Human serum hypoxanthine as a biomarker to predict recurrent major depressive disorder: a cross-sectional metabolomic study.

Major depressive disorder (MDD) is a multifactorial and highly recurrent illness. Patients are typically required to take antidepressants for 6-12 months following a single depressive episode, even if symptoms are alleviated. However, some individuals are reluctant to use these medications or adhere to prescribed dosing instructions. Therefore, this study aimed to identify biomarkers that can predict MDD recurrence, thus facilitating early detection of relapses and providing strong clinical justification for sustained antidepressant therapy. Serum samples were collected from participants, categorized into two groups: major depressive disorder with a single episode (MDD-S) and recurrent episodes (MDD-R) groups. Candidate biomarkers were identified via targeted tandem mass spectrometry, with features extracted using MassHunter Profinder v10.0 and Mass Profiler Professional software v 15.1 (p < 0.05, fold-change ≥ 1.2). After spectral matching, hypoxanthine was finally identified. Subsequently, a multiple reaction monitoring analysis, a targeted metabolomics technique, was performed to validate hypoxanthine. This analysis confirmed that hypoxanthine levels were significantly lower in the MDD-R group than in the MDD-S group. Validation results demonstrated that this difference was independent of sex and the presence or absence of antidepressant treatment. Moreover, receiver operating characteristic analysis confirmed that the MDD-S and MDD-R groups were significantly distinct (Area Under the Curve = 0.87, sensitivity = 80%, specificity = 80%). In conclusion, this study identified hypoxanthine as a biomarker for predicting MDD recurrence, confirming lower hypoxanthine levels in patients with recurrent MDD than in those with single-episode MDD. Hypoxanthine is a key intermediate in purine metabolism and is known to be involved in the regulation of neuronal energy homeostasis and oxidative stress; these processes are increasingly recognized as being closely linked to the pathophysiology of major depressive disorder. This biomarker may enable the identification of patients at a high risk of recurrence, thereby facilitating the development of personalized treatment strategies.