Long Duration Response in Parkinson's Disease: Levodopa Revisited

Werner Poewe; Alberto J. Espay


Brain. 2020;143(8):2332-2335. 

In This Article

Abstract and Introduction


Parkinson's disease stands out among the neurodegenerative diseases by the availability of highly efficacious symptomatic therapies. This is largely due to a series of seminal discoveries made in the second half of the last century when the Swedish pharmacologist Arvid Carlsson and his colleagues showed that reserpine-induced dopamine depletion, which resulted in profound akinesia, could be reversed by the dopamine precursor levodopa—a discovery for which he was awarded the Nobel prize in 2000. The discovery of striatal dopamine deficiency in the brains of subjects with Parkinson's disease by the Viennese pharmacologist Oleh Hornykiewicz was equally important and led to the first trials of levodopa as treatment for Parkinson's disease, which were eventually brought to success by George Cotzias and colleagues (Lees etal., 2015). More than 50 years later, levodopa remains unsurpassed by any other treatment regarding its symptomatic efficacy, with novel delivery formulations remaining the focus of clinical drug development programmes (LeWitt and Fahn, 2016). Despite its long history, the profound and universal efficacy of levodopa on the motor symptoms of Parkinson's disease obscured our ability to fully understand aspects related to its mechanism of action, differential efficacy on motor symptoms, evolution of motor complications and, paradoxically, even the duration of its effect. In this issue of Brain, Cilia and colleagues (2020) present data that clarify important elements related to the duration of response to levodopa that cannot be explained by its known mechanism of action.

Cilia and colleagues studied a group of 30 patients with Parkinson's disease from Ghana, who gained access to levodopa only after long periods of untreated Parkinson's disease (mean, 7 years) and were carefully observed for 2 years. Baseline clinical assessments included the full Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr staging to quantify motor impairment. The first-ever exposure to levodopa was standardized as a levodopa challenge of 100/25 mg or 150/37.5 mg of dispersable levodopa/benserazide with motor assessments pre-dose and after 90 min, followed by a minimum of 4 h of clinical observation. Subjects were subsequently titrated to optimized motor function, with assessments after 12 and 24 months. These included a levodopa challenge test after an overnight withdrawal to document the presence of motor fluctuations and dyskinesia. Data obtained by this design enabled the analysis of baseline severity of motor features after prolonged untreated disease and the modelling of motor progression in untreated Parkinson's disease, as well as assessments of the dynamics of the short and long duration response to levodopa over 2 years of treatment.