Recognizing and Treating Neuropsychiatric Symptoms in Parkinson's Disease

Pathogenesis

The pathogenesis is not fully understood, however, mesolimbic dopamine alterations are strongly suspected. It has been long speculated that the high doses of dopamine needed to replete the relatively depleted dorsal striatum overdose the “intact” ventral striatum and cause this neuropsychiatric disorder [7–9]. The additional cognitive impairments in PD, which can include problems with attention, working memory, planning, forethought and decision-making, are faculties that can markedly increase susceptibility to impulse control disorder [8].

The role of serotonin deficiency in the PD brain and its part in inhibiting the patient’s ability to delay rewards adds to the complexity of impulse control disorder pathogenesis. Dorsal raphe nuclei disease in PD results in loss of serotonin innervation to substantial portions of the prefrontal and motor cortices in addition to basal ganglia substructures like the striatum, pallidum and subthalamic nucleus [10]. Together with dopamine, serotonin may work to regulate risk-sensitive decision making, response inhibition, waiting for future rewards, and overall impulse control. Its relative loss therefore also likely contributes to tipping the balance towards impulse dyscontrol [11,12]. The role of other neurotransmitters such as opiate systems involved in the process of acquisition and maintenance of addictive behaviors like dopamine dysregulation syndrome remains to be fully understood.

Treatment

The most successful strategy to address this problem is to reduce or eliminate the offending medication, usually the dopamine agonist. This may be associated with worsening apathy, anxiety or depression; however, substituting levodopa can be a successful strategy in many cases [13]. Zonisamide was described to be possibly effective in a trial of 15 subjects; however, the open label nature of this evidence must be considered as with other case reports using valproate, donepezil, and selective serotonin reuptake inhibitors (SSRIs) [14–16].

Fatigue

An easy to understand operational definition of fatigue is that it is a state of extreme tiredness, weakness, or exhaustion, either physical or mental or both. Fatigue is not uncommon in the general population [17] but is increasingly recognized to occur in numerous disease conditions and is frequently encountered in PD and multiple sclerosis. The latter is of special significance in the consideration of the neurotransmission of fatigue, as it is not thought to be a disease of dopamine deficiency. The pathophysiology remains unclear, and it may differ depending on whether the fatigue is experienced as more physical or mental, or rather motor versus nonmotor as some authors propose.

Fatigue has been conceptualized as central or peripheral in character. Peripheral fatigue is best understood as muscular fatigue caused by repetitive muscular contraction or reduced force generation [18]. Central fatigue however, is divided into mental or physical fatigue. Mental fatigue can occur after sustained attentive or emotional activity. It may alternatively be provoked after boring repetitive tasks or lack of intellectually stimulating activity. Physical fatigue is the sense of body exhaustion or energy to perform physical tasks even though the ability to carry them out exists.

Epidemiology

As recognition of the problem of fatigue increased in the last 2 decades, the realization that one-third to one-half of patients experience it at some point has improved opportunities for recognition and treatment [19]. Fatigue may be the presenting symptom in one-third of patients prior to actual motor symptom onset [20]. Half of untreated PD patients in a biomarker cohort study reported fatigue [6]. Unfortunately, it is also described by patients as one of the most disabling symptoms, causing significant impact on quality of life [19]. Fatigue in PD is associated with higher rates of depressive symptoms, but occurs with higher prevalence in nondepressed patients [21]. Poor ability to initiate and sustain activity due to fatigue is different from depression, excessive sleepiness, or impaired motor function [22,23].