Depression, apathy, and anhedonia in Parkinson's disease : meta-analytic review

Transcription

1 The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects Depression, apathy, and anhedonia in Parkinson's disease : meta-analytic review Jiyi Yin The University of Toledo Follow this and additional works at: This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

2 Running head: A META-ANALYTIC REVIEW IN PARKINSON S DISEASE 1 Depression, Apathy, and Anhedonia in Parkinson s Disease: A Meta-Analytic Review Jiyi Yin Research Advisor: David L. Nelson, Ph.D., OTR/L Occupational Therapy Doctorate Program Department of Rehabilitation Sciences The University of Toledo May 2011 This scholarly project reflects individualized, original research conducted in partial fulfillment of the requirements for the Occupational Therapy Doctorate Program, The University of Toledo.

3 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 2 Abstract Parkinson s disease (PD) is primarily a movement disorder, but its non-motor features, including depression, apathy, and anhedonia, can severely impact quality of life. The goal for this metaanalytic review is to determine whether depression, apathy, and anhedonia can occur independently in PD and to analyze their co-variations. A systematic review of literature identified 24 studies measuring at least two of the three variables with various instruments (22 published studies and 2 unpublished ones), with 18 meeting the criterion of providing crosstabulation information. Across 16 studies (N = 1,696), 371 subjects had both apathy and depression, but 240 had depression without apathy and 267 had apathy without depression. Meta-analysis of this cross-tabulation indicated that depression was moderately correlated with apathy (r =.34). Across 5 studies (N = 861), 266 subjects had both anhedonia and depression, but 76 had anhedonia without depression and 315 had depression without anhedonia. This metaanalysis showed that depression was weakly related with anhedonia (r =.27). From 2 studies (N = 102), 8 subjects had both anhedonia and apathy, but 2 had anhedonia without apathy and 40 had apathy without anhedonia. This meta-analysis implied that apathy was weakly correlated with anhedonia (r =.21). When measured continuously, depression was moderately correlated with apathy (K= 4, r =.51) and anhedonia (K= 2, r =.31), while apathy was moderately correlated with anhedonia (K= 2, r =.49). In summary, the correlations among depression, apathy, and anhedonia are not strong so that the variance in one variable largely cannot be predicted by the other variables. Occupational therapists should treat each of these three features of Parkinson s disease as potentially separate problems to be addressed in the occupational therapy process. Key Words: Movement disorder, Neurological condition, Psychosocial factors,

4 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 3 Correlation, Systematic review, Occupational therapy

5 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 4 Depression, Apathy, and Anhedonia in Parkinson s Disease: A Meta-Analytic Review Parkinson s disease (PD) is a progressive neurodegenerative disease with no known etiology and cure. The core biochemical pathology in PD is degeneration of the nigrostriatal dopamine system that results in marked loss of striatal dopamine content. The cardinal motor features are tremor, bradykinesia, rigidity, loss of posture reflexes, flexed posture, and freezing. The prevalence of PD is approximately 160 per 100,000, and the incidence is about 20 per 100,000 per year. The prevalence and incidence increase with age. At the age of 70, the prevalence is approximately 550 per 100,000 and the incidence is 120 per 100,000 per year. PD is more common in men, with the ratio of 3:2 between male and female (Fahn & Przedborski, 2010). It is the second most common neurodegenerative disease after Alzheimer disease. Besides motor symptoms, non-motor symptoms of PD are common and occur across all stages of the disease. The most common and most important neuropsychiatric symptoms in PD are sleep disturbance, depression, apathy, fatigue, anxiety, cognitive impairment, and pain (Aarsland, Marsh, & Schrag, 2009). They are often under-reported or ignored in medical practice. However, non-motor symptoms can lead patients with PD to increased disability if left untreated and can dramatically impact their quality of life (Chaudhuri & Schapira, 2009). Nonmotor symptoms also frequently cause patients to be admitted to hospitals or force them to move into nursing facilities, thereby increasing the cost of care of these patients with PD by four times (Global Parkinson s Disease Survey Steering Committee, 2002; Schrag, Jahanshahi, & Quinn, 2000; Findley et al., 2003; Hagell, Nordling, Reimer, Grabowski, & Persson, 2002). The causes of these non-motor disorders are probably very complicated and multifactorial, including neurodegenerative process, psychosocial mechanisms, and side effects from pharmacological and non-pharmacological treatments.

