov⁴, Chiang-Shan R Li², L Elliot Hong⁴, Yunlong Tan⁵

Affiliations

¹ Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China.
² Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
³ Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, Estonia.
⁴ Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, USA.
⁵ Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China. Electronic address: yltan21@126.com.

PMID: 40479922
DOI: 10.1016/j.psyneuen.2025.107501

Abstract

Stress plays a critical role in schizophrenia pathogenesis, and blunted cortisol responses to acute stress exposure among patients with schizophrenia may be related to damaged white matter (WM) fibers in specific brain regions. The present aim was to assess correlations between cortisol response patterns and changes in WM integrity in patients with schizophrenia and to determine if such changes relate to the duration of illness. This study included patients with chronic schizophrenia (PCS, n = 92), patients with first-episode schizophrenia (PFS, n = 86), and healthy controls (HC, n = 77). All participants were subjected to the Paced Auditory Serial Addition Task and the Mirror Tracing Persistence Task. Saliva samples were collected 0 min before tasks, 20 and 40 min after task completion. Cortisol levels were assessed using highly sensitive liquid chromatography and tandem mass spectrometry. We used diffusion tensor imaging (DTI) to assess WM microstructural integrity. Clinical psychopathology was assessed using the Positive and Negative Syndrome Scale. The repeated measures analysis of variance and pairwise comparisons demonstrated distinct cortisol response patterns across groups. In the HC group, cortisol levels peaked before tasks, declining rapidly thereafter. In the PFS group, cortisol levels significantly increased 20 min post-exposure, with no significant decrease observed at the final 40-minutes time point. In the PCS group, cortisol levels remained relatively high, with no significant fluctuations over time. Furthermore, WM integrity progressively deteriorated as disease duration increased. A negative correlation was observed between WM tract integrity and prolonged cortisol reactivity in the PFS group, whereas this correlation was positive in the HC group and absent in the PCS group. Changes in salivary cortisol levels did not correlate with clinical symptoms in our patients with schizophrenia. These findings suggest that stress has the potential to contribute to schizophrenia by exacerbating WM damage. Stress-induced cortisol response patterns, which vary according to disease duration, may represent a potential biomarker of schizophrenia.

Keywords: Biomarker; Cortisol; Damage; Schizophrenia; Stress; White matter integrity.