Paper Title
EMERGING NON-INVASIVE BIOMARKERS FOR MAJOR DEPRESSIVE DISORDER: CLINICAL EVALUATION AND COMPARISON OF CIRCULAR RNAS IN SALIVA AND PLASMA

Abstract
Background: Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function. However, the objective, rapid and accurate biomarkers for MDD were urgently needed to achieve precise diagnosis and effective treatment. Circular RNAs (CircRNAs) are envisioned as promising objective biomarkers due to their high stability and conserved natural expression specificity. Methods: CircRNAs in saliva and plasma samples were identified by circRNA microarray. Validation cohorts and replication cohorts were done in independent cohorts by real-timepolymerase chain reaction (PCR). Correlation coefficient analysis was employed to investigate the correlation between circRNAs and clinical score scales of depressive symptoms. Finally, receiver operating characteristic (ROC) curve was applied to evaluate diagnostic performance of circRNAs. Results: Of the randomized participants, circZBTB25 and circFAR2 in MDD patients exhibited specific enrichment in saliva samples compared to HCs. In addition, circPARN and circZBTB25 were specifically enriched in plasma samples of MDD patients. Notably, the presence of circZBTB25 was detected in both saliva and plasma samples in microarray analysis. Three circRNAs significantly correlated with clinical primary and secondary score scales in MDD patients, the combination of three circRNAs resulted in an area under the curve (AUC) for 0.940 (95% CI, 0.900-0.980) in saliva samples and 0.975 (95% CI, 0.955-0.995) in plasma samples. Moreover, the identified circRNAs displayed distinct and specific high expression pattern in MDD patients compared to those with bipolar depression, bipolar mania and schizophrenia. Conclusions: Our prospective investigation shed light on the promising usage of saliva testing in clinical research, expanding the range of potential sources for liquid biopsy samples for identifying the unique signatures of MDD. Keywords - Major depressive disorder, circRNAs, saliva biomarkers