6 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 5 Depression Depression is a common symptom in PD, and approximately 30% to 40% patients with PD have significant depressive symptoms (McDonald, Richard, & Delong, 2003). According to DSM-IV, common characteristics of depression are apparent sadness, loss of interest in activity and work, insomnia, fatigue, suicidal ideas, and loss of concentration (American Psychiatric Association, 2000). Unfortunately, DSM criteria for depression were not developed for patients with PD, and they may not be valid in this disease, especially because some features for diagnosing depression also occur in PD itself. In December 2003, the National Institute for Neurological Diseases and Stroke (NINDS) and the National Institute of Mental Health (NIMH) assembled a group of researchers with expertise in movement disorders, geriatric psychiatry, and neuropsychology to review the reliability and validity of existing approaches to the diagnosis of depression in PD and to recommend changes to DSM diagnostic criteria for provisional use in diagnosis of depression in patients with PD in clinical studies (Marsh, McDonald, Cummings, Ravina, & NINDS/NIMH Work Group on Depression and Parkinson s Disease, 2006). This group recommended: a) use of inclusive approach to assess patients depression symptoms; b) inclusion of subsyndromal depression in clinical research studies; c) awareness of whether mood disorders related to motor function change; and d) use of both patient s and caregiver s input to rate symptoms. In PD research, eight scales have been used to assess depression: the Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), the Geriatric Depression Scale (GDS), the Unified Parkinson s Disease Rating Scale (UPDRS) Part I, the Neuropsychiatric Inventory (NPI), and the Center for Epidemiologic Studies Depression Scale (CES-D). All these scales have some utility in the assessment of depression in

7 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 6 PD. Among them, the BDI and the HAM-D have been validated and widely used in patients with PD. According to Schrag et al. (2007), the HAM-D and MADRS have superior psychometric qualities and are observer-rated. Apathy Apathy is a mental disorder characterized by diminished motivation, lack of goal-directed behavior, and lack of emotion, all of which lead to a significant decrease in engaging occupations of daily living (Morrison, 2001). It is a common feature of PD (Starkstein et al., 1992). In PD research, five scales have been used to assess apathy: the Apathy Evaluation Scale (AES), the Apathy Scale (AS), the Neuropsychiatric Inventory (NPI) apathy items, the Lille Apathy Rating Scale (LARS), and the Unified Parkinson s Disease Rating Scale (UPDRS) Part I question 4 (motivation item). Among these scales, the AS and LARS were specifically developed for PD, and they have been validated in patients with PD (Leentjens et al., 2008). Anhedonia Anhedonia is defined as inability to experience pleasure (Snaith et al., 1995). It is sometimes considered a symptom that is part of various syndromes, such as depression, dementia, or apathy, and some authors have stated that there is no clear definition for anhedonia (Leentjens et al., 2008). Currently, there are two scales used to measure anhedonia: the Snaith- Hamilton Pleasure Scale (SHAPS) and the Chapman Scales for Physical and Social Anhedonia. The SHAPS has 14 items while the latter has 101 items. Depression, Apathy, and Anhedonia in PD Researchers have done many studies on depression and apathy in patients with PD (Starkstein et al. 1992; Levy et al., 1998; Aarsland et al., 1999; Pluck & Brown, 2002; Isella et al., 2002; Kirsh-Darrow, Fernandez, Marsiske, Okun, & Bowers, 2006; Santangelo et al. 2009; Pederson, Alves, Aarsland, & Larsen, 2009; Aarsland et al., 2009; Dujardin, Sockeel, Delliaux,

