Neuropsychiatric Symptoms in Clinically Defined Parkinson's Disease: An Updated Review of Literature

Background Neuropsychiatric symptoms (NPS) are a common and potentially serious manifestation of Parkinson's disease (PD) but are frequently overlooked in favor of a focus on motor symptomatology. Here, we conducted a literature review of the prevalence and type of NPS experienced by PD patients with a clinically defined course of their illness. Methods We identified reports of NPS in patients with PD and mean disease duration over 3 years. Three databases—PubMed, Scopus, and Dialnet—were searched for relevant literature published between 2010 and 2020. Predefined exclusion criteria were applied prior to a descriptive analysis of the literature base. Results In all, 87 unique reports were identified and 30 met inclusion and exclusion criteria. These included 7142 patients with PD (male: 67.3%; mean age: 66.2 years; mean disease duration: 6.7 years). The most frequent NPS were mood disorders (apathy, depression, and anxiety), psychosis, and impulse control disorders (ICD). Treatment with dopamine agonists was identified as an important risk factor for ICD. Co-occurrence of NPS and cognitive dysfunction was also evidenced in a number of studies. Patients with more significant cognitive deficits and higher levels of NPS appeared to be of older age with a longer disease duration and to have more severe motor symptoms. Conclusions NPS, most commonly mood disorders (apathy, depression, and anxiety), psychosis, and ICDs are frequent manifestations of PD. The results of this review reflect the need to develop unified validated assessment protocols for NPS in PD, as well as to improve their management in clinical practice.


Introduction
Parkinson's disease (PD) is a neurological process of chronic course, characterized by a complex clinical pattern of motor and non-motor symptoms. The precise etiology of PD remains unknown but is thought to involve a combination of both environmental and genetic factors. PD is the second most frequent neurodegenerative disorder after Alzheimer's disease [1] with an estimated prevalence of 0.3-1.0% for the general population and an incidence of around 3.0% among individuals aged >80 years [2,3]. PD is more preva-lent among males compared with females with an incidence ratio of around 2 : 1 [3].
The main symptoms associated with PD include rigidity, bradykinesia, tremor, and instability, as a result of an impairment in the striatal dopaminergic pathway (Table 1). Dopamine-replacement therapy is the current mainstay of treatment for such symptoms. However, patients with PD also experience non-motor symptoms including cognitive and psychiatric disorders, pain, and autonomic nervous system dysfunction. The prodromal phase of the disease may extend up to 20 years before the manifestation of motor symptoms and is additionally characterized by the presence of anosmia, depression, constipation, and rapid eye movement (REM) sleep behavior disorders [4]. Although the burden of non-motor symptoms is usually larger and more prolonged than that conferred by motor symptoms, they are typically underrecognized despite their significant contribution to the functional impairment patient's experience [5].
Due to the marked functional impairment associated with PD, management strategies have focused principally on the palliation of the motor symptoms of the disease. As the disease progresses, up to 90% of patients experience some form of NPS including mood disorders, fatigue, psychosis, cognitive impairment, sleep problems, and addictions [6]. However, despite the high prevalence of the NPS and the insidious impairment provoked on patients' and their caregivers' quality of life (QoL), there is no standardized evaluation criteria for NPS in clinically defined PD. Importantly, the manifestation of NPS during the different stages of the disease and the impact of current treatments for motor symptoms on NPS in these patients is not well defined. For this reason, we undertook a review of the recent literature on the prevalence and nature of NPS during the initial years following a diagnosis of PD in order to inform rational consideration of appropriate treatments and management strategies to address all the manifestations of this progressive and debilitating disease.
The objective of the present literature review and descriptive analysis was to summarize the prevalence, nature, and the current stage of NPS among patients with PD, specifically focusing on recent studies involving patients experience during the initial years following their clinical diagnosis. Additional objectives were to identify the most common NPS among PD patients in relation to their clinical characteristics and the prevalence of cognitive impairment and to explore the relationship between NPS and current approaches to the treatment of PD.

