Parkinson's disease: how to initiate treatment to optimize the benefit-risk ratio in both the short and long term?

A major challenge: limiting treatment-related complications

Parkinson's disease affects more than 270,000 people in France. Its reference treatment, levodopa,has been effectively improving symptoms for over 50 years. But over time, this treatment can lead to the appearance of involuntary movements, sometimes disabling in everyday life, called dyskinesias. These dyskinesias result from the combined effect of disease progression and exposure to levodopa. They can affect up to 1 in 3 patients after a few years, and more in the longer term.

Therapeutic strategies still controversial, due to different adverse effect profiles, confirmed in real life by data from the French NS-PARK network cohort

For years, doctors and people with Parkinson's disease have been faced, from the earliest stages of the disease, with a therapeutic dilemma still unresolved: begin immediately with levodopa, at the risk of subsequent dyskinesias, or favor other alternatives, such as dopaminergic agonists, alone or in combination. These alternatives reduce the risk of dyskinesias, but on the other hand expose patients to other adverse effects that are sometimes more troublesome than the involuntary movements themselves, in particular impulse control disorders. Results recently published by investigators from the réseau NS-PARK, a national clinical research network of excellence with F-CRIN accreditation and specializing in Parkinson's disease and abnormal movements, analyzing data from the national NS-PARK cohort, in more than 1,700 French patients followed in 26 expert centers between 2011 and 2021, confirm this dilemma: people treated with levodopa alone indeed present a higher risk of developing dyskinesias, whereas those benefiting from alternative strategies, mainly based on the use of dopaminergic agonists, develop fewer dyskinesias. Nevertheless, these people show more impulsive behavioral changes (Lanore et al, CNS Drugs 2025).

In an attempt to better understand these phenomena and in the hope of better predicting and preventing these risks in the future, both in the short and long term, the NS-PARK network is currently prospectively monitoring, with the support of the Association France Parkinson, a new cohort of 2,500 people at the onset of their disease: the PRECISE-PD cohort. The aim of this cohort is to identify the clinical, genetic, biological and pharmacological factors associated with the occurrence of these various adverse effects, so as to facilitate and improve initial therapeutic choices for each individual in a more personalized approach than is currently the case.

PREMANDYSK: encouraging results by intervening from the first year

In this context and pending data from the PRECISE-PD cohort, the PREMANDYSK trial was conducted. This trial was alsocoordinated by the NS-PARK network, with financial support from the French Ministry of Health and thanks to the promotion of Toulouse University Hospital. The aim of this trial was to evaluate a new strategy for the early treatment of Parkinson's disease, by combining levodopa from the first months of its prescription with another drug, amantadine. The choice of this "old" drug, marketed as early as the 1960s but whose use in early Parkinson's disease subsequently largely fell into disuse, was based on the fact that NS-PARK network had previously been shown to improve dyskinesias when present at a more advanced stage of the disease (Ory-Magne et al, Neurology, 2014). The originality of the project was therefore to determine whether the early association of this drug with levodopa reduced the subsequent risk of dyskinesias occurring in patients who were still free of them.

To this end, the PREMANDYSK trial involved 207 people with early Parkinson's disease, treated with levodopa for less than a year and with no dyskinesias at baseline. After 18 months' follow-up, the results were unambiguous: participants receiving the amantadine + levodopa combination developed twice as many dyskinesias as those treated with levodopa alone (combined with placebo): 11% in the amantadine group versus 22% in the placebo group. Patients receiving amantadine also required lower dose increments of levodopa over time. Furthermore, improvements were also observed on other disease symptoms, such as fatigue, as well as on a quality of life scale (Rascol et al, Mov Disorders, 2025).

These results therefore suggest that a combined strategy, implemented early in the disease, could help limit the onset of this type of complication.

In summary, these new data serve as a reminder that decisions made in the early years of the disease can have long-term consequences, and reinforce the value of continuing efforts in the direction of more personalized management, tailored to each patient's profile, in order to better balance the benefits of treatments with their adverse effects. These data also illustrate the key role of F-CRIN-approved clinical research networks in developing large-scale clinical trials and improving medical practices.