Anxiety and Depression in Patients with Parkinson s Disease

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1 ORIGINAL ARTICLE Anxiety and Depression in Patients with Parkinson s Disease Toshiyuki Yamanishi 1, Hisao Tachibana 1, Miyako Oguru 1, Kiyohiro Matsui 1, Kazuo Toda 2, Bungo Okuda 3 and Nobuyuki Oka 4 Abstract Objective To investigate the prevalence and clinical correlates of anxiety and depression in patients with Parkinson s disease (PD) and to examine the relationship between anxiety and depression and the quality of life (QOL). Methods One hundred and seventeen patients with PD completed the State-Trait Anxiety Inventory (STAI), the Beck Depression Inventory Second Edition (BDI-II), Starkstein s Apathy Scale (AS) and QOL battery. Hoehn and Yahr (HY) staging, the Unified Parkinson s Disease Rating Scale (UPDRS) and the Mini-Mental State Examination (MMSE) were administered on the same day. Results Anxiety (STAI score 41 for men or 42 for women) was diagnosed in 55% of the patients and depression (BDI-II score 14) was diagnosed in 56% of the patients. Anxiety coexisted with depression in 41% of the patients, while depression without anxiety was observed in 15% of the patients and anxiety without depression was observed in 14% of the patients. The STAI score was found to be significantly correlated with the UPDRS (I, IVC) and AS scores, whereas the BDI-II score was found to correlate with the HY stage and the UPDRS (I, III, IVB, C) and AS scores. Both the STAI and BDI-II scores were found to negatively correlate with QOL. A multivariate analysis revealed that depression and anxiety are similarly associated with the PD specific QOL (PDQ-39), while motor severity, as judged by the HY stage and UPDRS III score, is not. Conclusion These findings indicate that recognizing anxiety and depression in patients with PD is important, since both conditions are commonly observed in patients with PD and are similarly associated with the QOL, independent of motor severity. Key words: Parkinson s disease, anxiety, depression, QOL, apathy (Intern Med 52: , 2013) () Introduction Although Parkinson s disease (PD) is primarily a movement disorder, it is accompanied by various nonmotor symptoms, including psychiatric and behavioral problems. Depression and anxiety are common in patients with PD and are frequently associated in the same patient. However, it is unclear whether these two symptoms share common pathophysiological mechanisms (1, 2). The effects of depression on quality of life (QOL) in patients with PD have been intensively studied; however, less attention has been paid to anxiety (3-5), even though anxiety can contribute to a patient s discomfort. Although earlier studies describing the QOL in patients with PD found either depression or disease severity to be the most frequently associated with the QOL (6-8), the majority of these studies did not include both anxiety and depression in their models. The purpose of this study was to examine the prevalence of anxiety and depression in a case series of PD patients, the relationships between anxiety and depression and disease-related factors such as the severity of motor symp- Department of Internal Medicine, Hyogo College of Medicine, Japan, Toda Internal Medicine-Rehabilitation Clinic, Japan, Department of Neurology, Ehime Prefectural Central Hospital, Japan and Department of Rehabilitation, NHO South Kyoto Hospital, Japan Received for publication July 17, 2012; Accepted for publication November 21, 2012 Correspondence to Dr. Hisao Tachibana, htachiba@hyo-med.ac.jp 539

2 toms, levodopa therapy, complications of pharmacotherapy and duration of disease and the relationship between anxiety and depression and the QOL. Patients Materials and Methods One-hundred and twenty-five consecutive patients with idiopathic PD who attended four outpatient clinics (Hyogo College of Medicine Hospital, Toda Internal Medicine- Rehabilitation Clinic, NHO South Kyoto Hospital and Ehime Prefectural Central Hospital) between April 2010 and September 2010 were included in this study. PD was diagnosed according to the UK Parkinson s Disease Society Brain Bank Criteria (9). Treatment with antiparkinsonian drugs improved the parkinsonian signs and symptoms in all treated patients. Patients with either secondary parkinsonism or evidence of more generalized neurological disease were excluded. Participants were excluded if they declined to participate later or were unable to complete the selfadministered questionnaires due to dementia. Therefore, data were obtained from 117 patients with PD. None of the patients underwent deep brain stimulation (DBS) surgery during the course of the study. Written informed consent was obtained from all study participants. The study protocol was approved by the human research ethics committee at the participating institutions, and the study was conducted according to the Declaration of Helsinki. Assessment instruments/questionnaires The patients were clinically assessed using assessment instruments that included both