The Impact of Anxiety and Depression on Outcomes of Pulmonary Rehabilitation in Patients With COPD

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1 CHEST Original Research PULMONARY REHABILITATION The Impact of Anxiety and Depression on Outcomes of Pulmonary Rehabilitation in Patients With COPD Andreas von Leupoldt, PhD ; Karin Taube, MD ; Kirsten Lehmann ; Anja Fritzsche, PhD ; and Helgo Magnussen, MD Background: Anxiety and depression are prevalent comorbidities in COPD and are related to a worse course of disease. The present study examined the impact of anxiety and depression on functional performance, dyspnea, and quality of life (QoL) in patients with COPD at the start and end of an outpatient pulmonary rehabilitation (PR) program. Methods: Before and after PR, 238 patients with COPD (mean FEV 1 % predicted 5 54, mean age 5 62 years) underwent a 6-min walking test (6MWT). In addition, anxiety, depression, QoL, and dyspnea at rest, after the 6MWT, and during activities were measured. Results: Except for dyspnea at rest, improvements were observed in all outcome measures after PR. Multiple regression analyses showed that before and after PR, anxiety and depression were significantly associated with greater dyspnea after the 6MWT and during activities and with reduced QoL, even after controlling for the effects of age, sex, lung function, and smoking status. Moreover, before and after PR, anxiety was related to greater dyspnea at rest, whereas depression was significantly associated with reduced functional performance in the 6MWT. Conclusions: This study demonstrates that anxiety and depression are significantly associated with increased dyspnea and reduced functional performance and QoL in patients with COPD. These negative associations remain stable over the course of PR, even when improvements in these outcomes are achieved during PR. The results underline the clinical importance of detecting and treating anxiety and depression in patients with COPD. CHEST 2011; 140(3): Abbreviations: 6MWD 5 6-min walking distance; 6MWT 5 6-min walking test; ATS 5 American Thoracic Society; BDI 5 Baseline Dyspnea Index; HADS 5 Hospital Anxiety and Depression Scale; PR 5 pulmonary rehabilitation; QoL 5 quality of life; SF Item Short Form Health Survey; TDI 5 Transitional Dyspnea Index Manuscript received November 12, 2010; revision accepted February 19, Affiliations: From the Department of Psychology (Drs von Leupoldt and Fritzsche), University of Hamburg; the Department of Systems Neuroscience (Dr von Leupoldt), University Medical Center Hamburg-Eppendorf; and Atem-Reha GmbH (Dr Taube and Ms Lehmann), Hamburg; and the Pulmonary Research Institute at Hospital Grosshansdorf (Dr Magnussen), Grosshansdorf, Germany. Funding/Support: This study was supported by a stipend [Heisenberg-Stipendium, LE 1843/9-1] from the German Research Society (Deutsche Forschungsgemeinschaft) (to A. v. L.). COPD is a chronic respiratory disease with significant systemic effects. It is characterized by not fully reversible and usually progressive airflow limitation based on abnormal intrapulmonary inflammatory responses to noxious particles or gases. 1,2 COPD is a leading cause of morbidity and mortality worldwide and is associated with significant social and economic burden and considerable reductions in patients quality of life (QoL). 1,3 Anxiety and depression are highly prevalent comorbidities in COPD. Recent reviews reported prevalence rates of up to 75% for anxiety and up to 80% for depression in this patient group. 4-6 Importantly, symptoms of anxiety and depression in COPD were shown to be associated with a worse course of disease, including reduced QoL and increased symptom burden, health-care use, and even mortality Correspondence to: Andreas von Leupoldt, PhD, Department of Psychology, University of Hamburg, Von-Melle-Park 5, Hamburg, Germany; andreas.vonleupoldt@uni-hamburg.de 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( site/misc/reprints.xhtml ). DOI: /chest Original Research

2 Recent research has provided consistent evidence that pulmonary rehabilitation (PR) can considerably alleviate the burden of COPD by reducing respiratory symptoms such as dyspnea and by improving functional performance and QoL in patients with COPD Furthermore, improvements in the symptoms of anxiety and depression were reported after PR However, the impact of anxiety and depression on the main outcomes of PR, such as dyspnea, functional performance, and QoL, is less clear, with some studies even reporting conflicting results. A recent workshop conducted by the American College of Chest Physicians concluded that further research is warranted to examine the influence of anxiety and depression on health outcomes in COPD. 6 Similarly, the joint statement of the American Thoracic Society (ATS) and the European Respiratory Society on PR hypothesized an impact of anxiety and depression on functional performance, but expressed the need for further research on potential interactions between mood disturbances and functional limitations. 