Peripheral blood miR-15b-5p and ABCC6 are candidate biomarkers of early antipsychotic treatment response in first-episode schizophrenia.

BACKGROUND

Second-generation antipsychotics (SGAs) are the mainstay of schizophrenia treatment, but early response varies markedly across patients. We aimed to identify peripheral miRNA-mRNA signatures associated with subsequent early SGA response and to explore the discriminative and incremental predictive value of selected baseline biomarkers.

METHODS

First-episode, drug-naïve schizophrenia patients (n = 65) receiving SGA monotherapy were classified as responders or non-responders after 4 weeks using a ≥ 25% reduction in Brief Psychiatric Rating Scale scores. Peripheral blood miRNA and mRNA profiles were analyzed by RNA sequencing in a discovery cohort (n = 15) and validated by qRT-PCR in an independent cohort (n = 50). Exploratory differential-expression and weighted gene co-expression network analyses were used for candidate prioritization in the discovery cohort. Candidate biomarkers were further evaluated by receiver operating characteristic analysis, and dual-luciferase assays.

RESULTS

Exploratory transcriptomic analyses prioritized 45 miRNAs and 190 mRNAs showing differential expression between subsequent responders and non-responders, enriched in transporter activity and neurotrophin signaling pathways. The miR-15b-5p-ABCC6 emerged as the most consistent candidate: miR-15b-5p was upregulated and ABCC6 downregulated in non-responders (both P < 0.001), and luciferase reporter assays supported a sequence-specific interaction between miR-15b-5p and the predicted binding site within the ABCC6 3'-UTR (P < 0.001). In the validation cohort, baseline miR-15b-5p, miR-584-3p, and ABCC6 showed apparent single-marker discrimination between subsequent responders and non-responders, with AUCs of 0.862, 0.935, and 0.856, respectively. The association of miR-15b-5p with treatment response remained significant after adjustment for SGA type.

CONCLUSION

Baseline peripheral blood miR-15b-5p, miR-584-3p, and ABCC6 were associated with subsequent early antipsychotic response and showed preliminary discriminative value in first-episode schizophrenia. The miR-15b-5p-ABCC6 pair represents a hypothesis-generating candidate interaction supported by sequence-specific reporter evidence and requires further endogenous and mechanistic validation.