Peripheral biochemical parameters for discrimination between bipolar disorder and major depressive disorder in female patients of reproductive age: a CRP-stratified exploratory study

BACKGROUND: Bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD) due to overlapping clinical syndromes. Although numerous studies have investigated biomarkers to differentiate these two disorders, no clinically applicable differential diagnostic panel has been established. Notably, sex-specific differences play a critical role in this context. Females are more prone to experience depressive episodes and exhibit more pronounced immune-inflammatory dysregulation, which further increases the risk of misdiagnosis. This study aimed to explore whether C-reactive protein (CRP)-based stratified modeling of routinely available biochemical parameters could improve discriminative performance in reproductive-age women. METHODS: A total of 502 female patients of reproductive age were enrolled, including 263 with BD and 239 with MDD, grouped according to CRP levels. Fourteen clinical biochemical indexes were compared: white blood cells (WBC), platelets, uric acid (UA), direct bilirubin (DBIL), indirect bilirubin (IBIL), glutamic oxaloacetic transaminase (GOT), lactate dehydrogenase (LDH), prealbumin, triglycerides, low-density lipoproteins (LDL), testosterone, free triiodothyronine (FT3), free tetraiodothyronine (FT4) and thyroid stimulating hormone (TSH). Binary logistic regression analysis was employed to develop predictive models for distinguishing BD from MDD. Model performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC), and the holistic model was internally validated with 10-fold cross-validation. RESULTS: In the Normal-CRP group, BD patients had higher levels of WBC, IBIL, GOT, LDH, and FT4, and lower DBIL, prealbumin, and triglycerides compared to MDD patients. In the high CRP group, BD patients had higher IBIL and LDH, and lower DBIL (p < 0.05). Five predictive models were constructed. The Holistic model yielded an apparent AUC of 0.805 (cross-validated mean AUC: 0.808), the High-Risk model (3 ≤ CRP <5 mg/L) achieved an AUC of 0.887, and the High-CRP model (CRP ≥ 5 mg/L) had an AUC of 0.929. Detailed results for the Low-Risk and Normal-CRP models are available in the Supplementary Material. CONCLUSIONS: The CRP-stratified models demonstrated promising discriminative performance, with the highest AUC observed in the High-CRP model. These results suggest that CRP-based stratification may serve as an exploratory approach to aid differential diagnosis in women of reproductive age. LIMITATIONS: Given their limited sample sizes, the High-Risk and High-CRP models were considered exploratory approaches and were not internally validated. The CRP-based stratified models are still in the exploratory phase and require external validation to confirm their clinical applicability.