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Jiangjing Dai,1– 3 Qingling Li,1 Biqiong Ren1,2 1College of Integrated Traditional Chinese and Western Medicine, Hunan University of Traditional Chinese Medicine, Changsha, Hunan Province, People’s Republic of China; 2Department of Science and Education, The Second People’s Hospital of Hunan Province (Hunan Provincial Brain Hospital), Changsha, Hunan Province, People’s Republic of China; 3Department of Clinical Laboratory, Shaoyang Central Hospital, Shaoyang, Hunan Province, People’s Republic of ChinaCorrespondence: Biqiong Ren, Department of Science and Education of The Second People’s Hospital of Hunan Province (Hunan Provincial Brain Hospital), Changsha, Hunan Province, 410007, People’s Republic of China, Tel +86 13808481211, Email 13808481211@163.comObjective: To investigate changes in peripheral blood non-enzymatic antioxidant levels in patients with major depressive disorder (MDD) and bipolar disorder (BD) across different disease stages from a laboratory perspective, and to explore their potential clinical applications.Methods: This single-center retrospective case-control study was conducted at Hunan Provincial Brain Hospital between January and December 2023. A total of 290 participants aged ≥ 16 years were enrolled, including 140 BD patients, 72 MDD patients, and 78 healthy controls (HC). Between-group comparisons for two groups were performed using independent samples t-tests, and one-way analysis of variance (ANOVA) was employed for multi-group comparisons of continuous variables. Analysis of covariance (ANCOVA) was further used to compare serum levels of uric acid (UA), albumin (Alb), and total bilirubin (TBIL) among the MDD, BD, and HC groups, with age and sex as covariates. Multivariable logistic regression analyses were conducted to identify independent predictors of MDD and BD. Receiver operating characteristic (ROC) curves were generated based on predicted probabilities from the regression models. Statistical significance was set at a two-tailed P < 0.05.Results: Compared with HC, MDD patients exhibited significantly lower serum UA levels (P = 0.022), whereas BD patients demonstrated significantly higher UA levels (P = 0.006); both patient groups showed markedly reduced TBIL and Alb levels (all P < 0.0001). BD patients presented elevated UA, Alb, and TBIL levels during manic episodes and decreased levels during depressive episodes. The combined detection of these indices yielded an area under the curve (AUC) of 0.919 for MDD (sensitivity: 75.6%; specificity: 90.0%) and 0.842 for BD (sensitivity: 67.9%; specificity: 89.7%). MDD patients with hospitalization duration ≤ 15 days had higher serum UA levels, which were negatively correlated with hospitalization duration (r = − 0.28). In contrast, BD patients with hospitalization duration ≤ 15 days exhibited lower UA, Alb, and TBIL levels, with UA positively correlated with hospitalization duration (r = 0.19). BD patients in depressive episodes who received antidepressants had significantly prolonged hospitalization (P < 0.0001).Conclusion: Serum UA level could serve as a potential biomarker for distinguishing MDD from BD, with lower UA levels observed in MDD patients and relatively higher levels in BD patients. The combined detection of UA, Alb, and TBIL demonstrated favorable diagnostic performance for both disorders, and was associated with the length of hospital stay. Furthermore, antidepressant use during the depressive episode of BD may be associated with prolonged hospital stay. These findings may help improve the early differential diagnosis and clinical management of MDD and BD, and provide a reference for individualized treatment and hospitalization strategies in clinical practice.Keywords: depression, bipolar disorder, antioxidant, differential diagnosis