Abstract
Abstract
INTRODUCTION
Parkinson’s disease (PD) is a neurodegenerative disease characterized by a wide range of motor and non-motor symptoms. Even though current diagnostic criteria relay exclusively on motor features [1], non-motor symptoms are increasingly being reported [2], along with their impact on the quality of life (QoL) [3–6]. Neuropsychiatric manifestations are among the most frequent non-motor symptoms, and are considered relevant not only due to its high frequency but also for its diversity and relationship with excess disability, poor outcomes andcaregiver burden [7, 8].
Several clinimetric scales are currently available for the assessment of neuropsychiatric symptoms, most of them are non-specific for PD, or do not encompass all the neuropsychiatric manifestations on a single instrument. Addressing this issue, the International Parkinson and Movement Disorder Society (MDS) has recently published a series of recommendations for the use of clinical scales in the assessment of neuropsychiatric symptoms, various scales achieved the level of “recommended”, but as mentioned before very few are specific for PD [9–12]. The Scale for Evaluation of Neuropsychiatric Disorders in Parkinson’s disease (SEND-PD) has recently been validated and proposed as a short, simple, single scale for evaluating major neuropsychiatric features including psychotic symptoms, mood/apathy alterations and impulse control disorders (ICDs)[13].
The impact of neuropsychiatric symptoms on the QoL has recently become a relevant topic and several publications have addressed this issue obtaining consistent results about the symptoms with greater impact on QoL [14–16]. These studies mostly used non-specific scales, and to our knowledge no study has been published assessing the impact of a single scale such as SEND-PD on the quality of life. The objective of this study is to determine the impact of neuropsychiatric symptoms in the quality of life of patientswith PD.
MATERIAL AND METHODS
Subjects
Consecutive patients attending the movement disorders outpatient clinic at five different centers in Mexico (Mexico City, Zacatecas, Monterrey and Guadalajara), with diagnosis of PD based on the UK Parkinson’s Disease Society Brain Bank criteria were included for the study [17]. All patients agreed with the study and gave full written consent for participation as dictated by the local Ethics Committee. The study was approved by the Institutional Review Board.
Data collection
Both clinical and demographic data were recorded by the clinician. Clinical information included years since motor onset, predominant symptoms at onset and current treatment. Levodopa equivalent daily dose (LEDD) and dopamine agonist LEDD (DA-LEDD) were calculated [18]. All patients were evaluated by a neurologist with expertise on movement disorders. The Spanish version of Movement Disorders Society Unified Parkinson’s disease Rating Scale (MDS-UPDRS) [19] was applied to all subjects. Disease severity was assessed according to the Hoehn and Yahr scale (HY) [20]. Independent evaluators blinded to the motor evaluation applied the Spanish versions of the SEND-PD and the Parkinson’s Disease Questionnaire Short Form (PDQ-8) separately. Information was obtained directly from patients or along with caregivers if needed.
The SEND-PD scale is a recently validated instrument used to record both the presence and severity of neuropsychiatric symptoms [13]. The scale consists of 12 items divided into three subscales evaluating psychotic symptoms, mood/apathy alterations and impulse control disorders (ICDs). Score is determined according to a five point Likert scale (0–4 for each question); maximum score for psychotic symptoms is 16, for mood/apathy alterations is 20, and 12 for ICDs. For each subscale, neuropsychiatric symptoms were considered present when score was ≥1. In all cases, higher scores indicate a greater severity.
The PDQ-8 scale was used to measure quality of life. This scale consists of eight items scored according to a five point Likert scale. Final score is determined by adding all the points and converting the result to a summarized index that ranges from 0 to 100. This scale has been validated [21] and is among the recommended instruments for assessing QoL by the MDS [22]. The higher the PDQ-8 summarized index score, the lower the quality of life.
Statistical analysis
Quantitative data was calculated and expressed in terms of means and standard deviations. Qualitative variables were presented in terms of frequencies and percentages. Normality was testes for all variables. Comparison of the PDQ-8 summarized index according to the presence of each neuropsychiatric symptom was determined using independent Student’s T test. Cohen’s d was calculated to determine effect size of each neuropsychiatric symptom on PDQ-8 summarized index. Relationship of antiparkinsonian medication with the presence of neuropsychiatric symptoms was assessed using Chi square tests. Independent Student’s T tests were performed to compare antiparkinsonian mean doses for all neuropsychiatric symptoms. Correlation of PDQ-8 with clinical and demographic data, as well as neuropsychiatric symptoms severity was assessed using correlation coefficients. A sequential multiple regression analysis was conducted to determine the impact of neuropsychiatric symptoms and motor manifestations on quality of life. Independent variables were selected based on the results of the bivariate analysis. Other demographic and clinical variables were included on theoretical grounds in order to avoid an overfitted model. The goodness-of-fit of the model was assesses using analysis of residuals, F-test and adjusted r2. A p level of <0.05 was considered significant. Statistical analyses were performed using SPSS, version 17 (SPSS, Inc., Chicago Illinois).
