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 challenges in clinical diagnosis, there is an urgent need for objective diagnostic biomarkers to accurately 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 logistic regression and receiver operating characteristic analysis (ROC) were employed to identify potential biomarkers, while decision curve analysis (DCA) was performed to evaluate the clinical utility 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 reduced levels of cyclo (D-trp-D-asp-pro-D-val-leu) were associated with an increased risk of comorbid 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 benefits 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 elevated 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 association 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 anxiety disorders. Its biological role as an endothelin A receptor antagonist not only provides a potential tool for clinical differentiation but also suggests a novel pathophysiological link to cardiovascular comorbidities, thereby offering new directions for elucidating the underlying mechanisms of these conditions.