Peripheral S100B, Cell-Free DNA, and Circulating RNA Biomarkers in Psychotic Disorders: A Systematic Review of Schizophrenia-Spectrum Findings and Primary–Secondary Comparisons

Background/Objectives: Peripheral S100B, circulating cell-free DNA (cfDNA), and circulating cell-free RNA (cfRNA)-related biomarkers have been investigated in psychotic disorders, but their relevance to etiological differentiation remains uncertain. This systematic review assessed patient–healthy-control comparisons and direct comparisons between primary and secondary psychoses. Methods: Five databases were searched through 11 October 2026 without publication-year or participant-age restrictions, and reference lists of six reviews were screened. The review followed a pre-existing protocol and was subsequently registered in PROSPERO (CRD420261437487). Results: Of 1262 identified records, 101 full-text reports were assessed and 36 were included: 23 investigated S100B, eight cfDNA-related measures, and five circulating microRNAs. An exploratory random-effects meta-analysis of nine serum S100B comparisons (340 patients; 305 controls) showed higher concentrations in schizophrenia-spectrum patients (Hedges’ g = 0.78, 95% CI 0.32–1.24; I2 = 80.5%), although the 95% prediction interval spanned zero (−0.54 to 2.10). Three total-plasma cfDNA effects (g = 0.35–1.12) were not pooled because of analytical heterogeneity and possible cohort overlap. Circulating microRNA studies examined distinct targets. Risk-of-bias assessment using review-adapted Joanna Briggs Institute (JBI) tools identified recurrent concerns regarding biomarker measurement, residual confounding, and statistical reporting. Only two included cfDNA reports directly compared schizophrenia with alcohol-induced psychotic disorder; one reported an unadjusted area under the receiver operating characteristic curve of 0.6684 without external validation. Conclusions: Neither S100B nor microRNA reports directly compared etiologies; clinical utility remains unestablished.