Longitudinal analysis of 159 early-stage PD patients shows daytime sleepiness increases over time independent of levodopa (notably in patients >65), while fatigue increases are associated with levodopa dose escalation (primarily in patients ≤65).

Distinguishing disease-driven daytime sleepiness from medication-associated fatigue highlights modifiable targets for symptomatic management and informs therapeutic development and trial stratification for PD non-motor symptoms.

BACKGROUND: Weariness-related symptoms (WRS), i.e. fatigue, daytime sleepiness, and sleep problems are common non-motor symptoms in Parkinson's disease (PD) that impair quality of life. Although related, they represent distinct clinical domains, and the role of dopaminergic therapy in their progression remains unclear. We compared stable levodopa regimens with levodopa dose escalation to evaluate their impact on WRS evolution. METHODS: From a database of 1,521 PD patients, 159 individuals (mean age 64.7 ± 9.36 years; 61.7% male; Hoehn and Yahr stage 0-2) with two assessments 6-18 months apart were included. Patients were grouped into stable medication regimen (SMR) or increased levodopa dose (ILD). Longitudinal changes in fatigue, daytime sleepiness, and nighttime sleep problems were analyzed, including age-stratified comparisons. RESULTS: In the SMR group, daytime sleepiness increased significantly over time (0.21 ± 0.86, P = 0.001), while fatigue and sleep problems remained stable. In contrast, the ILD group showed a significant increase in fatigue (0.15 ± 0.89, P = 0.017), with no changes in daytime sleepiness or sleep problems. Worsening daytime sleepiness under stable medication was confined to older patients (>65 years, P = 0.003), whereas fatigue worsening after levodopa escalation was mainly observed in younger patients (≤65 years, P = 0.03). CONCLUSION: Daytime sleepiness appears disease-driven and independent of medication changes, while fatigue is more closely associated with levodopa escalation, supporting individualized management and targeted therapeutic development.