A novel sex-specific role for 27-hydroxycholesterol in early-onset schizophrenia

BACKGROUND: Although Schizophrenia is a serious mental illness which more common in adults, it can also manifest in childhood with disease onset before age 18 as "early-onset schizophrenia" (EOS). While our previous research identified circulating oxysterols-24(S)-hydroxycholesterol (24 S-OHC) and 27-hydroxycholesterol (27-OHC)-as potential biomarkers in adult schizophrenia, their role in EOS remains unknown. This study aimed to characterize the developmental trajectories of these oxysterols during early life and evaluate their clinical relevance in EOS, with particular emphasis on sex-specific effects. METHODS: We recruited 142 healthy individuals (aged 1 to 41 years) to define age-related oxysterol patterns and 71 EOS patients (aged 4 to 18 years) to identify disease-associated changes. Plasma concentrations of 24 S-OHC and 27-OHC were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Healthy participants exhibited significant age-dependent variations, with younger individuals showing higher 24 S-OHC and lower 27-OHC levels. While EOS patients showed no overall differences in oxysterol levels compared to age-matched healthy controls, a striking sex-based divergence emerged: male patients exhibited significantly elevated levels of 27-OHC compared to females. Additionally, the 24 S-OHC/27-OHC ratio showed a positive correlation with negative symptom severity, which did not survive correction for multiple comparisons but may still indicate a potential relationship. Notably, sex-stratified analysis revealed opposing correlations between 27-OHC levels and PANSS scores, most prominently for positive symptoms. CONCLUSIONS: This study represents the first evidence of sexually dimorphic oxysterol regulation in EOS and highlights 27-OHC as a sex-sensitive factor linked to clinical symptom expression, even in the absence of group-level oxysterol alterations.