RESULTS
A total of 492 subjects (54.5% male and 45.5% female) were included for the study. The mean age was 66.7 ± 10.1 years. The mean disease duration was 6.9 ± 5 years. The SEND-PD and PDQ-8 were responded by patients alone (42.5%), caregivers alone (7.5%), or by both (50%). From the total of patients 84.6% (416) presented neuropsychiatric symptoms, as assessed by a score ≥1 on the SEND-PD scale; 44.5% had psychotic symptoms, 76.5% had alterationson mood/apathy domains, and 27% presented ICDs. A total of 36.6% of patients had only one neuropsychiatric symptom; on the other hand, 32.3% and 15.7% had two and three symptoms, respectively. Clinical and demographic data comparison according to the presence of neuropsychiatric symptoms is shown in Table 1. In regards to antiparkinsonian treatment, patients with any neuropsychiatric symptom had a higher mean LEDD s (p = 0.02). When patients with specific neuropsychiatric symptoms were compared, the use of dopamine agonists was only associated with ICDs (p = 0.003). Also, patients with ICDs had a higher LEDD (p = 0.001) and DA-LEDD (p < 0.001) when compared to those without ICDs.
The association between the presence of neuropsychiatric symptoms and QoL is summarized in Table 2. Overall, a higher mean PDQ-8 summarized index was found in patients with neuropsychiatric symptoms in comparison to patients without any neuropsychiatric manifestation. Effect size was calculated and found to be 0.91 for the overall presence of any neuropsychiatric symptoms. Effect size for individual domains was, 0.61 for the presence of psychotic symptoms, 0.62 for mood/apathy alterations and 0.35 for the ICDs.
Regarding the severity of neuropsychiatric symptoms, the mean SEND-PD score for patients with any neuropsychiatric symptom was of 7.6 ± 6.4. Individual mean scores for psychotic symptoms, mood/apathy alterations and ICDs were of 2.6 ± 2.4, 6 ± 4.5 and 2.3 ± 1.7, respectively. Correlation coefficients between the severity of neuropsychiatric symptoms and PDQ-8 score are shown in Table 3. Statistically significant correlations were found between PDQ-8 score and the following variables: severity of neuropsychiatric symptoms (rs = 0.62, p < 0.001), severity of psychotic symptoms (rs = 0.34, p < 0.001), severity of mood/apathy alterations (rs = 0.63, p < 0.001), severity of ICDs (rs = 0.17, p < 0.001), disease duration (rs = 0.23, p < 0.001), levodopa treatment (rs = 0.19, p < 0.001), LEDD (rs = 0.26, p < 0.001), disease stage (rs = 0.47, p < 0.001) and MDS-UPDRS III score (rs = 0.50, p < 0.001).
A sequential multiple regression model was conducted to determine predictors of PDQ-8 (dependent variable). The independent variables considered for the analysis included gender, age, disease duration, as well as the neuropsychiatric symptoms and the MDS-UPDRS III. HY stage was not included to avoid multicollinearity. The model is summarized in Table 4. All variables achieved statistical significance (p values<0.005) within the model, except for severity of psychotic symptoms (p = 0.54) and gender (p = 0.399). Psychotic symptoms showed a significant association with mood/apathy alterations (X2 = 36.5; φ= 0.272; p < 0.001). This model explained at least 51% the variance in the PDQ-8 scale (F = 74.71, p < 0.001). Analysis of residuals showed that the goodness of fit of the model was acceptable.
When demographic variables were exclude from the model, three variables (ICDs, mood/apathy and MDS-UPDRS III) explain at least 49.8% of the variance in PDQ-8 scale with statistical significance (F = 122.98, p < 0.001). Standardized coefficients (β) were as follows: 0.08 for ICDs (p = 0.009), 0.29 for MDS-UPDRS III (p < 0.001), and 0.53 for mood apathy alterations (p < 0.001).
DISCUSSION
Our findings suggests that neuropsychiatric problems are common among patients with PD. In our series, over 84% of patients were found to have neuropsychiatric symptoms as assessed by the SEND-PD. Prevalence for psychotic symptoms, mood/apathy alterations and ICDs was higher than reported by other studies [7, 8]. This may be explained by the fact that SEND-PD has been validated for the screening, and not for the diagnosis, of neuropsychiatric symptoms. Therefore, increased recognition is expected with this instrument.
