Impact of Parkinson Medication on Neuropsychiatric and Neurocognitive Symptoms in Patients with Advanced Parkinson Disease Prior to Deep Brain Stimulation

• Abstract
• Introduction
• Materials and Methods
• Subjects
• Setting
• Outcome parameters
• Statistical analysis
• Results
• Baseline Characteristics
• Neuropsychological Testing
• Structured clinical interview for DSM-IV (SKID-II)
• Quality of Life (PDQ-39)
• Positive and Negative Syndrome Scale (PANSS)
• Depression Scales
• Impulsivity Test
• Unified Parkinson Disease Rating Scale (UPDRS)
• Correlation analysis of LED with the clinical and cognitive dependent variables
• Discussion
• Declarations
• References

Abstract

Introduction This study evaluates the impact of Parkinson disease (PD) medication in advanced PD on neuropsychological performance, psychiatric symptoms, impulsivity and the quality of life. In the 4-year period 27 patients with advanced PD, scheduled for deep brain stimulation (DBS) surgery (N=27, mean age: 58.9±7.1, disease duration: 10.0 years±4.2) were examined preoperatively. We hypothesized that a high dosage of PD medication or current use of dopamine agonists affect cognitive functioning and psychiatric wellbeing.

Methods We performed two subgroup analyses with low versus high levodopa-equivalent Dosage (LED) medication and without versus with dopaminagonistic medication.

Results The neuropsychological testing revealed significant differences in the verbal learn- and memory-test (VLMT) during the learning passage (U=36.500, Z=− 2.475, p=0.012) and in the subtest of the semantic fluency of Regensburg verbal fluency test (RWT) (t(25)=− 2.066, p=0.049) with better results for patients without dopaminagonistic medication. Pearson correlation analyses of LED in correlation with the clinical and cognitive dependent variables showed a significant higher PANSS total score in patients with higher LED medication (r=0.491, p=0.009). In addition, lower LED treatment was associated with significant higher scores in the impulsivity perseverance subtest (r=− 0.509, p=0.008).

Discussion In conclusion, we found lower LEDs to be correlated with a better perseverance in the impulsivity test and additional treatment with a dopamine agonist influenced some verbal learning tasks and the PANSS total score in patients with advanced PD. This should be considered prior to DBS surgery.

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of older people, affecting 2–3% of the population>65 years [1]. It is primarily characterized by bradykinesia and additional symptoms such as muscular rigidity or a 4–6 Hz rest-tremor or postural instability, as well as non-motor signs and symptoms [2]. The socioeconomic burden of this progressive neurodegenerative disease and the personal impairment due to the continuing deterioration is high [3] [4]. Especially for patients who experience drug effect fluctuations in their disease course, it has been shown that deep brain stimulation (DBS) at a relatively early disease stage is beneficial for their further clinical course and their further participation in normal social and working life [4]. Cognitive dysfunction and psychiatric symptoms affect almost all PD patients sooner or later in the disease course and tend to be more severe as the illness progresses [5]. Compared to healthy age-matched people, patients with PD exhibit a more rapid cognitive decline in a number of cognitive domains – in particular, executive, attentional, and visuospatial domains, as well as memory [6]. Even at diagnosis, a substantial one-third of patients exhibit significant cognitive impairments. This prevalence doubles within a span of 4 years, and in the early stages, dementia may be as prevalent as 10% [7] [8]. It is assumed that the dopaminergic medication shows a U-shaped relationship between dopamine levels and the integrity of cognitive domains affected in PD patients [9]. As DBS is considered for patients who experience motor fluctuations, it is critical to evaluate the extent of cognitive impairment and behavioral issues that might not allow a safe surgery outcome [10] [11] [12]. Threshold values of recognized measuring instruments (e. g., MoCA, MMSE) have been postulated in the past, but are not covered by data [13]. While manifest dementia was already defined as an absolute contraindication for DBS surgery, there are currently no clear recommendations regarding mild cognitive impairment [11]. In addition to the defining dopamine-related motor and non-motor symptoms, PD has been increasingly recognized as a heterogeneous multisystem disorder involving other neurotransmitter systems such as the serotonergic, noradrenergic, and cholinergic circuits [6], leading to the clinical symptomatology of affective disorders, mainly depressive episodes, but also psychotic episodes, frequently provoked by the PD related medication in the course of the disease. Depression is considered the most common psychiatric comorbidity [14] and occurs with a prevalence of 30–35% in PD patients [15]. Early recognition of depressive episodes and consequent treatment are crucial, particularly concerning the evaluation of potential DBS as a treatment option for PD. Especially severe depression and suicidal tendencies are considered exclusion criteria for DBS [13]. This is explained by the fact that an insufficiently stabilized postoperative depression possesses a significant risk factor associated with the attempt or completion of suicide following DBS [16]. In relation to this, it was stipulated that, with respect to psychiatric disturbances, surgery should be deferred in patients with unstable psychiatric conditions until the symptoms have been managed adequately [11]. Furthermore, there is evidence that the target of DBS may influence affective outcomes, although the published data on this is insufficient [15] [17]. Psychotic symptoms are also common phenomena in PD, especially in the progressed course of the disease when dopaminergic medication has to be stepwise adjusted. Risk factors for developing Parkinson’s disease psychosis (PDP) are disease duration and severity, as well as treatment involving dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors [18] [19]. Furthermore, PD patients are at increased risk of PDP with concomitant cognitive impairment, depression, and treatment with anticholinergics [18].

