Methylphenidate

Parkinson's disease (PD) affects about 1 % of the population over the age of 60 years and is characterized by a combination of rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait (FoG). However, the clinical spectrum also spans a wide range of non-motor symptoms, such as depression, apathy, cognitive disorders, sleepiness, fatigue and pain. Given that the loss of dopamine in the striatum is the primary pathochemical hallmark in PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission. The currently licensed dopaminergic treatments for PD modulate all the key steps in the dopamine transmission except the most powerful determinant of extracellular dopamine concentrations: the presynaptic dopamine transporter (DaT). Methylphenidate is a CNS stimulant that blocks the DaT and the noradrenaline (norepinephrine) transporter in the striatum and the prefrontal cortex in particular. Here, we report on and discuss the main open-label studies and randomized controlled trials on the effect of methylphenidate on severe gait disorders (e.g. the FoG) and non-motor symptoms in advanced PD. The various pharmacodynamic effects of methylphenidate mean that the drug may have significant value in the treatment of PD. However, there is a lack of randomized controlled trials in this field. Furthermore, more rigorous selection of the types and doses of the associated dopaminergic treatments is required because these parameters may profoundly influence the mechanisms of action of methylphenidate and the clinical outcomes. Pharmacogenetic tools could be of use in better defining study patients as a function of their dopaminergic metabolism and drug responsiveness.