Parkinson's disease (PD) is a complex illness with a constellation of environmental insults and genetic vulnerabilities being implicated. Strikingly, many studies only focus on the cardinal motor symptoms of the disease and fail to appreciate the major non-motor features which typically occur early in the disease process and are debilitating. Common comorbid psychiatric features, notably clinical depression, as well as anxiety and sleep disorders are thought to emerge before the onset of prominent motor deficits. In this review, we will delve into the prodromal stage of PD and how early neuropsychiatric pathology might unfold, followed by later motor disturbances. It is also of interest to discuss how animal models of PD capture the complexity of the illness, including depressive-like characteristics along with motor impairment. It remains to be determined how the underlying PD disease processes contributes to such comorbidity. But some of the environmental toxicants and microbial pathogens implicated in PD might instigate pro-inflammatory effects favoring α-synuclein accumulation and damage to brainstem neurons fueling the evolution of mood disturbances. We posit that comprehensive animal-based research approaches are needed to capture the complexity and time-dependent nature of the primary and co-morbid symptoms. This will allow for the possibility of early intervention with more novel and targeted treatments that fit with not only individual patient variability, but also with changes that occur over time with the evolution of the disease.