Disentangling amantadine response variability in levodopa related dyskinesias: Role of clinical and genetic factors.

Background

Amantadine is the most commonly used pharmacologic treatment for levodopa-related dyskinesias (LRD), yet its efficacy and tolerability vary substantially, challenging clinical decision-making.

Objective

To explore clinical, demographic, and genetic factors associated with variability in amantadine treatment outcomes.

Methods

Cross-sectional study of Parkinson's disease (PD) patients treated with amantadine for LRD. Participants were classified as responders or non-responders; with non-responders further subdivided according to the presence of intolerable side effects. Clinical and demographic data were collected and participants underwent genotyping. Polygenic risk scores for PD risk (PD-PRS) and genetic variants associated with levodopa or amantadine metabolism and LRD susceptibility were assessed.

Results

A total of 146 participants were included (male 57%, mean age 66.9 years); 94 provided biological samples and 86 passed quality control. Responders had a longer interval from PD diagnosis to amantadine initiation (median 5.5 vs. 3 years, p = 0.005) and higher levodopa equivalent daily dose (LEDD) (1057.6 mg ± 431.5 vs. 831.1 mg ± 504.7, p = 0.006). Among non-responders, LEDD was lower in those experiencing side effects (725.2 mg ± 397.5 vs. 1013.5 mg ± 613.6, p = 0.015). The DRD1 rs4532-C allele was nominally associated with favorable response, whereas ANKK1, DRD2, and COMT variants were nominally associated with side effects. PD-PRS showed no association with response.

Conclusions

Clinical and genetic factors may influence amantadine response. Earlier amantadine initiation and lower LEDD were associated with a poorer response to amantadine. Genetic markers in the dopaminergic pathways may facilitate a personalized treatment approach in PD.