Serum Cyclic Pentapeptide Cyclo(D-Trp-D-Asp-Pro-D-Val-Leu) as a Candidate Diagnostic Biomarker for Depression-Anxiety Comorbidity

Introduction:: The comorbidity rate of depression and anxiety disorders is as high as 50%, with patients suffering from both conditions facing an elevated risk of suicide. Given the chal-lenges in clinical diagnosis, there is an urgent need for objective diagnostic biomarkers to accurate-ly identify patients with comorbid depression and anxiety disorders. Methods:: The case-control study enrolled 77 participants, including healthy controls (n = 38) and patients with comorbid depression and anxiety disorders (n = 39). Serum levels of short peptides were assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Binary lo-gistic regression and receiver operating characteristic analysis (ROC) were employed to identify po-tential biomarkers, while decision curve analysis (DCA) was performed to evaluate the clinical util-ity of the candidate cyclic pentapeptide. Results:: A total of 25 differentially expressed short peptides were identified, among which 19 were significantly downregulated, and 6 were upregulated. Logistic regression analysis revealed that re-duced levels of cyclo (D-trp-D-asp-pro-D-val-leu) were associated with an increased risk of comor-bid depression and anxiety disorders. The area under the ROC curve (AUC) for this cyclic pen-tapeptide in diagnosing comorbid depression and anxiety disorders was 0.941 (95% CI, 0.884-0.997; P < 0.0001). DCA demonstrated that the cyclic pentapeptide provides meaningful net bene-fits when the threshold probability exceeded 0.11. Notably, this cyclic pentapeptide is an endothelin A receptor antagonist, which is implicated in vasoconstriction, hypertension, and anxiety, and ele-vated blood pressure was indeed observed in the patient cohort. Discussion:: The identified cyclic pentapeptide serves as a potential diagnostic tool, linking the pathophysiology of comorbid depression and anxiety disorders to the endothelin system. This asso-ciation offers a novel integrative perspective on the co-occurring psychiatric and cardiovascular manifestations observed in these patients. Conclusion:: In conclusion, this study identifies a specific cyclic pentapeptide as a promising serum biomarker that may facilitate the objective diagnosis of patients with comorbid depression and anx-iety disorders. Its biological role as an endothelin A receptor antagonist not only provides a poten-tial tool for clinical differentiation but also suggests a novel pathophysiological link to cardiovascu-lar comorbidities, thereby offering new directions for elucidating the underlying mechanisms of these conditions.