14 Although the associations of anxiety and/or depression with reduced functional performance in patients with COPD have been examined in some previous studies, most studies have been limited by relying exclusively on patient self-report measures of functioning, a small sample size, 22,23 and/or inclusion of predominantly male participants preselected for high levels of anxiety and depression. 24 Two recent studies in large samples found anxiety to be related to reduced 6-min walking distances (6MWDs), but these studies either included only patients with emphysema 25 or reported only results for anxiety without controlling for the parallel symptoms of depression, which are often correlated. 26 Interestingly, those studies that examined the impact of both anxiety and depression on the 6MWD as a measure of functional performance found a greater negative impact of anxiety than depression on the 6MWD, and also on QoL. 24,25 In contrast, two studies with limited sample sizes reported no, or only a weak, impact of anxiety and depression on functional performance. 22,23 In addition to these contrasting results, no study has explored the effect of PR on the associations of anxiety and depression with outcome measures. The present study addressed these issues by examining the impact of both anxiety and depression on functional performance, dyspnea, and QoL in patients with COPD undergoing a 3-week outpatient PR program. We hypothesized anxiety and depression is associated with worse outcomes at the start of PR, even after controlling for the effects of potential confounders such as age, sex, lung function, and smoking status. In addition, we examined whether PR would change these associations, by studying the impact of anxiety and depression on these outcomes at the end of PR. Participants Materials and Methods We studied 238 consecutive patients with COPD who were referred to and completed an established, standardized, 3-week, outpatient PR program at an urban outpatient PR center (Atem-Reha GmbH; Hamburg, Germany) between January 1, 2008, and December 31, Anamnestic interviews and diagnostic classification were performed by one (out of two) pulmonary physicians according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines. 1 While participants were seated, spirometry was performed by one specialized, trained nurse using a SpiroPro (Jaeger-Thoennies CareFusion; Hoechberg, Germany) according to ATS/European Respiratory Society guidelines. 27 Reference normal values were taken from the European Community for Steel and Coal. 28 Inclusion criteria were (1) diagnosis of COPD according to GOLD guidelines, 1 (2) stable clinical condition with no exacerbations in the preceding 2 weeks, and (3) willingness to participate in the PR program. Exclusion criteria were (1) exacerbations or (2) hospitalizations during the 3-week PR program. The study was approved by the local ethics committee (reference number 2546). Pulmonary Rehabilitation The intensive 3-week outpatient PR program was performed 6 h/d for 5 d/wk. In accordance with evidence-based guidelines, 14,15 the multidisciplinary PR program consisted of exercise (endurance training on a stationary cycle ergometer, treadmill, and arm cycle ergometer, and strength training for upper, lower, trunk, and respiratory muscles), patient education, nutrition counseling, breathing therapy, relaxation therapy, psychosocial education (improvement of coping strategies, self-efficacy, compliance, stress management, and social resources), and smoking cessation support. 29 Active caregivers in the PR program were two pulmonary physicians, one psychologist, four physiotherapists/sports therapists, one sports scientist, one dietitian, and one specialized nurse. Measurement of Anxiety and Depression Anxiety and depression were measured at the start and end of PR using the validated German version of the Hospital Anxiety and Depression Scale (HADS), 30,31 a validated instrument designed to detect clinically significant anxiety and depression among medical patient groups, including COPD. 12,26 The HADS contains seven items each for anxiety and depression, which are condensed into respective summary scores (ranges, 0-21). Scores 8 reflect symptoms of anxiety and depression, respectively. Measurement of Functional Performance At the start and end of PR, subjects performed a 6-min walking test (6MWT) according to ATS standards, in a corridor of 30 m in length, which was supervised by one (out of three) specifically trained physiotherapists. 32 The primary outcome measured was the 6MWD. Measurement of Dyspnea Dyspnea was rated at rest and after 6MWTs on a modified Borg scale, 33 ranging from 0 (not noticeable) to 10 (maximally tolerable). Dyspnea during the activities of everyday life was assessed at the start of PR with the Baseline Dyspnea Index (BDI) and after PR with the Transitional Dyspnea Index (TDI) as change in dyspnea during activities over the 3-week period. 34 BDI and TDI are widely used validated instruments for measuring dyspnea CHEST / 140 / 3 / SEPTEMBER,

