Disease-Modifying Trials in Treated Parkinson's Disease: "Stable Treated" Does Not Equate with Biological Stability

Traditionally, clinical trials of putative disease-modifying therapies in Parkinson's disease have enrolled untreated patients at the earliest clinical stages of their disease. Due to a number of challenges inherent with this approach, there has been a recent move to a different study design, enrolling patients who are already taking "stable" anti-parkinson medication. However, typically, the symptomatic treatment regimen has not been defined uniformly with respect to drugs and dosages utilized or duration of therapy. More importantly, this approach fails to consider or account for the major pharmacodynamic changes induced in the parkinsonian brain by varying dopaminergic therapies (particularly levodopa) and the impact of these on both clinical and neuroimaging outcome measures. In this review, we highlight what is known about the changes induced by dopaminergic therapy and the challenges these will present in the interpretation of outcomes of studies using this trial design. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.