Therapeutic strategies for nonmotor symptoms in early Parkinson's disease: the case for a higher priority and stronger evidence.

It is now recognized that the neuropathology of early Parkinson's disease (PD) is not limited to the nigrostriatal dopaminergic system, but also involves various brainstem nuclei, the hypothalamus, the olfactory system, and the peripheral autonomic nervous system. Given the disseminated neuropathology of early PD, the earliest clinical signs include a myriad of non-motor manifestations including sleep-wake cycle regulation, cognition, mood and motivation, olfactory and gustatory functions, autonomic functions, and sensory and pain processing. Despite this realization, there is clearly a paucity of trials that have systematically evaluated the treatment of non-motor symptoms of PD in the early stages. For example, only one large-scale, placebo-controlled randomized trial has been conducted on the treatment of depression in PD patients. There are no reports of randomized controlled trials of therapeutic agents looking at the frequently reported anxiety and fatigue in early PD patients. Based on this lack of evidence, therapy for early non-motor manifestations is often ignored and the focus remains on dopamine replacement strategies with main outcomes being restricted to motor measurements, such as the Unified Parkinson's Disease Rating Scale. This article presents the case for prioritizing well-designed, controlled clinical trials of therapeutic interventions focusing on non-motor symptoms in early PD patients.