Overall, severity of neuropsychiatric symptoms was low. This may be in association with theunderrepresentation of patients with a more severe disease and with the uncontrolled use of psychiatric medications such as antipsychotics and antidepressants. ICDs were found more frequently in patients treated with a dopamine agonist; also patients with ICD were receiving higher LEDD and DA-LEDD than those without ICDs. These findings are in line with current published evidence [23].
Effect size on PDQ-8 score was calculated and found to be large (>0.8) for the presence of all neuropsychiatric symptoms except for ICDs in which the effect was lower [24].
These data suggests that the presence of neuropsychiatric symptoms may have a great impact on QoL, independently of severity; making assessment of these non-motor manifestations a priority when evaluating patients with PD.
From our analyses, two of the three neuropsychiatric symptoms (mood/apathy alterations and ICDs) evaluated by SEND-PD subscales, along with MDS-UPDRS III score, were found to be responsible for nearly 50% of the variance in PDQ-8 score.
Psychotic symptoms severity did not achieved statistical significance (p = 0.54) within the regression model. We believe that this is explained by the fact that a significant association between the presence of psychotic symptoms and mood/apathy alterations was found accounting for the moderate correlation found with PDQ-8 on the bivariate analysis. Interestingly ICDs showed to be independently related to PDQ-8 even after adjusting for mood/apathy. This finding is in line with previously reported evidence suggesting that these abnormal behaviors affect activities of daily living and have a negative impact on quality of life of patients and their families [23]. From these symptoms mood/apathy alterations was the best predictive variable and had the highest correlation coefficient with quality of life. This finding is consistent with other published studies assessing the impact of depression on QoL [14–16, 26]. From demographic and clinical variables, only gender did not achieved statistical significance within the model, meanwhile both age and disease duration showed a mild impact on quality of life as measured by adjusted r2 and standardizedcoefficients. This minor impact on quality of life may be attributed to the fact that both age and disease duration are associated with disease severity.
In this regard, it must be taken into consideration that some items in the PDQ-8 directly assesses symptoms that are either part of the clinical phenomenology of depression or are semantically related with psychiatric symptoms. Moreover, there is also considerable overlap between symptoms of PD and depression [16]. Consequently, statistical relationships between mood symptoms and PDQ-8 may be the result of overlapping content and not from true associations between separate constructs. This issue has been widely reported by other authors exploring the impact of mood alterations on QoL [14, 15]. As a matter of fact, any QoL assessment tool, either general or disease-specific, has some degree of overlap with neuropsychiatric symptoms [27]. It can be argued that there is a difference between a conceptual and metrical overlap. As a result, items that could potentially measure both QoL and depression does not indicate they are both the same construct [28]. Neverthells, the overlap in the content of QoL and neuropsychiatric scales is inherent to the instruments and should be taken into account when interpreting the results.
Interestingly, severity of neuropsychiatric symptoms was found to be a better predictor of a worse QoL as compared with motor status determined using the MDS-UPDRS III. Nevertheless, this finding must be interpreted carefully since the MDS-UPDRS III does not evaluate the presence of motor fluctuations and treatment complications such as dyskinesia which have been found as important determinants of QoL in some studies [3, 26].
Variance in the PDQ-8 score not explained by the model may be attributed to other neuropsychiatric symptoms not assessed by SEND-PD; as well as other motor and non-motor symptoms that were not explored for this study but that have been clearly associated to QoL in other studies [3–6, 29].
It is important to identify the limitations of this study. Interpretation of associations between neuropsychiatric symptoms and quality of life should take into consideration the fact that some degree of overlapping is expected between SEND-PD and PDQ-8 as previously explained. It should also be highlighted that the SEND-PD does not evaluates cognitive impairment. Since the study was mostly carried out in referral hospitals, a referral bias was present with underrepresentation of patients with more severe forms of the disease. Thus, extrapolation of our results to this population should be taken with caution. Another limitation is that neuropsychiatric symptoms were not assessed using gold standard evaluation, nevertheless the SEND-PD has been validated previously with such instruments, performing adequately for screening purposes.
In conclusion the present study confirms the impact of neuropsychiatric symptoms on QoL in patients with PD. The presence of any neuropsychiatric symptom has a considerable effect on PDQ-8 score suggesting that screening in the evaluation of these patients should be considered. Also, severity of neuropsychiatric manifestations, especially mood/apathy alterations, was shown to be a major predictor of QoL. The identification of these variables will help us to improve our treatment approach to achieve the main goal of improving the QoL of the subjects with PD.
CONFLICT OF INTEREST
The authors have no conflict of interests to report.