8 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 7 Destée, & Defebvre, 2009; Hill, 2009; Oguru, Tachibana, Toda, Okuda, & Oka, 2010; Butterfield, Cimino, Oelke, Hauser, & Sanchez-Ramos, 2010; Lambarth, 2011). However, there are few studies of anhedonia in patients with PD (Isella et al., 2003; Lemke, Brecht, Koester, Kraus, & Reichmann, 2005; Santangelo et al., 2009; Lambarth, 2011). While these studies on depression, apathy, and anhedonia have contributed to the understanding of PD, controversies concerning these features of PD continue. Are these three conditions inherently related to each other, or are they potentially independent of each other? DSM-IV criteria for a major depression diagnosis suggest that depression includes symptoms of apathy and anhedonia (DSM-IV criterion #2). However, Levy et al. (1998) and Kirsch-Darrow et al. (2006) found that apathy could be dissociated from depression. Lemke et al. (2006) found that anhedonia and depression were significantly correlated while Isella et al. (2003) did not find a significant correlation between them. Pluck and Brown (2002) detected higher anhedonia in apathetic patients with PD while Isella et al. (2003) suggested anhedonia was not necessarily related with apathy. The potential reasons for these discrepancies are as follows: a) there is no generally accepted diagnostic criterion for depression in PD; b) there are no clear definitions for apathy and anhedonia; c) different studies have used different assessment scales; d) there are overlapping symptoms among commonly used definitions of depression, apathy, and anhedonia with PD; and e) the characteristics of PD patients may vary from study to study. The Purpose of This Meta-analysis Given that discrepancies exist among studies of depression, apathy, and anhedonia in patients with PD, can an expert take the results from these studies and synthesize a new conclusion through narrative analysis? The answer is no because narrative analysis has limitations in drawing clear conclusions because it is like doing arithmetic with words. In contrast, meta-analysis can analyze each study quantitatively in the context of all the other

9 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 8 studies. To do this, meta-analysis works with effect sizes, not only p-values (Borenstein, Hedges, Higgins & Rothstein, 2009). Effect size quantifies the strength of the relationship between the measurements in each study; so measuring effect size addresses the practical importance of the results as assessed by the magnitude of the effect. Meta-analysis calculates effect size for each study, with studies being weighted by between-studies variance of the true effect size; it also determines whether effect sizes are consistent across studies. All of the effects are included in a single statistical synthesis, which is a summary effect. Meta-analysis can be used to calculate fixed or random effects. Under the fixed effects model, it is assumed that all the studies included in the meta-analysis have one true effect size. In contrast, under the random effects model, the studies included in the analysis might not have a single true effect size (the effect could vary from study to study). Another consideration in designing a meta-analysis is that research studies with statistically significant results are more likely to be published than studies without significant results, so these publications will lead to a bias in meta-analysis (Dickersin, Chan, Chalmers, Sacks, & Smith, 1987; Dickersin, Min & Meinert, 1992). Therefore, meta-analysis takes into account all available literature and addresses possible publication bias toward significant results. There are several reasons why a meta-analysis of this literature is needed: a) there are controversies among the relationships of depression, apathy, and anhedonia in studies on patients with PD; b) a meta-analytic review of the depression, apathy and anhedonia in PD could help quantify the actual size of the relationship among depression, apathy, and anhedonia in PD; and c) no meta-analysis of the relationship among depression, apathy, and anhedonia has been reported in literature. The goal for this analysis is to determine whether depression, apathy, and anhedonia can occur independently and to analyze their co-variations. This analysis will also determine if there are significant differences across studies. Publication bias will also be

10 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 9 investigated in this analysis. Method Literature Search Procedures The literature search procedure for this analysis was designed to locate published research articles. The method of retrieval was through searching major electronic databases, including PUBMED, CINAHL, and HealthSource (Nursing/Academic Edition and ProQuest Nursing and Allied Health Source). Publication date was not restricted in these searches. Keywords used included a) Parkinson s disease AND depression AND apathy, b) Parkinson s disease AND depression AND anhedonia, c) Parkinson s disease AND apathy AND anhedonia. If title and abstract of the publication indicated the article might contain data relevant to this analysis (see inclusion criteria below), the full document was retrieved. In addition, the citations of all relevant articles were reviewed for earlier publications which might fit the search criteria; however, no additional study was found. Inclusion and Exclusion Criteria To be included in this research synthesis, an article needed to be printed in English and to measure a) depression and apathy, or b) depression and anhedonia, or c) apathy and anhedonia in patients with PD. Articles needed to measure the association between any two of the three variables. Studies that measured only one of these variables were excluded from the analysis. In addition to peer-reviewed articles, two unpublished studies done in the Occupational Therapy Doctoral Program of University of Toledo were located. Data Collection Data extraction was done by reading through each publication. If there was no proportion of participants with depression, apathy, and/or anhedonia provided in tables or figures, proportions were determined from the text. If proportions could not be inferred from

