Optimising Dopamine Treatment Strategies in Progressive Parkinson’s Disease

Dopamine replacement therapies are the most common treatment approach for motor-symptom relief in Parkinson’s disease (PD). Levodopa (L-DOPA) remains the gold standard therapy for PD, however its long-term use is associated with the emergence of L-DOPA-induced dyskinesia and fluctuations. The pathophysiology of these deficits is unclear. Emerging evidence suggests that delaying L-DOPA treatment does not have protective effects on the development of these motor complications, and proposes that dysfunction in other neurotransmitter systems and the progressive nature of the disease may play an important role. Specifically, hyperexcitability in glutamatergic neural transmission may be a key contributor throughout PD progression. Targeting non-dopaminergic systems may therefore provide an effective alternative to the current dopamine-centred approaches. In addition, non-motor symptoms in PD may likewise benefit from alternative pharmacological approaches. Safinamide is a PD treatment with an innovative dual mechanism of action combining modulation of both dopaminergic and glutamatergic pathways. Clinically, combination therapy with L-DOPA and safinamide improves motor functions, decreasing OFF time and increasing ON time with no/non-troublesome dyskinesia (the so called “good ON time”). In addition, safinamide significantly improves some non-motor symptoms such as pain and mood.