LC-MS/MS Analysis of Oxysterol Biomarkers in Early-Onset Schizophrenia

While schizophrenia is a serious mental illness which is more common in adults, it can also manifest in childhood with disease onset before age 18 as "early-onset schizophrenia" (EOS). Although a team comprised of researchers from Capital Medical University (Beijing, China) and Emory University School of Medicine (Atlanta, Georgia) previously 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.¹ The team conducted additional research in hopes of characterizing the developmental trajectories of these oxysterols during early life and evaluating their clinical relevance in EOS, with particular emphasis on sex-specific effects. Plasma concentrations of 24 S-OHC and 27-OHC were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).A paper based on their efforts was published in Annals of General Psychiatry.²

A severe neuropsychiatric disorder typically manifesting in early adulthood and is characterized by persistent and relapsing symptoms, approximately 4% of schizophrenia patients experience onset during childhood or adolescence, a condition designated as EOS.^3-5 Defined by the emerging of schizophrenic symptoms before age 18, EOS has progressively becomerecognized as a distinct clinical entity which isassociated with more pronounced negative symptoms and poorer functional outcomes compared to adult-onset forms.^6,7

For this study, 142 healthy individuals (aged 1 to 41 years) were recruited to define age-related oxysterol patterns and 71 EOS patients (aged 4 to 18 years) to identify disease-associated changes. As previously mentioned, plasma concentrations of 24 S-OHC and 27-OHC were measured using LC-MS/MS. The analysis revealed that healthy participants exhibited significant age-dependent variations, with younger individuals showing higher 24 S-OHC and lower 27-OHC levels. Although EOS patients displayed no overall differences in oxysterol levels when compared to age-matched healthy controls, a noticeable sex-based divergence emerged, with male patients exhibiting substantially elevated levels of 27-OHC compared to females. Furthermore, 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 possible relationship. The researchers reported that the sex-stratified analysis showed opposing correlations between 27-OHC levels and PANSS scores, most prominently for positive symptoms.²

“This study,” write the authors of the article,² “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.”

“While some clinical correlations did not survive correction for multiple comparisons,” the authors continued,² “and should therefore be interpreted with caution, the observed sex-specific patterns suggest that sexually dimorphic cholesterol metabolism may be relevant to differential disease expression in EOS. While overall oxysterol levels may not distinguish EOS patients from healthy individuals, the identified sex-specific patterns offer new avenues for understanding disease mechanisms and developing personalized interventions.”

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References

1. Sun, Z.; Zhao, L.; Bo, Q. et al. Brain-Specific Oxysterols and Risk of Schizophrenia in Clinical High-Risk Subjects and Patients with Schizophrenia. Front Psychiatry 2021, 12, 711734. DOI: 10.3389/fpsyt.2021.711734
2. Sun, Z.; Liu, M.; Yan, J. et al. A Novel Sex-Specific Role for 27-hydroxycholesterol in Early-Onset Schizophrenia. Ann Gen Psychiatry 2026.DOI: 10.1186/s12991-026-00642-9
3. Freedman, R. Schizophrenia. N Engl J Med. 2003, 349 (18), 1738-1749. DOI: 10.1056/NEJMra035458
4. Solmi, M.; Seitidis, G.; Mavridis, D. et al. Incidence, Prevalence, and Global Burden of Schizophrenia-Data, with Critical Appraisal, from the Global Burden of Disease (GBD) 2019. Mol. Psychiatry 2023, 28 (12), 5319-5327. DOI: 10.1038/s41380-023-02138-4
5. Correll, C. U.; Arango, C.; Fagerlund, B. et al. Identification and Treatment of Individuals with Childhood-Onset and Early-Onset Schizophrenia. Eur Neuropsychopharmacol. 2024, 82, 57-71. DOI: 10.1016/j.euroneuro.2024.02.005
6. Ropcke, B.; Eggers, C. Early-Onset Schizophrenia: A 15-Year Follow-Up. Eur Child Adolesc Psychiatry 2005, 14 (6), 341-350. DOI: 10.1007/s00787-005-0483-6
7. Giannitelli, M.; Levinson, D. F.; Cohen, D. et al. Developmental and Symptom Profiles in Early-Onset Psychosis. Schizophr Res. 2020, 216, 470-478. DOI: 10.1016/j.schres.2019.10.028