However, comprehensive evaluation of several psychiatric dimensions and their relationship to the treatment of motor symptoms in patients with advanced PD prior to DBS are sparse. Thus, we aimed to evaluate neuropsychiatric deficits, psychiatric symptoms, impulsivity, and the quality of life in PD patients with the neurological indication for DBS. We hypothesized that patients with a high dosage of dopaminergic medication or current use of dopaminagonistic medication show higher deficits in neurocognitive testing, more severe psychotic symptomatology or a higher impulsivity than patients with lower dopaminergic medication or without dopaminagonistic medication.

Materials and Methods

Subjects

Twenty-seven patients with advanced PD (N=27) participated in this study between February 2016 and July 2020, after providing written informed consent. The purpose of the psychiatric consultation, as part of the preoperative routine, was the assessment of a comprehensive psychiatric and neuropsychologic baseline assessment prior to the planned DBS operation. The study protocol was designed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of medical faculty at the Ludwig-Maximilians University (LMU) Munich (Reference Number: 110–16).

Setting

After neurological assessment and the indication for deep brain stimulation due to their advanced PD, patients were scheduled for an appointment at the psychiatric department of the Ludwig-Maximilians University Hospital, Munich. The assessment started with a detailed neuropsychological evaluation that lasted about 1 hour, a personality, impulsivity, and quality of life test, and psychosis and depression interviews as detailed below. Finally, the patients were examined and evaluated by a board-certified psychiatrist (AH) for manifest psychiatric illness. In total, the patients spent 4 to 6 hours to complete this evaluation protocol.