11 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 10 publications, s were sent to the corresponding authors to ask for original raw data or summary data. Methods of Data Integration There were three primary meta-analyses: random effects modeling of dichotomous associations between a) depression and apathy; b) depression and anhedonia; and c) apathy and anhedonia. These three analyses included all studies meeting the criteria. In addition to calculating the overall p value, effect sizes and possible differences among studies were calculated. There were three secondary analyses involving continuous data when available. Subanalyses based on the types of measures used (e.g., studies with single-item scored variables were excluded) were also carried out. All analyses of correlations among categorical and continuous variables were done with SAS program (SAS Institute Inc., Cary, NC). Effect size, weighted effect size, and overall correlation were analyzed by Comprehensive Meta-Analysis (CMA) program version 2 (Borenstein, Hedges, Higgins, & Rothstein, 2005). The random effects model was the primary model because it represents the best estimate of true effects across differently designed studies. Funnel plots were constructed to test publication bias (Light & Pilemer, 1984; Light, 1994). Publication bias was also analyzed based on Egger s regression intercept and the Begg and Mazumdar rank correlation. All these tests were done with Comprehensive Meta-Analysis (CMA) program version 2 (Borenstein et al, 2005). Results Identifying Eligible Studies The computer database search located 116 articles; 22 met the inclusion criteria with publication dates spanning from 1992 to Of the 22 published articles, twelve provided the proportions of participants with depression, apathy, and/or anhedonia, or these proportions could

12 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 11 be determined from tables or descriptions in these articles (Starkstein et al., 1992; Levy et al., 1998; Aarsland et al., 1999; Isella et al., 2002; Lemke et al., 2005; Lieberman et al., 2006; Kirsch-Darrow et al., 2006; Dujardin et al., 2007; Pedersen et al., 2009; Starkstein et al., 2009; Oguru et al., 2010, Butterfield et al., 2010). Corresponding authors of ten papers were sent s requesting original data or summary data. Five of them responded. Only one author sent original data (Pluck & Brown, 2002). Summary data from three articles were sent by their authors (Isella et al., 2003; Pedersen et al., 2009a; Pedersen et al., 2010). One author declined to send data (Aarsland et al., 2009), and another agreed in her first but never replied to follow-up s as of January, 2011 (McKinlay et al., 2008). Three other authors did not respond after second and third reminder s (Santangelo et al., 2009a; Santangelo et al., 2009b; Dujardin et al., 2009; Kulisevsky et al., 2008). Proportions could be determined in the Pluck et al. article (2002) from raw data scores (provided in 2007 & 2010). Six publications (Aarsland et al., 2009; McKinlay et al., 2008; Santangelo et al., 2009; Santangelo et al., 2009; Dujardin et al., 2009; Kulisevsky et al., 2008) had to be excluded from this analysis because their proportion data could not be inferred from publications and because no responses occurred to requests for data. All original data were available from two unpublished studies (Hill, 2009, Lambarth, 2011). A total of 18 studies were therefore included in this meta-analytic review. Characteristics of studies Table 1 summarizes all studies with authors, publication date, sample size, and instruments used for measuring depression, apathy, and anhedonia. Tables 2 to 4 reports crosstabulation data, the coefficient of correlation (r), the coefficient of determination (R 2 ), and coefficient of alienation (1 - R 2 ) for depression/apathy, depression/anhedonia, and apathy/anhedonia respectively, while table 6 to 8 presents continuous data for depression, apathy

13 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 12 and anhedonia. Table 5 summarizes all studies based on categorical scales. Table 2 included 16 studies on depression and apathy as categorical variables defined by cut-off scores. Their coefficients of correlation ranged from.09 to.56 (M =.32, SD =.12); the R 2 ranged from.01 to.31 (M =.12, SD =.08); and the 1 - R 2 ranged from.69 to.99 (M =.88, SD =.08). As a rule of thumb, correlation coefficients between 0 and.30 are considered weak, those between.30 and.70 are moderate, and coefficients between.70 and 1.00 are considered strong (Jackson, 2007). The correlation between depression and apathy for individual studies ranged from weak to moderate. The coefficient of determination indicates the proportion of variance in one variable that can be explained from knowledge of the second variable (Abdi & Williams, 2010). In the case of depression and apathy, the R 2 suggested that 1% to 31% of the variance in either apathy or depression could be predicted by the other variable. Complementing the coefficient of determination is the coefficient of alienation (1 - R 2 ), which suggested that 69% to 99% of the variance in either apathy or depression could not be predicted by the other variable in the 16 studies. Table 3 included five studies on depression and anhedonia as categorical variables defined by cut-off scores. Their coefficients of correlation ranged from.04 to.54 (M =.26, SD =.19); their coefficients of determination ranged from 0 to.29 (M =.10, SD =.11); and their coefficients of alienation ranged from.71 to 1.00 (M =.90, SD =.11). The correlations between depression and anhedonia for individual studies ranged from weak to moderate. The R 2 suggested that 0 to 29% of the variance in either anhedonia or depression could be predicted by the other variable, while 1- R 2 suggested that 71% to 100% of the variance in either anhedonia or depression could not be predicted by the other variable. Table 4 included two studies on apathy and anhedonia as categorical variables. Their coefficients of correlation were.19 and.25 (M =.22, SD =.04); their coefficients of

14 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 13 determination were.04 and.06 (M =.05, SD =.01); and their coefficients of alienation were.94 and.96 (M =.95, SD =.01). The correlations between apathy and anhedonia for individual studies were weak. The R 2 suggested that 4% to 6% of the variance in either anhedonia or apathy could be predicted by the other variable, while 1- R 2 suggested that 94% to 96% of the variance in either anhedonia or apathy could not be predicted by the other variable. Table 6 included 4 studies on depression and apathy as continuous variables. Their coefficients of correlation ranged from.34 to.52 (M =.47, SD =.09); their coefficients of determination ranged from.12 to.27 (M =.23, SD =.07); and their coefficients of alienation ranged from.73 to.88 (M =.78, SD =.07). The correlations between depression and apathy for individual studies were moderate. The R 2 suggested that 12% to 27% of the variance in either depression or apathy could be predicted by the other variable, while 1- R 2 suggested that 73% to 88% of the variance in either depression or apathy could not be predicted by the other variable. Table 7 included 2 studies on depression and anhedonia as continuous variables. Their coefficients of correlation were.26 and.34 (M =.30, SD =.06); their coefficients of determination ranged from.07 to.12 (M =.10, SD =.04); and their coefficients of alienation ranged from.88 to.93 (M =.90, SD =.04). The correlations between depression and anhedonia for individual studies were weak to moderate. The R 2 suggested that 7% to 12% of the variance in either depression or anhedonia could be predicted by the other variable, while 1- R 2 suggested that 88% to 93% of the variance in either depression or anhedonia could not be predicted by the other variable. Table 8 included 2 studies on anhedonia and apathy as continuous variables. Their coefficients of correlation were.45 and.51 (M =.48, SD =.04); their coefficients of determination were.20 and.26 (M =.23, SD =.04); and their coefficients of alienation were.74 and.80 (M =.77, SD =.04). The correlations between anhedonia and apathy for individual

15 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 14 studies were moderate. The R 2 suggested that 20% to 26% of the variance in either anhedonia or apathy could be predicted by the other variable, while 1- R 2 suggested that 74% to 80% of the variance in either anhedonia or apathy could not be predicted by the other variable. Meta-analyses Meta-analysis works with effect size, which represents the magnitude of the treatment effect or the strength of a relationship between two variables. Meta-analysis computes the effect size for each study, then assesses the consistency of the effect across studies and computes a summary effect. This meta-analytic review used the correlation coefficient as the effect size index. During the process of meta-analysis, the correlations were converted to the Fisher s Z scale; all computations were performed using the transformed values. The final results were converted back to the correlations for presentation. Apathy by depression meta-analysis. Sixteen studies (1,696 participants) included in this meta-analysis categorically evaluated the depression and apathy in patients with PD. During this analysis, it was found that significant heterogeneity existed across these studies (Q = 26.19, df = 15, I 2 = 42.72, p =.04). The overall correlation from the random effects meta-analysis was.34, and the 95% confidence interval (CI) was.28 to.40, with a statistically significant correlation (p <.01) (Figure 1). The overall result suggested moderate correlation between depression and apathy in patients with PD. For this meta-analysis, the funnel plot showed a symmetrical distribution; Egger s regression intercept showed that the intercept was (p =.14). This analysis indicates no publication bias. Of the 16 studies, 5 studies used one-item scales to measure depression or apathy in a possibly unreliable way, so a sub-analysis (total 1,031 participants) was carried out without these five studies. Significant heterogeneity also existed across these remaining 11 studies (Q = 23.75, df = 10, I 2 = 57.89, p <.01) (Figure 2). The overall correlation from this random effects meta-

