The persisting puzzle of OFF time in advanced Parkinson's disease

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 last five or more hours per day. Responding to this challenge are pump-delivered infusion therapies for delivering carbidopa-levodopa or apomorphine. However, despite their ability to offer 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 (and through levodopa-induced stimulation of ophthalmate release). To achieve better control of OFF time in advanced Parkinson's disease, there is a need for therapeutic strategies that act beyond the limits of today's dopaminergic therapies. Modelling brain circuitry with tools such as deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights to better understand motor fluctuations and to inform the selection of appropriate therapeutic targets.