Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson's disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of 'off' episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide
