Recognizing and Treating Neuropsychiatric Symptoms in Parkinson's Disease

Pathophysiology

The pathophysiology of fatigue remains somewhat unclear, though physical fatigue is likely a significant part of the problem and related to dopamine deficiency based on studies of time and force generation of keyboard strikes in PD subjects before and after L-dopa administration. These subjects had declines in force and increased physical fatigue which improved after L-dopa [24]. In other studies using transcranial magnetic stimulation to study changes in cortical excitability, the degree of physical fatigue correlated with abnormalities in motor evoked potentials during fatiguing exercising. These studies also support the hypothesis that fatigue is a motor symptom [25,26]. In the ELLDOPA study, fatigue worsened more in PD subjects treated with placebo [27]. Other imaging studies have suggested suggested nondopaminergic mechanisms including serotonergic pathway abnormalities [28], thus the question behind the etiology and solution for all cases of fatigue remains to be settled.

Diagnosis

The diagnosis is fatigue may be challenging as it may mask as depression or apathy. There are a number of fatigue rating scales available; however, the validated Parkinson’s Fatigue Scale (PFS) supersedes many of the problems of using a generic scale which could overlap motor questions and potentially be confounding [29,30].

Treatment

Most important is awareness and vigilance for the symptoms of fatigue, depression, and apathy and effort to distinguish between them. It may require structured interviews or assessment tools to properly diagnose the problem. Treatment is less clear in that few studies have clearly indicated the best treatment options. In placebo-controlled trials, methylphenidate did improve fatigue as did levodopa [31]. Modafinil, a hypocretin modulator and a drug first approved by the FDA for treatment of narcolepsy, has demonstrated mixed results in recent years. It may reduce physical fatigue and reduce excessive daytime sleepiness but likely does not reduce subjective symptoms of fatigue [32]. L-dopa can significantly reduce fatigue in many patients, which would argue that it often is a motor symptom [33,24]. In a post-hoc analysis of the ADAGIO delayed start study, patients taking rasagiline 1 mg/day and 2 mg/day (the latter dose exceeds the usual clinical dosing) showed significantly less worsening of symptoms on the PFS compared to placebo over time [34]. It is important to realize that once motor symptoms are optimally treated with dopaminergic medications, while many patients will feel significant relief from fatigue some patients will continue to feel symptomatic.

Apathy

The definition of apathy has become more complicated and refined, incorporating findings from the study of brain disease and behavioral analysis. Marin’s classic elaboration of apathy as lack of motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress has been built upon by Levy and Dubois [35–37]. They suggest apathy may be better thought of as an observable behavioral syndrome characterized by a quantitative reduction of self-generated voluntary and purposeful behaviors. They suggest 3 apathetic subtypes: emotional, cognitive, and auto-activational, which reflect different disease states accounting for failure of normal goal-directed behavior.

Epidemiology

Prevalence estimates for apathy in PD vary. This is likely due to the varying recruitment criteria among studies, with some including patients with comorbid depression and dementia and others containing only “pure apathy.” Other reports may have had referral bias issues, as community-based studies report lower prevalences in general. In a group of newly diagnosed PD patients, using more restrictive criteria (apathy subscale of the neuropsychiatric inventory and the diagnostic consensus criteria for apathy validated in PD), Pedersen reported a prevalence of apathy of 14.3% [38]. In a 4-year prospective longitudinal cohort study, an annual incidence rate of 12.3% was reported, with apathy developing in 60% of the cohort by the study’s conclusion [39].