Depression in Patients with Parkinson’s Disease: Current Understanding of its Neurobiology and Implications for Treatment

Abstract

Depression is one of the most frequent and burdensome non-motor symptoms in Parkinson's disease (PD), across all stages. Even when its severity is mild, PD depression has a great impact on quality of life for these patients and their caregivers. Accordingly, accurate diagnosis, supported by validated scales, identification of risk factors, and recognition of motor and non-motor symptoms comorbid to depression are critical to understanding the neurobiology of depression, which in turn determines the effectiveness of dopaminergic drugs, antidepressants and non-pharmacological interventions. Recent advances using in vivo functional and structural imaging demonstrate that PD depression is underpinned by dysfunction of limbic networks and monoaminergic systems, depending on the stage of PD and its associated symptoms, including apathy, anxiety, rapid eye movement sleep behavior disorder (RBD), cognitive impairment and dementia. In particular, the evolution of serotonergic, noradrenergic, and dopaminergic dysfunction and abnormalities of limbic circuits across time, involving the anterior cingulate and orbitofrontal cortices, amygdala, thalamus and ventral striatum, help to delineate the variable expression of depression in patients with prodromal, early and advanced PD. Evidence is accumulating to support the use of dual serotonin and noradrenaline reuptake inhibitors (desipramine, nortriptyline, venlafaxine) in patients with PD and moderate to severe depression, while selective serotonin reuptake inhibitors, repetitive transcranial magnetic stimulation and cognitive behavioral therapy may also be considered. In all patients, recent findings advocate that optimization of dopamine replacement therapy and evaluation of deep brain stimulation of the subthalamic nucleus to improve motor symptoms represents an important first step, in addition to physical activity. Overall, this review indicates that increasing understanding of neurobiological changes help to implement a roadmap of tailored interventions for patients with PD and depression, depending on the stage and comorbid symptoms underlying PD subtypes and their prognosis.

Psychometrics and diagnostics of the Italian version of the Beck Depression Inventory-II (BDI-II) in Parkinson’s disease

“…Even though a unified pathophysiological model of depression in PD, considering the interaction with incidental depression after diagnosis, is still lacking [5], its onset may precede the motor manifestations [6] and affects patients' overall prognosis [7].…”

Neuroinflammation in Parkinson’s Disease: From Gene to Clinic: A Systematic Review

“…Patients with PD experience non-motor symptoms related to the accumulation of α-syn and the loss of dopaminergic and noradrenergic innervations in certain brain regions (among which LC stands out) and in some regions of the limbic system, and the main repercussions involve neuropsychiatric or autonomic dysfunctions [ 78 , 82 , 84 ]. The most frequent are depression [ 85 , 86 ], anxiety [ 86 ], fatigue and sleep disorders [ 82 ].…”

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

“…In conclusion, modern in vivo imaging studies demonstrated that DPD is mainly underpinned by dysfunction of basal ganglia-cortico-limbic networks and monoaminergic systems, depending on the stage of PD and associated symptoms, including autonomic dysfunctions, CI, and RBD. In particular, the evolution of dopaminergic and serotonergic dysfunction and abnormalities of limbic circuits across time, involving the orbitofrontal and anterior cingulate cortices, ventral striatum, amygdala, thalamus, and other important brain networks, help to delineate the variable expression and severity of depression in patients with preclinical/prodromal, early and advances stages of PD (Prange et al 2022 ). A history of depression may also be an increased risk of adverse effects following subthalamic nucleus deep brain stimulation (Kratter et al 2020 ).…”

“…Overall, these data suggest that depression and PD may share common pathophysiological mechanisms, although these are multifactorial and complex, related to a variety of pathobiological mechanisms associated with the underlying neurodegenerative process of PD (Jankovic and Tan 2020 ; Prange et al 2022 ; Weintraub et al 2022 ), the essential ones will be critically reviewed.…”

“…On the contrary, other studies found a significantly higher density of DAT in the bilateral striatum, particularly in the left caudate and right putamen in depressed PD patients in comparison to non-depressed ones, suggesting increased dopaminergic transmission at the synapse (Felicio et al 2010 ), or no dopaminergic striatal change related to depression using (l8F)FP-CIT PET (Park et al 2019 ). It should be considered that DAT imaging provides evidence for presynaptic dopaminergic dysfunction related to DPD either via a reduced availability due to greater degeneration or an increased availability of DAT possibly due to abnormal dopamine clearance (Prange et al 2022 ).…”