16 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 15 analysis was.33; the 95% CI was (p <.01). The result for this sub-analysis was very similar to original analysis. The funnel plot showed a symmetrical distribution, with Egger s regression intercept = (p =.15). Hence publication bias did not appear to exist. Three studies (total 225 participants) reported continuous scales of depression and apathy. Meta-analysis showed that there was no significant heterogeneity among these three studies (Q =.03, df = 2, I 2 =.00, p =.98). The overall correlation from the random effects metaanalysis was.51, and the 95% CI was (p <.01). The correlations across the three studies showed very little variance. With respect to the funnel plot, it showed a symmetrical distribution; Egger s test yielded an intercept of -.39 (p =.36). Anhedonia by apathy meta-analysis. Two studies assessed apathy and anhedonia in patients with PD. Categorically, there was no heterogeneity found in these two studies (Q =.12, df = 1, I 2 =.00, p =.73). The overall correlation between apathy and anhedonia was.21, and the 95% CI was (p =.03) (Figure 4). However, the correlation was considered weak. For continuous data, no heterogeneity was present between these two studies (Q =.13, df = 1, I 2 =.00, p =.72), The combined correlation was.49, and the 95% CI was (p <.01) (Figure 5). The correlation for continuous data was considered moderate. No funnel plot for publication bias for these two analyses could be done because at least three studies are needed for this analysis. Anhedonia by depression meta-analysis. Five studies (893 participants) contributed data on anhedonia and depression in patients with PD. Meta-analysis implied that there was a significant heterogeneity across these 5 studies (Q = 31.52, df = 4, I 2 = 87.31, p <.01) so the random effects model was used for analysis. The overall correlation between anhedonia and depression was.27 and the 95% CI was (p =.04), a weak correlation (Figure 6).

17 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 16 Egger s test for publication bias returned an intercept of 2.82 that was not statistically significant (p =.25). Two of these five studies used one-item scales to measure depression or anhedonia, so a sub-analysis was conducted with remaining three studies. There was no significant heterogeneity (Q =.33, df = 2, I 2 =.00, p =.85). Overall, the accumulated correlation was.26, and the 95% CI was (p <.01) (Figure 7). There was no publication bias. Two studies (total 99 participants) evaluated depression and anhedonia in patients with PD using continuous scales. There was no significant heterogeneity between these two studies (Q =.16, df = 1, I 2 =.00, p =.69). The combined correlation was weak:.31. The 95% CI was (p <.01) (Figure 8). No publication bias was done because of the number of studies. Discussion These findings suggest that the correlations among depression, apathy, and anhedonia are not strong. Depression, apathy, anhedonia appear to be related yet identifiably different syndromes, as evidenced by the weak to moderate correlations. Even these relatively small correlations could be caused by overlap among items from test to test. For example, the HAM-D (Hamilton, 1960) item 7 measures interest in work and activities, but this overlaps with items 1, 2, 3, 5, and 11 in the AS (Starkstein et al., 1992). The coefficients of alienation in tables 2-4 and 6-8 may also reflect this notion. When measuring depression, apathy, and anhedonia as categorical variables, tables 2-4 suggested that 69% to 100% variance of either depression or apathy or anhedonia could not be predicted by the other two. When measuring them as continuous variables, tables 6-8 implied that 73% to 90% variance of any one of these variables could not be predicted by the others. Although the correlations for all studies on depression, apathy, and anhedonia were positive, the majorities of their variances could not be held

