Dynamic comorbidity trajectories spanning the diagnosis of depression: nationwide cohort study.

BACKGROUND: Depression is often accompanied by multisystem comorbidities, but the time trajectories of these comorbidities remain unclear. AIMS: We aimed to define the temporal sequence of comorbidity accrual relative to depression diagnosis, and examine how this trajectory differs in recurrent depression. METHOD: A total of 32 953 individuals with depression were identified in the UK Biobank cohort, including 2402 with recurrent depression. The time between diagnosis of depression or recurrent depression and ten common comorbidities was established to determine the temporal order and rate of comorbidity diagnosis in relation to depression, based on the sequence of recorded diagnostic events. We further stratified the cohort by polygenic risk score, gender, age and history of antidepressant or antihypertensive medication use. RESULTS: The study included 32 953 participants (mean age at diagnosis 52.6 years; 63.1% female). Hypertension and dorsopathies preceded depression diagnosis by a median of 2.6 years (interquartile range (IQR) -7.0 to 0.0) and 1.0 year (IQR -5.0 to 2.0), respectively. Alzheimer's disease and obesity emerged after diagnosis at medians of 2.5 years (IQR 0.0-5.0) and 0.8 years (IQR -2.0 to 3.0). High genetic risk was associated with an earlier onset of pre-depression cardiometabolic conditions, with hypertension occurring 2.8 years before diagnosis in individuals with a high polygenic risk score compared with 2.3 years in individuals with a low polygenic risk score. Crucially, individuals with recurrent depression exhibited a profoundly different trajectory, with most comorbidities manifesting many years after the index diagnosis. Stratification by medication history indicated that antihypertensive drug use was associated with an earlier recorded diagnosis of cardiometabolic conditions, whereas antidepressant use was linked to a later diagnosis of neurodegenerative diseases. CONCLUSIONS: These findings identify three critical windows for intervention and reveal a distinct, delayed comorbidity trajectory in recurrent depression. This underscores the need for long-term, integrated surveillance strategies tailored to depression subtype and treatment history.