Dysregulated miRNAs and downstream gene expression associated with poor treatment response in first-episode psychosis

Treatment response in first-episode psychosis (FEP) is highly variable, and reliable biomarkers for poor outcomes remain limited. MicroRNAs (miRNAs), important post-transcriptional regulators, have been implicated in psychotic disorders. However, genome-wide miRNA profiling and analyses of their downstream gene networks related to treatment response in FEP remain insufficiently explored.

We analyzed baseline miRNA expression in peripheral blood mononuclear cells from 41 antipsychotic-naïve or minimally treated FEP patients with six-month follow-up. Patients were classified as good (n = 17) or poor responders (n = 24) based on ≥20% symptom improvement on the Positive and Negative Syndrome Scale. Differentially expressed miRNAs were identified by microarray. RNA sequencing was performed to detect candidate target genes, followed by differential expression and functional enrichment analyses.

Hsa-miR-34a and hsa-miR-299 were significantly associated with 6-month treatment response. RNA sequencing identified candidate target genes regulated by these miRNAs (704 for hsa-miR-34a and 262 for hsa-miR-299). After multiple-testing correction, three hsa-miR-34a- and five hsa-miR-299-related genes were expressed at higher baseline levels in poor responders than in good responders; their expression levels after 6 months in poor responders remained similar or slightly decreased, whereas in good responders G3BP1, PARD6B, DDHD2, and SLC25A4 showed significant reduction and C14orf28, RSBN1, CDC16, and PPM1K showed little or no reduction. These genes are involved in neural development, neural maintenance, and immune response.

Our multi-omics approach helps identify miRNAs and their downstream target genes associated with FEP patients' poor responses to antipsychotics, highlighting potential biomarkers for personalized therapy.