3 during activities and they provide a summary score (range of BDI, 0 5 severe impairment to 12 5 no impairment; range of TDI, 29 5 maximal deterioration to +9 5 maximal improvement). Measurement of QoL QoL was assessed at the start and end of PR with the generic 36-Item Short Form Health Survey (SF-36). 35 The SF-36 is a widely used instrument that has been validated in various patient groups, including COPD, 36 and consists of eight subdomains that are condensed into a physical and mental summary score (range, 0-100), with higher scores reflecting better QoL. Procedure On the first day of PR, participants provided informed written consent, underwent pulmonary function testing and diagnostic classification, and filled out the HADS, SF-36, and BDI, which were administered by a physician. This was followed by the 6MWT, with dyspnea being assessed at rest and after the test. Thereafter, participants completed the 3-week outpatient PR. On the last day of PR, all measurements were repeated. In addition, the change in dyspnea during activities, over time, was assessed with the TDI. Analyses PR effects were characterized with repeated-measures analyses of variance on all outcome measures except TDI (one-sample t test). The impact of anxiety and depression on 6MWD, dyspnea scores, and SF-36 summary scores was analyzed by calculating hierarchic multiple linear regression analyses for each dependent variable at the start and end of PR. For each model, we controlled for age, sex, lung function (FEV 1 % predicted), and smoking status by entering these variables in step one. HADS anxiety scores were entered in step two and HADS depression scores in step three. Thus, the effects of anxiety alone (after controlling for age, % predicted, and smoking status) were tested in step two, and the additional effects of depression in step three (ie, after controlling for the effects of anxiety). This order of entering anxiety and depression in the models was based on previous findings demonstrating a greater impact of anxiety than depression on 6MWD and QoL measures. 24,25 As previously suggested, this strategy allowed control of the commonly observed correlations between anxiety and depression in psychopathology, which could have biased multiple regression analyses. 37 In addition, we ensured that criteria for multicollinearity were not met by computing variance inflation factors and tolerance statistics for all independent variables. All analyses used a significance level of P,.05. Participants Results The data of 238 patients were analyzed. In general, the study population was elderly, and 57% were men ( Table 1 ); 63% (n 5 151) of the patients lived with a partner, and 37% (n 5 87) lived alone. The prevalence of symptoms of anxiety was 41% (n 5 98) and of depression, 30% (n 5 71). Effects of PR Compared with at the start of PR, improvements were observed after PR in 6MWD ( P,.001), paral- leled by improved dyspnea after the 6MWT ( P,.01) ( Table 2 ). Dyspnea at rest remained stable ( P..90), whereas a TDI score of 3.1 indicated improvements in dyspnea during activities ( P,.001) (Table 2 ). The physical and mental summary scores of the SF-36 showed increased QoL after PR ( P,.001). Similarly, symptoms of anxiety and depression were reduced after PR ( P,.001 and P,.01, respectively) (Table 2 ). Effects of Anxiety and Depression on Outcomes Regression analyses for the start of PR showed that anxiety was significantly associated with greater dyspnea at rest, after the 6MWT, and during activities (BDI), even after controlling for the effects of age, % predicted, and smoking status ( Table 3 ). Similarly, anxiety was significantly associated with reduced QoL in both the domains of physical and mental health after controlling for the effects of age, % predicted, and smoking status ( Table 3 ). No significant effect of anxiety on 6MWD at the start of PR was observed. Depression at the start of PR was not related to dyspnea at rest but was significantly associated with greater dyspnea after the 6MWT and during activities (BDI), even after controlling for the effects of age, % predicted, smoking status, and anxiety ( Table 3 ). Moreover, depression was significantly associated with reduced QoL in the physical and mental health domains, and with reduced 6MWD after controlling for the effects of age, sex, FEV 1 % predicted, smoking status, and anxiety ( Table 3 ). Table 1 Baseline Characteristics of Participants Characteristic Data Age, y 62.0 (9.9) Sex, female (male), No. 103 (135) Partner status, married or partner 151 (87) (not married or no partner), No. Weight, kg 75.5 (17.9) Height, cm (8.5) BMI, kg/m (5.5) FEV 1, L 1.48 (0.55) FEV 1 % predicted 53.9 (18.1) FVC, L 3.01 (0.93) FVC, L, % predicted 85.7 (19.7) COPD severity according to GOLD standards I 16 II 110 III 87 IV 25 Smoking status Never smoker 11 Former smoker 159 Current smoker 68 Data are presented as mean (SD) or No. unless otherwise indicated. GOLD 5 Global Initiative for Chronic Obstructive Lung Disease. 732 Original Research