Identification of Relevant
Literature. The literature was systematically searched on January 13-15, 2020, and again on December 18, 2020, taking into account only articles published in peer-reviewed journals. Three electronic databases-PubMed, Scopus, and Dialnet (Table 2)-were chosen according to the following factors: accessibility, availability, and relevance for the research question to be addressed. The Boolean operators used to search the databases are detailed in Table 3. Duplicate reports were removed and predefined inclusion criteria applied to identify relevant reports as follows: (i) Clinical studies of patients with a diagnosis of PD and with a mean disease duration over 3 years. This criterion was applied in order to reduce a potential confounding effect due to the subsequent development of other neurological signs and to ensure the exclusion of patients with atypical PD

Results
A total of 130 articles were identified (PubMed, n = 50; Scopus, n = 77; Dialnet, n = 3), of which 83 were unique reports and 30 met the predefined inclusion and exclusion criteria ( Figure 1). Supplementary Table 1 details the reports that were excluded from the analysis and the reasons for exclusion. The incidence of each exclusion criteria was as follows 28.1%, 5.3%, 11.5%, 1.8%, 14.0%, 38.6%, and 7.0% for exclusion criteria from 1 to 7, respectively.
The 30 reports accepted for further review included a total of 7142 patients with PD located in countries in Africa (2), Asia (5), Europe (15), North America (5), South America (1), and Oceania (2). The top-line demographics of the patient cohort for each included report are summarized in Table 4. The mean PD patient age was 66:2 ± 8:8 years, 67.3% were male, and the average duration since diagnosis of PD was 6:7 ± 4:5 years .
A summary of the neuropsychiatric assessments undertaken and the results of the assessments in each report are included in Table 5. 3.1. Prevalence of NPS. The most commonly reported NPS encountered in the studies included in the current review were mood disorders, particularly apathy, depression and anxiety, psychosis, and impulse control disorders (ICDs; Figure 2).
In one study, a cohort of 492 patients with PD found that both the presence and severity of apathy had a significant negative impact on patient QoL (as measured using the PDQ-8) [8]. The presence of apathy and mood alterations were associated with the highest correlation coefficient (0.63; p ≤ 0:001) and effect size (0.62; p ≤ 0:001) for all the       19:0 ± 11:9 21:5 ± 11:6 19:1 ± 12:7 1:8 ± 0:5 2:0 ± 0:5 1:9 ± 0:8     Only 65.2% of the patients who were treated with pramipexole (47% out of 250 patients) showed clinically significantly lower total scores than those who received ropinirole as treatment (69.3% out of 115 patients). Patients on pramipexole manifested a significant lower frequency for apathy (11.2%) than those who were on ropinirole (20.3%) and levodopa (23.8%). No other significant differences were found in NPI subscores between groups 64% of the total sample manifested at least one comorbidity (depression, psychosis, or anxiety). NPS prevalence in the total sample: depression (43.7%), suicidal risk (31%), psychosis (23.8%), anxiety (35.7%), visual hallucinations (20.6%), tactile hallucinations (13.5%), auditory hallucinations (7.2%), and olfactory hallucinations (1.6%). Depression was more likely to be manifested in patients with higher disability, psychosis, longer disease duration, and older age 9 Behavioural Neurology No between-group differences were found in response rates for depression (22.7% vs 9.5%, for atomoxetine and placebo, respectively). Therefore, atomoxetine was not effective for depression in PD. Neither anxiety nor apathy rates showed variation between both groups. Nevertheless, patients on atomoxetine showed a significant improvement in global cognition and daytime sleepiness NPS identified in this study (including psychotic symptoms and ICD) [8].
Two studies reported on the rates of hallucinations and delusions among patients with PD [29,30]. Both studies reported higher rates for hallucinations (23.8% and 11.5%, respectively) than delusions (13.5% and 2.2%, respectively). The most common types of hallucinations were visual (20.6%), somatic (13.5%), auditory (7.2%), and olfactory (1.6%) [29]. Only two studies reported the manifestation of minor hallucinations and concretely visual misperceptions [15,30]. No information related was found in any other article included in this review.
One study reported on the rates of negative symptomatology among patients with PD and found that negative symptoms (as measures using the SANS) were more severe among those with PD than among a control group of patients without PD (SANS score for patients with PD,  Apathy Anxiety Psychosis ICDs Figure 2: Most prevalent NPS in the PD sample. Only data from articles which reported NPS prevalence in percentage format was included in this figure [8,11,16,20,24,25,29,30,33,36]. It should be noticed that the data reported may not have a unique origin as different instruments of assessment were used. Data reported in scoring format was not included.
In a study of pathological gambling and other variants of ICD (ICD-not otherwise specified [NOS]) among patients with PD, it was observed that both conditions were associated with a longer duration of PD in comparison to PD patients without ICD (PD + pathological gambling vs PD without ICD: p = 0:003; PD + ICD-NOS vs PD without ICD: p = 0:007; PD with pathological gambling vs PD with ICD-NOS: p = 0:4849) [27].
The presence of ICDs was positively associated with the consumption of dopaminergic agonists (p = 0:003) and more severe psychotic symptomatology (PPRS: PD+ pathologic gambling vs PD without ICD: p = 0:004; PD + ICD-NOS vs PD without ICD: p ≤ 0:001) [27]. The most notable positive symptoms were visual hallucinations (PD + ICD-NOS vs PD without ICD; p = 0:017), paranoid ideations (PD + ICD-NOS vs PD without ICD; p = 0:002), and illusions (PD + ICD-NOS vs PD without ICD; p = 0:018) [27]. ICDs in PD are suggested to arise as a result of dopaminergic involvement in the reward circuitry. However, one study found no correlation between ICDs and dopaminergic agonists [10]. This may be explained by the short duration of this longitudinal study of 2 years.
Finally, in a study led by Solla et al. (2011), it was found that PD patients with dyskinesias (22.2%; p ≤ 0:001) manifested a higher frequency of ICDs than PD patients without motor complications (3.4%), PD patients with motor complications (12.2%), and PD patients with motor fluctuations (11.8%; p ≤ 0:001) and that 92.9% of male patients with PD showed significant manifestations of hypersexuality in contrast to females (p ≤ 0:01) [33].  [24]. Only pramipexole was shown to exert a positive effect on NPS with a significantly lower frequency of clinically meaningful apathy (NPI apathy score ≥4) among those treated with this agent compared to those patients treated with either ropinirole or L-dopa (p = 0:002) [24].

