Dissection of the clinical phenome of major depressive disorder into subdomains and subgroups in relation to activated immune-inflammatory profiles

Background: Major depressive disorder (MDD) is a prevalent mood disorder characterized by low remission rates and a high risk of suicide. It encompasses various clinical domains, including depression, anxiety, vegetative, physiosomatic and melancholic symptoms, and suicidal behaviors. Aims: To dissect the clinical phenome of MDD, identify potential constructs within the symptom domains, delineate MDD subclasses, investigate the predictive role of recurrence of illness (ROI) on the phenome, and analyze the relationship between those clinical features and immune activation biomarkers. Methods: A total of 125 MDD patients and 40 healthy controls were recruited for this study. Assays included serum immunological features (M1, Th1, Th2, Th17, IRS, CIRS, and TNF signaling), negative acute phase proteins (APPs; transferrin, albumin), sCD40L, EGF, and Flt-3L. Results: Bifactor analysis integrated multiple clinical domains into a general factor, labeled OSOD (overall severity of depression), while extracting a single group factor of physiosomatic symptoms. Cluster analysis identified two subgroups of MDD: major dysmood disorder (MDMD) and simple dysmood disorder (SDMD). ROI mediates the impact of adverse childhood experiences on OSOD and correlates with enhanced immune activation (increased Th17). Downregulation of negative APPs and Flt-3L alongside increased EGF and TNF signaling distinguish MDMD versus SDMD or MDD from controls with great accuracy. Up to 60% of MDD patients show immune aberrations with a specificity of 92.1%. Conclusion: This study promotes a novel diagnostic approach that integrates ROI, OSOD, physiosomatic symptoms, MDMD versus SDMD, and immune profiling. It has the potential to establish the groundwork for future personalized therapeutic strategies.