4 Regression analyses for the end of PR showed similar associations between anxiety and depression and outcome measures. Again, anxiety was significantly associated with greater dyspnea at rest and after the 6MWT, and with reduced improvements in dyspnea during activities (TDI), even after controlling for the effects of age, % predicted, and smoking status ( Table 4 ). Similarly, anxiety was significantly associated with reduced QoL in both the domains of physical and mental health after controlling for the effects of age, % predicted, and smoking status ( Table 4 ). Again, no significant effect of anxiety on 6MWD at the end of PR was observed. Depression at the end of PR was significantly associated with greater dyspnea at rest and after the 6MWT, and with reduced improvements in dyspnea during activities (TDI), even after controlling for the effects of age, % predicted, smoking status, and anxiety ( Table 4 ). In addition, depression was significantly associated with reduced QoL in the physical and mental health domains, and with reduced 6MWD after controlling for the effects of age, % predicted, smoking status, and anxiety (Table 4 ). Discussion The present results show that PR was significantly associated with improvements in 6MWD, dyspnea after the 6MWT and during activities, and increased physical and mental QoL, as well as reduced anxiety and depression, which converges with many previous findings Most importantly, we observed that anxiety and depression were related to worse outcomes not only at the start of PR, but also at the end of PR. At both time points, anxiety and depression (after controlling for the effects of anxiety) were significantly associated with greater dyspnea after the 6MWT Table 2 Outcome Measures at Start and End of PR Outcome Start of PR End of PR 6MWD, m (90.6) (91.7) a Dyspnea at rest 1.7 (1.5) 1.6 (1.4) Dyspnea after 6MWT 3.6 (1.6) 3.3 (1.6) b Dyspnea during activities, BDI/TDI 6.5 (2.3) 3.1 (2.6) a SF-36 physical summary score 34.4 (8.8) 37.5 (10.0) a SF-36 mental summary score 49.4 (12.0) 52.5 (10.7) a HADS (anxiety) 6.9 (4.2) 6.2 (4.1) a HADS (depression) 6.0 (3.8) 5.6 (3.8) b Data are presented as mean (SD). 6MWD 56-min walking dis tance; 6MWT 56-min walking test; BDI 5 Baseline Dyspnea Index; HADS 5 Hospital Anxiety and Depression Scale; PR 5 pulmonary rehabilitation; SF Item Short Form Health Survey; TDI 5 Tran sitional Dyspnea Index. a P,.001. b P,.01. and during activities, as well as with reduced physical and mental QoL, even after controlling for the effects of age, sex, lung function, and smoking status. Moreover, before and after PR, anxiety, but not depression, was related to greater dyspnea at rest, whereas depression, but not anxiety, was significantly associated with reduced functional performance in the 6MWT. Thus, the present data suggest that the negative impact of anxiety and depression on functional performance, dyspnea, and QoL in patients with COPD remains stable over time, even when improvements in these outcomes are achieved during PR. The present results confirm the findings of previous studies that showed symptoms of anxiety and depression in patients with COPD to be associated with a worse course of disease, including reduced functional performance and QoL and increased dyspnea.10,11,19-21,24-26,38 Our findings contrast with those of two reports that found no, or only a weak, impact of anxiety and depression on functional performance in COPD 22,23 ; however, these studies were limited by small sample sizes. Key features of the present study that extend the previous findings are not only the examination of these associations before and after PR, but also the relatively large sample size, an improved sex ratio, no preselection for high levels of psychologic comorbidities, and the inclusion of measures for both anxiety and depression that are not overlapping with physiologic symptoms of COPD (eg, fatigue, weight loss). In addition, the assessment of functional performance was not based on questionnaires, but on the results of a 6MWT. Notably, we found no association of functional performance in the 6MWT with anxiety, but only with depression, which contrasts with the previous findings of Giardino et al 25 and Cully et al. 24 In both studies, anxiety was related to reduced 6MWD, whereas depression had no such effect. This divergence might be explained by differences in the measurement of anxiety and depression between the