Moving to a non-dopaminergic approach for the treatment of OFF fluctuations in Parkinson’s disease

In levodopa treated patients with Parkinson’s disease (PD), the standard approach to managing motor fluctuations is to adjust dopaminergic therapy. However, despite the availability of a wide armamentarium of dopaminergic medications, most patients treated with levodopa will still experience significant OFF time, and it is increasingly clear that motor fluctuations have a significant non-dopaminergic component. In this narrative review, we compare and contrast the therapeutic profiles of the only two non-dopaminergic medications approved in the US for the management of OFF time, namely amantadine and istradefylline. When compared against each other the two agents exemplify two different pharmacological approaches to treatment. Whereas amantadine has a multimodal pharmacology, istradefylline has highly specific actions at A_2A receptors which are highly expressed in the indirect pathway of the basal ganglia. We discuss how both offer an important alternative approach to treatment, without increasing total dopaminergic load. Clinicians can also consider that amantadine and istradefylline each have overlapping indications with classic dopaminergic medications, but with distinct mechanisms of action that can complement each other to reduce motor complications in patients already being treated with other dopaminergic agents.