neurologist-administered rating scales and self-administered questionnaires. The neurologistadministered assessments included the modified Hoehn and Yahr Scale (HY) (10) to stage PD severity according to the patient s best on state, the Unified Parkinson s Disease Rating Scale (UPDRS) (11) and the Mini-Mental State Examination (MMSE) (12). These examinations were performed by a neurologist on the same day. The selfadministered scales included the State-Trait Anxiety Inventory (STAI) (13), the Beck Depression Inventory (BDI) (14), an apathy scale (AS) (15) and two QOL instruments: the EuroQoL (EQ-5D) (16) and the 39-item Parkinson s disease questionnaire (PDQ-39) (17). Anxiety was evaluated with the Japanese version of the STAI (18). The STAI consists of two scales designated to differentiate between the temporary condition of the state of anxiety (Form X-1) and the more general and long-standing quality of trait anxiety (Form X-2). Each item on the STAI scale is scored on four levels of anxiety intensity from 1 = not at all to 4 = very much, with a sum score between 20 and 80. Twenty items are designed to record the presence of anxiety symptoms, while the other items are scored to record the absence of anxiety symptoms. The latter are inverted for the purpose of calculating the sum score. The cutoff score for the STAI was set at 41 for men and 42 for women (15). Depression was evaluated using the Japanese version of the BDI Second Edition (BDI-II) (19), which is widely used in Japan to assess depression and is reported to have excellent reliability and validity. The BDI-II is a 21- item scale. The items are rated from 0 to 3, with a sum score between 0 and 63. The resulting scores are added across the items to yield an overall measure of the intensity of depressive symptomatology. The cutoff score for the BDI-II was set at 14, as is standard in Japan and is also indicated in the original version (19). The Japanese version (20) of Starkstein s Apathy Scale was used to assess apathy. This scale was chosen based on a review of apathy and anhedonia rating scales in patients with PD by Leentjens et al. (21) in which they recommended only this scale be used to assess apathy in PD patients. The Japanese version (22) of the EQ-5D, a 5-item questionnaire, and the PDQ-39, a 39-item questionnaire, were used for the QOL assessments. The EQ-5D is a generic health-related QOL measure developed by the European Quality of Life Group that has been translated into Japanese and validated. It includes five dimensions: mobility, self-care, usual activities, pain/discomfort and psychological status, with three possible answers for each item (1=no problem, 2=moderate problem, 3=severe problem). A summary index with a maximum score of 1 can be derived from the five dimensions by conversion using a table of scores. The maximum score of 1 indicates the best health state, in contrast to the scores of individual questions where higher scores indicate more severe or frequent problems. The PDQ-39 is a widely used diseasespecific health-related QOL measure that was translated and validated in Japan by Kohmoto et al. (23). The PDQ-39 contains 39 questions, each with five different answer options, from which eight subscores (mobility activity of daily living [ADL], emotional well-being, stigma, social support, cognition, communication and bodily discomfort) and one summary index (SI) can be calculated. The maximum score of 100 indicates the worst quality of life. Statistical analysis Group differences were analyzed using nonparametric tests (Mann-Whitney U-tests). Anxiety was evaluated using the trait anxiety (Form X-2) score because both the QOL and BDI-II scores investigated long standing qualities. Spearman s rank correlation coefficients were used to assess the degree of correlation between the BDI-II and STAI scores (Form X-2) and the following variables: age, age at onset, disease duration, HY stage, UPDRS total and individual subscale scores, MMSE score, AS score, Levodopa dose equivalent, PDQ-39 score and EQ-5D score. The total levodopa dose equivalent was calculated as (24): (regular Levodopa dose 1) + (pramipexole dose 67) + (ropinirole dose 16.67) + (pergolide dose 100) + (bromocriptine dose 10) + (regular levodopa dose 0.25 if taking entacapone). A multivariate analysis using forced entry linear regression was performed to determine the factors associated with QOL. PDQ- 540

