¹Wan Fang Hospital - Taipei Medical University, Department of Psychiatry, Taipei City, Taiwan, ²Taipei Medical University, Department of Psychiatry, School of Medicine, College of Medicine, Taipei City, Taiwan, ³Taipei City Psychiatry Center, Department of Psychiatry, Taipei City, Taiwan, ⁴Taipei Medical University, Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei City, Taiwan, ⁵National Cheng Kung University, Department of Psychology, Tainan City, Taiwan, ⁶National Cheng Kung University, Institute of Allied Health Sciences, Tainan City, Taiwan, ⁷Taipei Medical University, International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei City, Taiwan

Background: Theory of mind (ToM), encompassing affective and cognitive components, is a core domain of social cognition that is critically impaired in schizophrenia and strongly associated with functional outcomes. Although oxytocin dysregulation and neuroinflammatory processes have been implicated in social cognitive deficits, it remains unclear whether these biological mechanisms differentially contribute to affective and cognitive ToM impairments across illness stages. Understanding such stage-dependent associations may provide biologically informed markers for social cognitive stratification in schizophrenia.

Aims & Objectives: This study aimed to investigate stage-related alterations in plasma oxytocin and glial fibrillary acidic protein (GFAP) levels in schizophrenia, and their differential associations with affective and cognitive ToM across recent-onset and chronic stages of illness.

Method: A total of 180 participants were enrolled, including individuals with recent-onset schizophrenia (n = 30), chronic schizophrenia (n = 90), and healthy controls (n = 60). Plasma oxytocin and GFAP levels were quantified using standardized immunoassays. Affective and cognitive ToM were assessed using Faux Pas Recognition Test, alongside control conditions to account for non-social cognitive demands. Childhood trauma exposure was measured using the Childhood Trauma Questionnaire–Short Form. Group differences were examined using general linear models or χ² tests as appropriate, with Bonferroni correction applied for multiple comparisons.

Results: Plasma oxytocin levels differed significantly across groups, demonstrating a graded reduction from healthy controls to recent-onset schizophrenia and chronic schizophrenia (p < .001). In parallel, affective ToM performance showed pronounced group differences (p < .001). Pairwise comparisons indicated significantly poorer affective ToM in recent-onset patients compared with healthy controls (p = .001), and further deterioration in chronic patients relative to recent-onset patients (p < .001). Plasma GFAP levels exhibited marked stage-dependent elevations (p < .001), being highest in chronic schizophrenia, intermediate in recent-onset schizophrenia, and lowest in healthy controls. Chronic patients showed significantly higher GFAP levels than recent-onset patients (p < .001), corresponding to more severe affective ToM impairment. In contrast, group differences in cognitive ToM were smaller in magnitude (p < .001), with modest pairwise differences and preserved performance on control conditions. Childhood trauma exposure was significantly higher in both schizophrenia groups than in healthy controls but did not differ between recent-onset and chronic patients after Bonferroni correction.

Discussion & Conclusions: Oxytocin deficiency and astrocytic activation exhibit distinct, stage-related associations with affective ToM impairment in schizophrenia. Reduced oxytocin may contribute to early disruptions in affective social cognition, suggesting an early disruption in emotional mental state attribution that is not solely attributable to illness chronicity. In contrast, progressive elevation of GFAP in chronic schizophrenia coincided with more severe affective ToM impairment, indicating a potential role of astrocytic and related neurobiological alterations in the deterioration of affective social cognition over time. The relative preservation of cognitive ToM and control task performance further supports the domain-specific association of GFAP with affective, rather than generalized, cognitive dysfunction. These findings support a biologically informed staging model of social cognitive dysfunction and highlight oxytocin and GFAP as complementary biomarkers for stratifying affective social cognitive impairment in schizophrenia.