Outcome parameters

Patients received a standardized clinical, neurologic and psychiatric evaluation, a standardized neuropsychological (NP) protocol consisting of: (a) the multiple choice vocabulary test (MCVT) form B according to Lehrl [20] evaluating the age- and degradation-stable language-related intelligence, (b) the repeatable battery for the assessment of neuropsychological status (RBANS) according to Randolf [21] evaluating immediate memory, visuospatial/constructional, language, attention and delayed memory, (c) the letter-number span (LNS) according to Gold [22] measuring the working memory capacity, (d) the verbal learn- and memory-test (VLMT) according to Helmstaedter [23] testing verbal learning and memory skills, (e) the Regensburg verbal fluency test (RWT) according to Aschenbrenner [24] testing cognitive flexibility and the recall of information from memory and (f) the planning test according to Kohler & Beck [25] which measures the ability to plan and implement goals with the intention to achieving them. Furthermore, we applied a personality disorder assessment with a structured clinical interview for DSM-IV (SKID) [26], evaluated the patients quality of life using the PD questionnaire-39 (PDQ-39) [27], the positive and negative syndrome scale (PANSS) evaluating psychotic experiences [28], the depression inventory with Hamilton [29] and Becks depression scale (BDI-II) [30], the geriatric depression scale (GDS) [31] testing depressive symptoms and an impulsivity rating with the impulsive behavior scale-8 (I-8) [32]. Finally, we performed a physical assessment of PD using the unified PD rating scale (MDS-UPDRS) by a board-certified neurologist (JH) [33].

Statistical analysis

All analyses were carried out using SPSS 28 (IBM, Armonk, NY, USA), with a significance level of α=0.05. Descriptive statistics were employed to assess baseline demographic data. The neuropsychological test results, PANSS results, depression tests, impulsivity test, PDQ-39 questionnaire, and UPDRS ratings were tested with the Shapiro-Wilk test for normal distribution (Supplement Table S1 and S2). Descriptive data were presented with mean±standard deviation, minimum, maximum, and standard error of the mean (SEM). Following baseline evaluation ([Table 1]), we applied a median split to categorize our sample into 1) patients with low Levo-Dopa Equivalent Dosage (LED [34] [35]) (≤1232 mg) and high LED Dosage (>1232 mg) (14 vs. 13 patients) and 2) patients with and without current dopamine-agonistic medication (17 vs. 10 patients). In cases where normal distribution was confirmed, further testing was conducted using independent t-tests (see Supplement Table S3 and S4); where normal distribution was violated, we performed Mann-Whitney-UTests (Supplement Table S5 and S6). Furthermore, we performed Pearson correlation analyses of LED with the other clinical and cognitive dependent variables ([Table 2]). Due to the exploratory nature of the study, results were not corrected for multiple comparisons.

Results

Baseline Characteristics

Twenty-seven patients with advanced PD (4 female, mean age: 58.9±7.1, disease duration: 10.0 years±4.2, mean LED: 1220 mg±367.6 mg, median LED: 1232 mg) participated in this study from February 2016 and July 2020 after giving informed consent ([Table 1]).

Neuropsychological Testing

The majority of patients reached average or even good results ([Table 1]) in NP testing. In the MCVT (mean: 34.07±3.882, normal range: 20–35), the VLMT (learning) (mean: 12.30±2.569, normal Range: 8–12), the VLMT (recall after interference) (mean: 10.30±3.473, normal range: 6–10), the VLMT (delayed recall) (mean: 11.04±3.777, normal range: 6–10), the Planning Test (moves) (mean: 41.48±5.648, normal range: 33–40), and the Planning Test (errors) (mean: 0.50±0.722), the average performance was at the upper border of the normal range. For the RBANS (recall story) (mean: 8.37±2.950, normal range: 6–11), the RWT (k-words) (mean: 16.89±7.255, normal range: 10–20), the RWT (gr-words) (mean: 16.81±6.282, normal range: 10–20), the RWT (food products) (mean: 28.93±9.770, normal range: 20–40), and the RWT (clothes/flowers) (mean: 15.00±6.051, normal range: 10–20), the average performance was average. The performance of patients in the RBANS (learning the story) (mean: 14.41±5.056, normal range: 12–20), the LNS (mean: 13.19±3.578, normal range: 12–20), and the planning test (solved tasks) (mean: 4.00±0.659, normal range: 4–6), was at the lower border of the normal range.