3 Table 1. Characteristics of the Study Patients Total (n = 117) Male (n = 46) Female (n = 71) Mean SD Mean SD Mean SD Age (yr) Age at onset (yr) Duration of disease (yr) Hoehn-Yahr stage UPDRS I (Mentation) UPDRS II (ADL) UPDRS III (motor) UPDRS IV (complications) A dyskinesia B motor fluctuation C others* UPDRS total MMSE BDI-II STAI Form X Form X AS L-dopa dose equivalents PDQ-39 Mobility ADL Emotional well-being Stigma Social support Cognition Communication Bodily discomfort Summary index EQ-5D Mobility ADL Work Pain Anxiety Summary NOTES: ADL: activity of daily living, UPDRS: Unified Parkinson s Disease Rating Scale, MMSE: Mini-Mental State Examination, BDI-II: Beck Depression Inventory-II, STAI: State-Trait Anxiety I n v e n t o r y, A S: A p a t h y S c a l e, P D Q-3 9 S I: P a r k i n s o n s d i s e a s e q u e s t i o n n a i r e, E Q-5 D: E u r o Q o L *anorexia, nausea, vomiting, sleep disturbance, symptomatic orthostasis 39 SI was considered to be a dependent variable, and variables found to be significantly associated with PDQ-39 SI on the basis of Spearman s rank correlations were included as independent (explanatory) variables. All data were analyzed using the Dr. SPSS software package (SPSS version 11.0). Statistical significance was set at p<0.05. Results Table 1 shows the clinical characteristics of the 117 PD study patients. There were no differences in the clinical variables between men and women, although this series included a larger number of women. Anxiety was present in 64 of the 117 patients (55%) based on the STAI trait scale and depression was present in 66 patients (56%). Anxiety in the absence of depression was evident in 16 patients (14%) and depression in the absence of anxiety was evident 18 patients (15%). Anxiety coexisted with depression in 48 patients (41%). The mean scores for the STAI and BDI items among the PD patients are shown in Table 2. Higher scores were observed for the inverted items on the STAI state scale, including at ease (No. 5), comfortable (No. 10), content (No. 16) and pleasant (No. 21). Higher scores were also observed for the STAI trait scale items tire quickly (No. 22), am losing out (No. 25), rested (No. 26), happy (No. 30), content (No. 36) and steady person (No. 39) High scores were noted on the BDI-II items of permission, loss of energy, changes in sleep patterns, tiredness or fatigue and loss of interest in sex, while low scores were noted on the items of guilty feelings, punishment feelings and suicidal thoughts or wishes. Table 3 shows the relationships between scores on the STAI and BDI-II and several clinical variables. The anxiety 541

4 Table 2. Mean Scores STAI and BDI Items for PD Patients scale scores showed significant correlations with the UPDRS I (rs=0.263, p=0.004), IVC (rs=0.237, p=0.01) and AS scores (rs=0.351, p<0.001). In contrast, the BDI-II scores showed significant correlations with the HY stage (rs=0.294, p< 0.001) and the UPDRS I (rs=0.316, p<0.001), III (rs=0.239, p=0.001), IVB (rs=0.213, p=0.021), IVC (rs=0.416, p<0.001) and total scores (rs=0.244, p=0.008). Neither the STAI nor the BDI-II scores showed any significant associations with levodopa dose equivalents. A significant correlation was noted between the STAI and BDI-II scores (rs=0.476, p< 0.001). Both the STAI and BDI-II scores showed significant correlations with the PDQ-39 SI scores (rs=0.362, p<0.001 and rs=0.564, p<0.001, respectively) and the EQ-5D total scores (rs=-0.222, p<0.016 and rs=-0.564, p<0.001, respectively). Multivariate analyses using forced entry regression were performed to determine which factors contribute to the QOL. Variables significantly associated with PDQ-39 SI were entered as independent variables (Table 4). The forced linear regression model revealed that the PDQ-39 SI scores were associated with the UPDRS II (p=0.021), BDI-II (p= 0.038), AS (p=0.044) and STAI scores (p=0.012; Table 5). Discussion The present study evaluated anxiety and depression using of the STAI and BDI-II, respectively. The STAI is a 40-item instrument that measures transient and ongoing levels of anxiety and has been used in many studies of PD patients. These studies indicate that the instrument is appropriate for use in screening anxiety, studying biological markers and as an outcome measure (21), although further validation studies in PD populations are necessary. The BDI-II is one of the most frequently employed measures of depression in PD patients and is a reliable and valid measure of depression in patients with PD (25). The present study found that among the 55% of the 117 PD patients with anxiety, 14% had no concomitant depression. Fifteen percent of the 56% of the patients with depression had no concomitant anxiety. Forty-one percent had both depression and anxiety. These findings suggest that both anxiety and depression are core features of PD and that anxiety can be present in the absence of depression. Richard (26) has also reported that anxiety can clearly occur in the absence of depression. In addition, Liu et al. (27) revealed that 14 of 58 patients with PD who lacked depressive symptoms fulfilled the DSM-IV R criteria for generalized anxiety disorder. The high prevalence of anxiety and depression reported in this study is consistent with the findings of previous studies (2, 3, 28) and underscores the fact that anxiety and depression are key neuropsychiatric features of PD. Although the frequency of anxiety observed in the current series is slightly higher than that reported elsewhere, differences in the anxiety rating scales, the size and selection of the study population and race employed in each study could explain the discrepancies observed in the results. In