Discussion
Our review of the literature has shown that NPS are a common feature of the symptomatology of PD. The most frequent NPS experienced by patients with PD are mood disorders (depression, apathy, and anxiety), psychosis, and ICDs [8,11,16,20,24,25,29,30,33,36]. Patients with PD also experience a range of other NPS including mental fatigue [16], sleep disturbances [17,24,25], and irritability [16,17,24,25]. Depression appears to be more likely to be manifested in female patients with PD [29,30,33] and those with more severe disease [29]. Similarly, anxiety seems to be more predominant in female PD patients [29,33]. A number of studies highlighted the prevalence of psychosis (specifically symptoms) among patients with PD, most commonly among those with older age [17,25,29] and longer disease duration [25,29]. No relation has been found for psychosis and PD severity [22], nor psychosis and any type of anti-parkinsonian drugs (dopaminergic agonists, amantadine, MAOI-B, and COMTI) in relation with item 2 from UPDRS subscale I scores [17].
ICD are also common among patients with PD and appear to be associated with longer PD duration, younger age, and sex [10,27], as well as to the consumption of dopaminergic agonists [8]. This latter observation is consistent with the hyperdopaminergic symptomatology observed in a large proportion of patients with longer disease duration and a higher dopaminergic dose. Postsurgical patients with PD evidenced lower rates of hyperdopaminergic symptomatology and higher rates of hypodopaminergic symptomatology. This may be a consequence of the decrease in dopamine agonist treatment following surgery and the slow desensitization to its effect in these patients [7,13].
A number of studies suggested that PD patients with cognitive impairment tended to be of older age and with longer disease duration [10,17,25] and were more likely to manifest a major motor disability [17,25] and NPS [10,25,26] (in particular mood disorders-apathy, anxiety, and depression) [26]. Patients with PD and dementia tended to have a higher prevalence of apathy than those without dementia, while the most significant NPS among patients without dementia was depression [16].
When considering the results presented here, a number of limitations should be noted. Although we offer an integrating description of the principal and most frequent neuropsychiatric symptomatology in PD according to the last-decade scientific literature, the keywords used for the literature searches may not have captured the full spectrum of NPS. Future investigations should include a major variety of related terms in the search strategy in order to guarantee full coverage of all the NPS aspects.
Audiovisuals and other alternative data sources were not consulted. A particular challenge arose from the wide diversity of perspectives and experimental samples used when studying the neuropsychiatric aspects of PD highlighting the need for a more systematic approach to research in this area.