Pharmacological treatment of apathy in Parkinson's disease, review of the literature
Apathy is a highly challenging factor in the general treatment of patients with Parkinson's disease (PD) and can present a major burden for caregivers. The objective of this study to answer the question of what is known about the current evidence-based pharmacological treatment of apathy, not combined with comorbid depression or dementia, in PD. Methods We searched for publications in online databases (PubMed, Embase.com, Cochrane Database of Systematic Reviews, CENTRAL and PsycInfo/Ebsco) and
... sycInfo/Ebsco) and performed a review of the literature. Included trials were based on patients with PD, with a drug intervention and apathy as an outcome measurement. Patients with comorbid dementia, severe depression, or patients after deep brain stimulation were excluded. Results Out of 1767 articles, we included 10 articles with a total of 723 patients who received intervention and 311 patients who received placebo, standard care or were healthy controls. Combining the results of the studies with a focus on favourable signi cant outcomes and the risk of bias, we would advise rivastigmine as a treatment of apathy in patients with PD, and pramipexole or selegiline in PD patients with apathy without cognitive disturbance. An important limitation of this study is that the included studies show a broad heterogeneity. Conclusions Research is sparse on the topic of evidence-based pharmacological treatment for apathy in PD. Combining the results of the studies with a focus on favourable signi cant outcomes and the risk of bias, we would advise rivastigmine as a treatment of apathy in patients with PD, and pramipexole or selegiline in PD patients with apathy without cognitive disturbance. Background Apathy is de ned in 1991 by Marin as a syndrome of primary motivational loss, that is loss of motivation not attributable to emotional distress, intellectual impairment or diminished level of consciousness(1). It is an important nonmotor neuropsychiatric feature of PD and has been described in the context of lack of motivation and diminished responsiveness to stimuli or reward-dependence. Apathy has been associated with depression, executive dysfunction and auto-activation failure (2), but it can also exist as an exclusive entity. Apathy is highly prevalent in PD and offers great challenge to clinicians as it contributes unfavorably to daily functioning, well-being and quality of life of the patient and caregivers(3). Essential criteria to diagnose PD is the presence of motor parkinsonism, which is de ned as bradykinesia, in combination with at least either resting tremor (4-6hz) and/or rigidity (MDS-PD criteria 2015)(4). Furthermore, the diagnosis can be con rmed by the UK brain bank criteria(5). The prevalence rate of apathy in PD rates from 13.9-70%, the mean prevalence is 35%. One important factor contributing to the wide variability across studies is represented by different recruitment criteria and apathy assessment. Pure apathy (without comorbid depression and/ or dementia) rates ranges from 3 to 47.9% (6). Spalletta et al described in their study the neuropsychiatric pro le of a cohort of 24 de novo, drug naïve PD patients and 8.3% of the cohort were apathic according to the Apathy rating Scale (7). Pedersen et al reported a prevalence rate of apathy in newly diagnosed patients with PD of 22.9%. The apathy in this study was described as "pure apathy", referring to lack of depression or dementia(8). Apathy can be an early sign in PD. It can even occur before the PD is diagnosed(9). Blonder et al concluded in their review that patients with PD suffering from apathy are more prone to be associated with rapid progression of motor and cognitive symptoms(10). Yahr et al even described apathy as the most disabling aspect of PD that result in inability to rapidly and easily perform the most ordinary motor activities(11). In daily life, these patients show delays in executive functions(12). This results in longer time needed for a daily meal, dressing and bathing, and other activities of daily life(13).