Abstract
Depression is a heterogeneous and complex psychological syndrome with highly variable manifestations, which poses difficulties for treatment and prognosis. Depression patients are prone to developing various comorbidities, which stem from different pathophysiological mechanisms, remaining largely understudied. The current study focused on identifying comorbidity-specific phenotypes, and whether these clustered phenotypes are associated with different treatment patterns, clinical manifestations, physiological characteristics, and prognosis. We have conducted a 10-year retrospective observational cohort study using electronic medical records (EMR) for 11,818 patients diagnosed with depression and hospitalized at a large academic medical center in Chengdu, China. K-means clustering and visualization methods were performed to identify phenotypic categories. The association between phenotypic categories and clinical outcomes was evaluated using adjusted Cox proportional hazards model. We classified patients with depression into five stable phenotypic categories, including 15 statistically driven clusters in the discovery cohort (n = 9925) and the validation cohort (n = 1893), respectively. The categories include: (Category A) the lowest incidence of comorbidity, with prominent suicide, psychotic, and somatic symptoms (n = 3493/9925); (Category B) moderate comorbidity rate, with prominent anhedonia and anxious symptoms (n = 1795/9925); (Category C) the highest incidence of comorbidity of endocrine/metabolic and digestive system diseases (n = 1702/9925); (Category D) the highest incidence of comorbidity of neurological, mental and behavioral diseases (n = 881/9925); (Category E) other diseases comorbid with depression (n = 2054/9925). Patients in Category E had the lowest risk of psychiatric rehospitalization within 60-day follow-up, followed by Category C (HR, 1.57; 95% CI, 1.07-2.30), Category B (HR, 1.61; 95% CI, 1.10-2.40), Category A (HR, 1.82; 95% CI, 1.28-2.60), and Category D (HR, 2.38; 95% CI, 1.59-3.60) with P < 0.05, after adjustment for comorbidities, medications, and age. Regarding other longer observation windows (90-day, 180-day and 365-day), patients in Category D showed the highest rehospitalization risk all the time while there were notable shifts in rankings observed for Categories A, B and C over time. The results indicate that the higher the severity of mental illness in patients with five phenotypic categories, the greater the risk of rehospitalization. These phenotypes are associated with various pathways, including the cardiometabolic system, chronic inflammation, digestive system, neurological system, and mental and behavioral disorders. These pathways play a crucial role in connecting depression with other psychiatric and somatic diseases. The identified phenotypes exhibit notable distinctions in terms of comorbidity patterns, symptomology, biological characteristics, treatment approaches, and clinical outcomes.