In the mid-1980s, the treatment of
Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on
dopamine systems and motor symptoms. A few
dopamine agonists and a
monoamine oxidase B inhibitor (
selegiline) were used as adjuncts in advanced
Parkinson's disease. In the early 2010s,
levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for
deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of
drug-refractory
levodopa-induced motor complications. Novel
dopamine agonists (
pramipexole,
ropinirole,
rotigotine), catecholmethyltransferase inhibitors (
entacapone), and
monoamine oxidase B inhibitors (
rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using
dopamine agonists early, before
levodopa, proved to delay the onset of
dyskinesia, although this is achieved at the price of potentially disabling
daytime somnolence or
impulse control disorders. The demonstration of an antidyskinetic effect of the
glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of
Parkinson's disease therapy. More recently, nonmotor symptoms (depression,
dementia, and
psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances,
Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of
Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like
rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and
biomarkers to assess disease modification have created hope for future therapeutic interventions.