In the subgroup analysis of patients comparing high versus low LED-treated patients, there were no differences in the neuropsychological test results (Supplement Table S3 and Table S5). However, the comparison of patients with versus without a dopaminagonistic medication revealed significant differences in the VLMT during the learning passage with higher scores and, thus, a better performance in the subgroup without dopaminagonistic medication (U=36.500, Z=− 2.475, p=0.012) (Supplement Table S6). Also, in the subtest of the food products of RWT, we found a significant difference (t₍₂₅₎=− 2.066, p=0.049) with better results for patients without dopaminagonistic medication as compared to those with a dopaminagonistic medication (Supplement Table S4). All other neuropsychological results did not differ significantly between groups (all p>0.151).

Structured clinical interview for DSM-IV (SKID-II)

The structured clinical interview for DSM-IV, part II revealed a trend towards an obsessive personality in 14 patients (52%) and in 2 patients a trend towards a dependent personality. Nevertheless, the criteria for a manifest personality disorder were not fulfilled.

Quality of Life (PDQ-39)

The PDQ-39 Quality of Life revealed impairments in the subtests of mobility (33.61±21.15), activities of daily living (30.71±20.68), emotional wellbeing (27.01±19.83), and bodily discomfort (35.49±22.83). These results were within the normal range of patients with advanced PD [36]. The PDQ-39 total score in this cohort was 24.89 (±13.14) ([Table 1]). The subgroup analyses revealed no differences, either in the low vs. high LED (all p>0.104) or in the without vs. with dopaminagonistic medication group (all p>0.19) (Supplement Table S3 and S4).

Positive and Negative Syndrome Scale (PANSS)

The PANSS results were in a normal range of the tested symptomatology ([Table 1]) with a mean total score of 42.63 (±7.00). In the subgroup analysis of high versus low LED patients, the PANSS total score with higher scores differed significantly in the group with higher LED medication (t₍₂₅₎=− 2.093, p=0.047) (Supplement Table S3). Analyses comparing patients with and without dopaminagonistic medication showed a trend towards higher PANSS-positive subscores in patients with dopaminagonistic medication (p=0.074; no significant results) (Supplement Table S4).

Depression Scales

With regard to depressive symptoms, five patients achieved scores on the self-ratings scales for mild depressive symptoms in the Geriatric Depression Scale (GDS; defined as GDS≥5), six patients in the BDI-II (defined as BDI≥14), and ten patients in the Hamilton-Depression scale (defined as HAMD≥9). However, none of the patients fulfilled the criteria for a clinically relevant depressive episode according to the consultant psychiatrist assessment ([Table 1]). Subgroup analyses comparing patients with lower versus high LED as well as with and without dopaminagonistic medication did not establish significant differences (all p>0.085) (Supplement Table S3, S4, S5 and S6).

Impulsivity Test

The impulsivity behavior scale-8 (I-8) showed average results in the four subtests of urgency, intention, perseverance, and risk-taking ([Table 1]). In the subgroup-analysis of low versus high LED, lower LED treatment was associated with higher scores in the perseverance subtest t₍₂₄₎=2.816, p=0.010 (Supplement Table S3). The subgroup-analysis of patients with versus without dopaminagonistic medication revealed no differences between groups (all p>0.288) (Supplement Table S4 and S6).

Unified Parkinson Disease Rating Scale (UPDRS)

The UPDRS testing showed mild to moderate impairment with the given medication according to the categorization proposed by Martinez-Martin [37] in the four total scores (total section 1: 10.07±6.44, total section 2: 14.37±6.23, total section 3: 20.22±12.24, total section 4: 8.89±4.89) which reflects a good medicinal adjustment of the patients with not yet pronounced fluctuations of the clinical symptomatology ([Table 1]). Subgroup analyses revealed no differences neither in the low vs. high LED nor in the without vs. with dopaminagonistic medication group (Supplement Table S3, S4, S5 and S6).

