MicroRNAs as potential biomarkers in schizophrenia: Current methodological limitations and challenges

Schizophrenia is a chronic and heterogeneous psychiatric disorder that affects approximately 1% of the global population. Despite advances in elucidating its neurobiological underpinnings, clinical diagnosis and treatment monitoring remain largely dependent on subjective assessment, highlighting the need for objective, biologically grounded biomarkers. MicroRNAs, small non-coding RNAs that regulate gene expression post-transcriptionally, have emerged as promising minimally invasive biomarker candidates due to their critical roles in neurodevelopment and synaptic function, as well as their detectability across multiple biofluids. This review synthesizes current knowledge on miRNA biogenesis and function, with emphasis on their regulatory roles in the central nervous system and especially their dysregulation in schizophrenia. MicroRNAs are consistently dysregulated in individuals with schizophrenia and converge on pathways related to glutamatergic transmission, dendritic architecture, calcium signaling, and apoptotic regulation. Although several studies have reported associations between specific microRNAs and the disorder, no robust biomarker panel has yet been established. Inconsistencies across studies often arise from variability in sample types, detection platforms, and data normalization methods. To address this, we critically evaluate the principal analytical approaches for miRNA detection, including PCR, microarrays, and next-generation sequencing, outlining their respective strengths and methodological limitations. Finally, we delineate the microRNAs most consistently implicated in schizophrenia, together with their target mRNAs and involved pathways. We further evaluate their translational potential for early diagnosis, prognostic assessment, and therapeutic stratification. Collectively, these findings may inform the development of precision medicine frameworks in psychiatry.