The pathobiological basis of depression in Parkinson disease: challenges and outlooks.

Depression, with an estimated prevalence of about 40% is a most common neuropsychiatric disorder in Parkinson disease (PD), with a negative impact on quality of life, cognitive impairment and functional disability, yet the underlying neurobiology is poorly understood. Depression in PD (DPD), one of its most common non-motor symptoms, can precede the onset of motor symptoms but can occur at any stage of the disease. Although its diagnosis is based on standard criteria, due to overlap with other symptoms related to PD or to side effects of treatment, depression is frequently underdiagnosed and undertreated. DPD has been related to a variety of pathogenic mechanisms associated with the underlying neurodegenerative process, in particular dysfunction of neurotransmitter systems (dopaminergic, serotonergic and noradrenergic), as well as to disturbances of cortico-limbic, striato-thalamic-prefrontal, mediotemporal-limbic networks, with disruption in the topological organization of functional mood-related, motor and other essential brain network connections due to alterations in the blood-oxygen-level-dependent (BOLD) fluctuations in multiple brain areas. Other hypothetic mechanisms involve neuroinflammation, neuroimmune dysregulation, stress hormones, neurotrophic, toxic or metabolic factors. The pathophysiology and pathogenesis of DPD are multifactorial and complex, and its interactions with genetic factors, age-related changes, cognitive disposition and other co-morbidities awaits further elucidation.