addition, a high frequency of anxiety may contribute to the prevalence of depression, as a significant correlation was found in the present study between the STAI and BDI-II scores, and the severity of depressive symptoms contributes to the overall level of anxiety. Although the number of women in the present study was larger than that of men, there were no differences in other clinical variables between the male and female groups. The present study further analyzed each item of the STAI and BDI-II in order to clarify the specific neuropsychiatric features of depression and anxiety that occur in PD patients. Kvaal et al. (29) reported that the STAI state scale has two underlying dimensions: nervousness and well-being. Their analysis suggests that the well-being factors are higher than the nervousness factors in PD patients. The BDI-II scores regarding permission, loss of energy, changes in sleep patterns, tiredness or fatigue and loss of interest in sex were high, while the scores for guilty feelings, punishment feelings and suicidal thoughts or wishes were low. The present results are generally consistent with previous findings that PD patients with depressive symptoms generally exhibit a loss of self-blame, guilt and sense of failure and fewer self-destructive thoughts than patients with primary major depression, and rarely commit suicide, while loss of interest and initiative, fatigue, indecisiveness and anhedonia are frequently encountered (30). The current STAI scores were significantly associated with the UPDRS (I, IVC) and AS scores and were not found to be correlated with age, age at onset, disease duration or HY rating. Similar results were shown in studies by Quelhas 542

5 Table 3. Relationships between the STAI or BDI-II Scores and Clinical Variables STAI BDI-II rs p rs p Age (yr) Age at onset (yr) Duration of disease (yr) Hoehn-Yahr stage < 0.001* UPDRS I (Mentation) * < 0.001* UPDRS II (ADL) UPDRS III (motor) * UPDRS IV (complications) A dyskinesia B motor fluctuation * C others * < 0.001* UPDRS total * MMSE AS < 0.001* < 0.001* Levodopa dose equivalents PDQ-39 SI < 0.001* < 0.001* EQ-5D summary * < 0.001* *significant rs: Spearman s rho correlation coefficient Table 4. Relationship between the QOL (PDQ-39 SI) and Clinical Variables Age (yr) Age at onset (yr) Dura on of disease (yr) Hoehn-Yahr stage < 0.001* UPDRS total < 0.001* UPDRS I (Menta on) < 0.001* UPDRS II (ADL) < 0.001* UPDRS III (motor) < 0.001* UPDRS IV (complica ons) A dyskinesia * B motor uctua on < 0.001* C others < 0.001* MMSE BDI-II < 0.001* STAI < 0.001* AS < 0.001* Levodopa dose equivalents * *significant rs p Table 5. Forced Linear Regression Model with the PDQ- 39 SI as the Dependent Variable Independent variable -weight t value p value Hoeln-Yahr stage UPDRS I (Menta on) UPDRS II (ADL) * UPDRS III (motor) UPDRS IV (complica ons) A dyskinesia B motor uctua on C others BDI-II * STAI * AS * Levodopa dose equivalents *significant R 2 =0.574, Adjusted R 2 =0.527, p<0.001 et al. (4) and Kummer et al. (31). On the other hand, the BDI-II scores were significantly correlated with the HY rating and the UPDRS (I, III, IVB, C) and AS scores. These results showed different clinical correlates between anxiety and depression in PD patients, although significant correlations were found between anxiety and depression, as evaluated by the STAI and BDI-II scores. The findings of significant correlations between depression and motor symptoms estimated by the UPDRS scores on subscale III and the HY stage are concordant with those of previous studies (32, 33) that reported depressed patients with PD to have more severe motor symptoms, more advanced HY staging, and a more severe global clinical condition (determined by UPDRS) than non-depressed patients with PD. These findings may support the hypothesis that dysfunction of the nigrostriatal pathway plays an important role in the pathophysiology of depression in patients with PD, although later stages (in which gait and balance are disturbed) are generally associated with more global brain involvement. On the other hand, no correlations were found between the STAI scores and the motor symptoms as evaluated by HY staging and the UPDR scores on subscales II and III. Nègre-Pagès et al. (2) also found anxiety and depression in patients with PD to be associated with different demographic and clinical factors. They found PD patients with anxious symptoms to be more frequently female and younger than those without such symptoms, whereas those with depressive symptoms tended to have more severe indices of parkinsonism, more comorbidities, and a lower cogni- 543

