**Background:** Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are among the most prevalent psychiatric conditions, affecting 15–17% of the US population for MDD and 0.6–2.8% for BD. These disorders are associated with significant disability and mortality, with an estimated lifetime suicide risk of approximately 20% for both conditions. A major challenge in psychiatry is the lack of objective biomarkers for diagnosis, treatment response prediction, and suicide risk assessment. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and have emerged as promising peripheral biomarkers because they show colinear expression changes between brain tissue and systemic circulation, are stable in body fluids, and can be detected in extracellular vesicles that carry tissue-specific molecular signatures.
**Methods:** The authors conducted a literature search using the PubMed database for original articles published over the last ten years. Keywords included "circulating microRNAs" combined with "Major depressive disorder," "MDD," "Major depression," "Bipolar disorder," "BD," "Suicide," "Suicidality," and "Biomarker." The review focused on studies examining circulating miRNAs as peripheral biomarkers in MDD, BD, and suicidality. Additionally, the authors performed a meta-analysis of the identified miRNAs, predicting target genes using brain-enriched databases and conducting functional pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.
**Key Results:** The review identified numerous studies demonstrating altered circulating miRNA expression in mood disorders. For MDD, key findings include: Maffioletti et al. found 10 altered miRNAs in whole blood of 20 MDD patients compared to 20 controls, with MDD-specific changes in let-7a-5p, let-7d-5p, let-7f-5p, miR-24-3p, and miR-425-3p targeting Wnt and mTOR signaling. Camkurt et al. identified miR-451a, miR-17-5p, miR-223-3p (upregulated), and miR-320a (downregulated) in plasma from 50 depressed patients. Roy et al. demonstrated ~3.5-fold increased miR-124-3p expression in serum of antidepressant-free MDD patients, with parallel changes in postmortem brain tissue. He et al. found miR-9 associated with childhood maltreatment in 40 untreated MDD patients. For BD, Tekdemir et al. reported significant increases in miR-132, miR-134, miR-152, miR-607, miR-633, and miR-652, and decreases in miR-15b and miR-155 in 66 lithium-treated BD patients. Lee et al. identified six differentially regulated serum miRNAs in BD-II patients (79 BD-II, 95 controls), achieving diagnostic accuracy with AUC of 0.907 using a combination of significant miRNAs. For suicidality, a genome-wide study of 42 inpatients with suicidal ideation found decreased expression of miR-424-5p, miR-378i, miR-6724-5p, and miR-10b-5p after recovery. The meta-analysis revealed 129 miRNAs uniquely associated with MDD, 91 uniquely associated with BD, and 23 shared between both disorders. Pathway analysis showed PI3K-AKT signaling had the maximum number of target genes (30) in MDD, while MAPK signaling had the maximum (22) in BD. For treatment response, miR-124 showed 83.33% sensitivity and 66.67% specificity for MDD diagnosis, with significant downregulation after eight weeks of antidepressant treatment. miR-134 demonstrated diagnostic accuracy with AUC of 0.901, 79% sensitivity, and 84% specificity for MDD.
**Clinical Implications:** Circulating miRNAs represent a promising avenue for developing objective, non-invasive biomarkers in mood disorders and suicide risk assessment. Their ability to cross the blood-brain barrier, stability in peripheral circulation, and correlation with brain tissue expression make them particularly valuable. However, significant challenges remain, including genetic heterogeneity, medication effects, and the need for standardized detection methods. The authors emphasize that while single miRNAs may provide diagnostic value, panels of multiple miRNAs likely offer greater prognostic accuracy. Future research should focus on longitudinal study designs, exosomal miRNA analysis for brain-specific detection, and stratification by clinical subtypes and endophenotypes. The higher suicide risk in BD (up to 20 times more likely than general population) underscores the urgent need for reliable biomarkers to identify at-risk patients and guide treatment decisions.