ObjectiveBipolar depression (BD) and major depressive disorder (MDD) are both common affective disorders. The common depression episodes make it difficult to distinguish between them, even for experienced clinicians. Failure to properly diagnose them in a timely manner leads to inappropriate treatment strategies. Therefore, it is important to distinguish between BD and MDD. The aim of this study was to develop and validate a nomogram model that distinguishes BD from MDD based on the characteristics of lymphocyte subsets.Materials and methodsA prospective cross-sectional study was performed. Blood samples were obtained from participants who met the inclusion criteria. The least absolute shrinkage and selection operator (LASSO) regression model was used for factor selection. A differential diagnosis nomogram for BD and MDD was developed using multivariable logistic regression and the area under the curve (AUC) with 95% confidence interval (CI) was calculated, as well as the internal validation using a bootstrap algorithm with 1,000 repetitions. Calibration curve and decision curve analysis (DCA) were used to evaluate the calibration and clinical utility of the nomogram, respectively.ResultsA total of 166 participants who were diagnosed with BD (83 cases) or MDD (83 cases), as well as 101 healthy controls (HCs) between June 2018 and January 2022 were enrolled in this study. CD19+ B cells, CD3+ T cells, CD3–CD16/56+ NK cells, and total lymphocyte counts were strong predictors of the diagnosis of BD and MDD and were included in the differential diagnosis nomogram. The AUC of the nomogram and internal validation were 0.922 (95%; CI, 0.879–0.965), and 0.911 (95% CI, 0.838–0.844), respectively. The calibration curve used to discriminate BD from MDD showed optimal agreement between the nomogram and the actual diagnosis. The results of DCA showed that the net clinical benefit was significant.ConclusionThis is an easy-to-use, repeatable, and economical nomogram for differential diagnosis that can help clinicians in the individual diagnosis of BD and MDD patients, reduce the risk of misdiagnosis, facilitate the formulation of appropriate treatment strategies and intervention plans.