6 tive function. The UPDRS subscale IVB score showed a correlation with the BDI-II score but not with the STAI score. Patients with motor fluctuations frequently experience prominent mood fluctuations. Depression and anxiety symptoms are often part of the off state with instant relief when patients turn on. Dissanayaka et al. (34) reported that the experience of dyskinesia or on/off fluctuations exhibits positive associations with anxiety. The present results, however, suggest that anxiety patients are less sensitive to motor fluctuations than depressive patients. This may be because anxiety was evaluated with the STAI trait score, not with the STAI state score. The current study found both the STAI and BDI-II scores to be significantly correlated with the QOL scores determined by the EQ-5D and PDQ-39. In addition, a multivariate analysis showed the BDI-II, STAI, AS and UPDRS III (ADL) scores to be significantly associated with the PDQ- 39 (disease-specific QOL) SI score, while motor severity judged by the HY stage and the UPDRS III (motor) score was not independently associated with these values. These results imply that the impact of PD on the QOL measures is independently influenced by non-motor disease aspects, while a primary motor component is that of ADL rather than the underpinning PD motor symptoms per se. Motor complications were not found to be correlated with the PDQ-39 SI, although some authors have shown the impact of motor complications of PD on QOL (35). These studies did not include nonmotor symptoms as independent variables. A recent systematic review concluded that depression, disease severity and disability negatively influence the patient-reported impact of PD and thus determined depression to be an important predictor of QOL (36). Similar results have been reported for anxiety (3-5); however, with insufficient supporting data (37). Many studies have heretofore focused on the impact of depression and motor disability on poor life quality while neglecting to examine the role of anxiety. Recent studies have demonstrated a correlation between anxiety and QOL in patients with PD (4, 5). Hanna et al. (5) reported that symptoms of anxiety, more so than depression, cognitive status or motor stage, significantly affected QOL among 38 non-demented patients with mild to moderate motor disability and that anxiety had a stronger impact on QOL in comparison to depression, although anxiety and depression were similarly associated with QOL in the present study. Quelhas et al. (4) also showed anxiety to be the strongest predictor of QOL. Further research is necessary to address this issue since these studies dealt with a small number of patients, used a generic measure for QOL (the Short Form-36 Health Survey questionnaire) and excluded specific aspects of PD management such as iatrogenic symptoms (4). The present study found apathy to also significantly correlate with QOL. Apathy can occur in PD patients in the absence of depression and is a distinct syndrome, not merely a symptom of depression (38). Both anxiety and apathy are frequent comorbid conditions of moderate and severe depression (39). The present study revealed that depression, anxiety and apathy are closely associated with QOL in PD patients and that nonmotor symptom progression contributes importantly to the decline of QOL in patients with PD (40). These findings suggest that primary management of nonmotor symptoms is important for optimizing the QOL of PD patients. Some limitations associated with the current study include the use of patient self-reports. No clinical diagnostic interviews were conducted using the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV or standardized psychiatric evaluations to establish the diagnosis of anxiety or depression. Using a brief self-report measure of anxiety and depression, although practical, does not allow for clarification of the nature of the anxiety and depressive disorder in this population or determination of whether the specific type of anxiety disorder has a differential impact on QOL; for example, generalized anxiety disorder versus social phobia versus panic disorder, although all are associated with PD. Using an actual diagnosis based on validated psychiatric diagnostic definitions might have produced different or additional conclusions. Another limitation is that anxiety and depression have overlapping symptoms, and therefore the scales overlap in content. The BDI-II includes items that overlap with anxiety. It is possible that a particular symptom endorsement on the BDI-II might represent anxiety but was counted in the total depression score. Although the results of this study indicate that mood symptoms are associated with reduced QOL in patients with PD, this is a cross-sectional study, and the direction of causation among the examined variables cannot be determined. Longitudinal studies would help to clarify the causal relationships between the variables evaluated in this study and help to assess how quality of life may change following treatment for anxiety and depression in this population. In conclusion, anxiety and depression are common behavioral disturbances in patients with PD. Recognizing that anxiety and depression are commonly present in PD patients is important since both conditions are associated with QOL, independent of motor severity. The authors state that they have no Conflict of Interest (COI). References 1. 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