Correlation analysis of LED with the clinical and cognitive dependent variables

Pearson correlation analyses of LED with the clinical and cognitive dependent variables revealed a trend for the PANSS general score r=0.369, p=0.058 and a significant result for the PANSS total score r=0.491, p=0.009 ([Table 2] and [Fig. 1]) with higher PANSS results in patients with higher LED medication. Regarding the impulsivity test the correlation showed a significant result r=− 0.509, p=0.008 ([Table 2] and [Fig. 2]) in the perseverance subtest with higher perseverance results in patients with lower LED medication.

Discussion

In this study, we evaluated cognitive performance and a range of neuropsychiatric symptoms in relation to the PD medication in a well-characterized group of patients with PD prior to undergoing DBS. We demonstrate that patients receiving additional dopaminergic medication exhibited poorer performance in the VLMT during the learning phase and in the RWT subtest focusing on semantic fluency (food products). Furthermore, we found a significant difference in the PANSS total score with higher scores in the group with higher LED medication. This observation was further supported by Pearson correlation analysis. The depression scales showed no differences between the medication subgroups, while our impulsivity test revealed better results in the perseverance subtest for patients with lower LED medication. Interestingly, more than 50% of our sample showed signs of an obsessive personality according to the structural interview testing. Overall, our comprehensive examination of the patients did not reveal any pathological findings that would contraindicate the planned DBS operation.

Considering the neuropsychological test results, our findings indicate that levodopa medication does not exhibit a dosage-dependent influence. However, the presence of additional dopaminergic medication has been shown to negatively impact performance in the VLMT learning phase and the RWT semantic fluency subtest (Supplementary Tables S4 & S6). Although the results may also be caused by the already advanced PD itself, previous studies have shown that dopamine depletion due to the disease and a negative impact of the fronto-striatal network, can impair the lexico-semantic system [38]. However, in that study, a negative effect of the lexico-semantic system was provoked in patients in depletion of the levodopa medication and in those in the Parkinson’s off-state, whereas these deficits diminished when patients were in the on-state [38]. Other publications have indicated that the verbal fluency performance in patients with PD did not differ irrespective of whether they were treated with levodopa or a dopamine agonist [39]. Our findings are in principle in accordance with those previously published studies.

The personality assessment of our cohort revealed an elevated frequency of obsessive-compulsive behavior and dependent behavior; however, the criteria for a diagnosable personality disorder were not met. The fact that the SKID-2 test is not standardized for patients with a neurodegenerative disease, but is designed for the diagnosis of young, healthy people, certainly limits the interpretation of the results. Personality changes have long been considered pre-motor features of patients with PD. Most of the studies that have explored the clinical correlates of personality in PD found no significant association between personality traits and clinical parameters such as disease duration, Hoehn & Yahr stage or UPDRS [40]. Only a few studies have investigated the association between PD drugs and personality traits. For example, one study showed no differences in the personality traits of patients who received dopamine agonistic therapy compared to the patients who did not receive dopamine agonists [41]. However, when medication was converted to LED, a significant effect on extraversion and openness to experience was observed with lower personality scores associated with higher LED levels [41]. Another study demonstrated that in young, drug-naive patients with PD, after the introduction of anti-Parkinsonian drugs, only dopamine agonists induced a significant increase in seeking novelty and reward processing [42]. Furthermore, in a large cohort study of the Swedish twin registry, an increased percentage of neuroticism and introversion in patients with PD has been established [43].

In the impulsivity testing, we found higher scores in the perseverance subtest in the patient group with lower LED scores, whereas the subgroup analysis of patients without versus with dopaminagonistic treatment revealed no significant difference. In the impulsivity behavior scale-8, the perseverance subitems reflect the abilities of the patients to complete their upcoming tasks and organize their time accordingly to be able to complete requirements on time. It is not surprising that patients with low LED manage their time accordingly to accomplish tasks, as they always have to reckon with off-phases or hypokinesia as the disease progresses. In contrast to our findings, there exists a well-established association between impulsive behavior and the administration of high doses of dopamine [44] [45] [46] [47]. The fact that our test results do not confirm the results of the previous literature may arise from the limitations of our test procedure; specifically, the use of the impulsive behavior scale-8 does not sufficiently capture and differentiate the symptoms of the patients.

