Abstract Despite multiple available strategies for managing motor fluctuations in advanced Parkinson’s disease, there is a continuing need for improved therapeutics. After 2-5 years of levodopa treatment, some patients start to experience OFF time that can occupy five or more hours/day. Responding to this challenge are pump-delivered infusion therapies for delivering carbidopa-levodopa or apomorphine. However, despite their ability to provide continuous dopaminergic stimulation, these options generally do not provide fluctuators with full control of daily OFF time. The complexity of managing motor fluctuations is further highlighted by the effectiveness of various non-dopaminergic adjunctive therapies for reducing OFF time in levodopa-treated patients, as shown by placebo-controlled clinical trials with adjunctive istradefylline, amantadine, zonisamide, and deep brain stimulation. Other recent paradigm shifts for understanding levodopa’s role in Parkinson’s disease therapeutics are observations that reserpine-induced Parkinsonism in mice can be reversed without its conversion to dopamine. For achieving better control of OFF time in advanced Parkinson’s disease, there is a need for discovering therapeutic strategies acting beyond the limits of today’s dopaminergic therapies. Modeling brain circuitry with tools like deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights for better understanding of motor fluctuations and the choice of appropriate therapeutic targets.
LeWitt Pa (2026) studied this question.