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

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.