18 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 17 accountable for others. The cross-tabulation data in tables 2-4 show whether there are positive or negative associations among the three categorical variables. A positive association indicates that two features are concomitant, as opposed to one feature occurring without the other. If a strong correlation exists, the number of patients who had both features should be relatively high in comparison to the number of patients who had one feature only. Table 2 for apathy by depression shows only 3 of 16 studies (Isella et al., 2002; Dujardin et al., 2007; Oguru et al., 2010) had more patients with both features than patients with one feature occurring independently. In the case of anhedonia by depression (Table 3), only 1 of 5 studies (Lieberman et al., 2006) had more patients with both features than patients with one feature occurring independently. In Table 4 of anhedonia by apathy data, both studies showed fewer patients who had both features than patients who had one only. When all the studies were summed (Table 5), the number of patients with both features was much less than those with single positive features for all three data summaries (i.e., apathy X depression, apathy X anhedonia, and depression X anhedonia). All these analyses indicate that depression, apathy, and anhedonia in patients with Parkinson s disease commonly occur independently of each other. These patterns occur whether or not psychometrically weak single-item scales are included in the analyses or not. Generally speaking, continuous data tend to generate more precise and stronger correlations than categorical data based on cut-off scores that ignore variance within the cutoff ranges. In this study, the correlations among continuous variables tended to be relatively large although still not large in absolute terms (the proportions of variance predicted were still less than 50%). It would be desirable to examine the original raw data of each of the studies included in the categorical analyses. Unfortunately, it was not possible to retrieve the original data from the authors.

19 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 18 PD is commonly considered a movement disorder; however, PD is associated with a broad spectrum of non-motor symptoms that include depression, apathy, and anhedonia, etc. Depression and apathy are the most common psychiatric complications in PD (Leentjens et al., 2008; Schrag et al., 2007). Of all 18 studies reviewed in this meta-analysis, the reported prevalence of depression ranged from 13% to 78% with a mean of 42%. Interestingly, in the 16 studies that evaluated apathy, the frequency of apathy was similar to the frequency of depression, even though the two problems often appeared independently (apathy frequencies varied from 14% to 70% with a mean of 39%). Depression in PD is a major contributor to poor quality of life and disability while apathy is associated with cognitive dysfunction and a decrease in occupations of daily living performance. In contrast with depression and apathy, anhedonia has been rarely studied, and its incidence is relatively low yet substantial. In the five studies reviewed, the occurrence of anhedonia varied from 7% to 44% with an average of 27%. According to a recent study (Fujiwara, Kimura, Hosokawa, Ishida, Sugino, & Hanafusa, 2011), patients with PD showed a significant reduction in hedonic tone regarding interest/pastimes when compared to a control group. However, social interaction was maintained in patients with PD. The patients with PD were reported to enjoy attracting attention and being smiled at, and were reported to want to be helpful to others. This information may be useful when caregivers and healthcare professionals who come into contact with these patients. The large ranges in frequencies for all three variables from study to study probably resulted from the use of different assessments, different cut-off scores, and differences in the samples in terms of disease progression. Much work remains to be done in terms of definitive epidemiology for these three characteristics of PD, and standardization of instruments appears necessary. However, even in the studies reporting the lowest levels of incidence, all three

20 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 19 characteristics appear at clinically significant frequencies. Depression, apathy, and anhedonia significantly affect the overall quality of patients life and impact their abilities to function. Currently, there are medications which can temporarily control the motor symptoms of PD effectively (Poewe, 2008). Non-motor dysfunction has developed into a major prognostic factor for overall disease burden and everyday function in patients with PD. It is important to take these psychosocial factors into consideration when treating people who have PD. Limitations Of 116 publications, 22 studies fit the inclusion criteria, but 6 of these had to be excluded because cross-tabulations of proportions of participants could not be inferred from their publications and could not be retrieved from authors. There were only five studies for depression and anhedonia as categorical variables and two studies as continuous variables. There were only two studies for apathy and anhedonia as categorical variables and continuous variables and only three studies for depression and apathy as continuous variables. Another limitation is that there were no consistent measuring scales across these studies. Some studies used well validated scales such as HAM-D, MADRS, AES, and AS (Starkstein et al., 1992; Pluck & Brown, 2002; Lieberman et al., 2006; Starkkstein et al., 2009; Hill, 2009; Lambarth, 2011) while others used one item scales such as NPI and UPDRS Part I (Levy et al., 1998; Aarsland et al., 1999; Pedersen et al., 2009; Pedersen et al., 2010). Some studies used standard cut-off scores while others used different cut-off scores. For examples, Pluck & Brown (2002) used 15 as the cut-off score for the BDI while Kirsch-Darrow et al. (2006) used 13 as their cut-off score for same measuring scale. In this review, only studies published in English were included so it is possible some studies fit in the inclusion criteria but were published in other languages. It is also possible that unpublished studies were not found.

