Premorbid depression across levodopa equivalent daily dose-defined treatment trajectories in Parkinson's disease: A nationwide register-based cohort study.

BACKGROUND: Depression is a common comorbidity in Parkinson's disease (PD) and may precede diagnosis by several years. It remains unclear whether prodromal depression is associated with specific PD subtypes or faster disease progression. We investigated whether pre-diagnostic depression incidence differs according to post-diagnostic proxies of PD progression, defined by dopaminergic treatment intensity and escalation. METHODS: In this Danish nationwide register-based cohort study, 19,165 individuals with incident PD (2007-2019) were identified. PD progression was approximated using two approaches: (1) mean levodopa equivalent daily dose (LEDD) during follow-up and (2) annual rate of LEDD escalation in the first five years after PD diagnosis. Incident depression was defined as the first redeemed antidepressant prescription or hospital diagnosis. Depression incidence rates were examined across a 7-year pre-diagnostic period and compared using hazard rate ratios. RESULTS: Overall, 11.7% of patients had registry-captured depression before PD diagnosis. Depression incidence increased progressively toward diagnosis, with a marked rise in the final year. However, no consistent differences in pre-diagnostic depression rates were observed across treatment intensity groups or LEDD escalation trajectories. CONCLUSIONS: Prodromal depression does not appear to be associated with accelerated motor progression of PD as approximated by dopaminergic treatment patterns. These findings suggest that depression is a general prodromal feature of PD rather than a marker of more aggressive disease subtypes. Future studies using more precise subtype markers are needed to clarify the relationship between neuropsychiatric symptoms and PD heterogeneity.