With regard to psychotic symptoms in advanced PD, it has already been shown that these symptoms are common side effects of the PD medication [18], which means that the results of our study are consistent with those in the literature. The prevalence of complex visual hallucinations among patients with PD ranges from 22% [48] to 38%, with minor psychotic symptoms present in up to 72% of patients with PD [49]. In our cohort, a mean positive PANSS score of 9.67 was in the low normal range (minimum: 7, maximum: 49) compared to positive PANSS scores in PD patients with psychotic symptoms (mean positive score: 15–17) [50]. Common risk factors for experiencing psychotic symptoms in PD patients are dopaminergic drugs, especially a therapy with dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors [18] [51] [52]; however other factors are also important, such as dementia and visuospatial impairment, as well as general factors such as old age and more advanced disease stage [52]. Our findings in patients with advanced PD prior to DBS are important, as psychotic experiences or major psychiatric symptoms are considered exclusion criteria for DBS. Our findings in this specific cohort underscore that psychotic experiences can be identified even in the absence of a clinical profile indicative of PDP, and these experiences are associated with pharmacological treatment. Concerning depressive symptoms and episodes among PD patients, ten individuals in our cohort scored above the lower limit on the self-rating HAMD, indicating values in the range of mild depressive symptoms. However, clinical evaluation did not reveal significant symptomatology indicative of a major depressive episode. A relatively high incidence of depressive episodes in patients with PD has been well-established in the literature, with episodes even preceding the diagnosis of PD [1] [15] [53]. The underlying mechanism for this is assumed to be the imbalance and changes in dopamine, serotonin, and noradrenergic transmitters [54]. Using dopamine agonists as a primary treatment for depression in patients with PD has led to mixed results [54]. A systematic review of ten non-RCT studies led to inconclusive results and insufficient evidence for the use of dopamine agonists in the treatment of depressive episodes in patients with PD [55]. Considering all our findings, one could conclude that cognitive symptoms and psychotic experiences are more relevant than depressive symptoms in patients with advanced PD prior to DBS.

One limitation of our study is that one should be aware that dichotomizing continuous variables using a median split may result in the loss of information, especially regarding individual differences. Thus, our analyses should be interpreted with caution [56]. Furthermore, we did not correct our results for multiple comparisons. Apart from that, our cohort might be too small to show significant differences in the subgroup analyses of the impulsivity test we used. A clear strength of the study is the comprehensive neurocognitive and psychiatric work-up of PD patients with advanced disease duration prior to DBS.

In summary, we present the findings of a comprehensive cognitive and psychiatric assessment of patients with advanced PD prior to DBS. We were able to establish a link between PD medication and cognitive functioning and psychotic experiences, as well as the presence of relevant obsessive-compulsive traits and impulsivity. Our findings highlight the need for comprehensive cognitive and psychiatric assessments prior to DBS as some of the presented findings can be modified through the adaption of PD medication or psychiatric treatment. Future trials should evaluate the impact of the longitudinal course of our findings prior to and post-DBS.

Declarations

Informed consent was obtained from all individual participants included in the study. The study protocol was designed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of medical faculty at the Ludwig-Maximilians University (LMU) Munich (Reference Number: 110–16).

Conflict of Interest

A. Hasan was a member of the advisory boards of Boehringer-Ingelheim, Lundbeck, Janssen, Otsuka, Rovi, and Recordati and received paid speakership by these companies as well as by AbbVie and Advanz. He is editor of the German schizophrenia guideline. T. Koeglsperger has been granted research funding and has received compensation for speaking engagements from Abbott, AbbVie, and Medtronic. All other authors report no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Correspondence

Publication History

Received: 09 March 2024

Accepted after revision: 23 July 2024

Article published online:
21 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

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