21 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 20 To correct these limitations, the following should be done: 1) more studies are needed to better understand the depression, apathy, and anhedonia in patients with PD; 2) clinical studies should adopt well-validated scales in their research; 3) measuring scales should be further optimized so that no overlapping items exist between different scales; and 4) sharing data across international research community should be advocated and implemented. Implications for occupational Therapy Occupational therapy emphasizes the arousal of patients interests and motivation. Without interest and motivation, patients will not make any effort in their therapies; on the contrary, if they have interest and motivation, they will find the missing energy, get motivated, determine to achieve as much as possible in their therapy sessions so that they can recover successfully from their conditions. A Circular of Information designed to introduce the National Society for the Promotion of Occupational Therapy (NSPOT) formulated a number of principles for the new profession (National Society for the Promotion of Occupational Therapy, circa 1920, p4-6). One of these principles was to arouse interest, courage, and confidence; to exercise mind and body in healthy activities to overcome functional disability. Adolf Meyer, one of pioneers in occupational therapy stated, A pleasure in achievement; a real pleasure in the use and activity of one s hands and muscles and a happy appreciation of time began to be used as incentives (Meyer, 1922). Given the importance of interest and motivation for achieving life goals in general and for meeting the challenges of the rehabilitation process, it is surprising that these psychosocial factors have received so little attention in rehabilitation. A few available studies showed that depression and apathy have been associated with poor rehabilitation outcomes and these associations may be due in part to decreased rehabilitation participation (Dorra, Lenze, Kim, Mulsant, Munin, Dew, & Reynolds, 2002; Lenze, Munin, Dew, Rogers, Seligman, Mulsant, &

22 META-ANALYTIC REVIEW IN PARKINSON S DISEASE 21 Reynolds, 2004; Heruti, Lusky, Danker, Ring, Dolgopiat, Barell, Levenkrohn, & Adunsky, 2002). In patients with stroke, even minor apathy had a strong negative association with rehabilitation participation and recovery whereas high apathy was associated with the poorest perceived health over time (Maclean, Pound, Wolfe, & Rudd, 2000; Mayo, Fellows, Scott, Cameron, & Wood-Dauphinee, 2009). In patients with schizophrenia, these with negative symptoms, such as apathy and anhedonia, have an impaired capacity to benefit from social skills training (Matousek, Edwards, Jackson, Rudd, & McMurray, 1992). Occupational therapists need to understand depression, apathy, and anhedonia and their precise relationships, all of which involve problems of interest and motivation. In order to plan an effective intervention, occupational therapists need to 1) collaborate with medical professionals to get the correct diagnosis; 2) set reasonable and achievable goals so that patients have confidence in their rehabilitation; 3) be creative in setting up meaningful and purposeful occupations for the patients; 4) provide positive feedback on successful participation; 5) create a rapport with patients and earn patients trust; 6) use evidence-based practice; and 7) provide information about rehabilitation to patients. Only in this way can occupational therapists provide the best possible services to patients and help them to live their lives to their fullest. Acknowledgments I would like to thank my research advisor Dr. David Nelson, Ph.D., OTR/L, FAOTA for his expert advice throughout this project. I would always be grateful for his dedication to occupational therapy research. I would also like to thanks the following personnel for their help during this project: Jennifer Lambarth, S/OT, Graham Pluck, Ph.D. (Sheffield, UK) for providing their raw data sets, Kenn Freddy Pedersen, M.D., Ph.D. (Stavanger, Norway) and Ildebrando Appollonio, M.D. (Via Pergolesi, Monza, Italy) for providing their summary data.

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