studies or by differences in patient characteristics. For example, Giardino et al 25 exclusively studied patients with emphysema, whereas the sample of Cully et al 24 consisted almost exclusively of male veterans with preselected high levels of anxiety and depression. Therefore, future studies are needed to test for potential differences in the relationship between anxiety, depression, and functional performance in specific subgroups of patients with COPD. In line with the findings of previous reports, our findings underline the importance of targeting symptoms of anxiety and depression in patients with COPD in order to improve their functional performance, dyspnea, and QoL, which might similarly improve the beneficial effects of interventions such as PR on these outcomes. 6,14,24,39 This is of considerable clinical importance, in particular when the high prevalence CHEST / 140 / 3 / SEPTEMBER,

5 Table 3 Associations of Anxiety and Depression With Outcome Measures at Start of PR Model Fit B SE b R 2 R 2 P Value 6MWD, m % predicted, smoking status ,.001 Anxiety ns Depression ,.01 Dyspnea at rest % predicted, smoking status ns Anxiety ,.01 Depression ns Dyspnea after 6MWD % predicted, smoking status ,.001 Anxiety ,.05 Depression ,.05 BDI % predicted, smoking status ,.001 Anxiety ,.001 Depression ,.001 SF-36 physical summary score % predicted, smoking status ns Anxiety ,.05 Depression ,.01 SF-36 mental summary score % predicted, smoking status ns Anxiety ,.001 Depression ,.001 Results from hierarchic multiple regression analyses that control for age, sex, lung function, and smoking status in step one include anxiety in step two and depression in step three (after controlling for anxiety). For brevity, only regression coefficients from step two (anxiety) and step three (depression) are presented. ns 5 not significant. See Table 2 for expansion of other abbreviations. rates of anxiety and depression in patients with COPD in the present study, but also in other studies, are taken into account. 4-6 Notably, a previous study demonstrated that clinically relevant anxiety and/or depression was correctly diagnosed in, 44% of patients with COPD and that only 31% of these patients received any treatment of these psychologic comorbidities. 40 Together with the present findings, these data suggest that large numbers of patients with COPD suffer from untreated psychologic comorbidities and, in addition, from increased dyspnea, reduced functional performance, and lower QoL, even after undergoing PR. Therefore, the detection and treatment of anxiety and depression in patients with COPD remains a major clinical target. Several limitations of the present investigation should be noted. Although we used a measure of anxiety and depression that has been validated in patient groups, the measure does not provide a clinical diagnosis of anxiety or depression according to the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders. 41 Moreover, the generalization of the present findings might be somewhat limited because the present patient sample showed relatively good functional performance in the 6MWT at the start of PR, but smaller improvements in the 6MWT after PR, when compared with previ- ous studies on this topic. 22,23,25 A further limitation of the present study is that we could not address to what degree anxiety or depression was related to attrition rates during the rehabilitation program and whether they impacted refusal and exclusion rates for participation in the rehabilitation program. We, therefore, cannot exclude the possibility of differences between those patients who participated and those who refused to participate or quit the program, which would be interesting to examine in future studies. In addition, the observed associations between anxiety and/or depression and outcomes of PR do not provide proof of causality between these variables. Although a recent population-based longitudinal study suggested that anxiety and depression were associated with the new onset of dyspnea, but not vice versa, 42 other authors emphasize the role of disease severity and/or repeated experiences with dyspnea as potential causes of psychologic comorbidities. 25,26 Because of the rather complex interactions between anxiety, depression, and COPD, further studies are needed to determine specific cause-effect relationships. However, irrespective of the cause-effect relationships, once symptoms of anxiety and depression have developed in patients with COPD, they deserve treatment, in addition to the treatment of the physiologic symptoms of COPD Original Research

6 Table 4 Associations of Anxiety and Depression With Outcome Measures at End of PR Model Fit B SE b R 2 R 2 P Value 6MWD, m % predicted, smoking status ,.001 Anxiety ns Depression ,.01 Dyspnea at rest % predicted, smoking status ,.05 Anxiety ,.001 Depression ,.01 Dyspnea after 6MWT % predicted, smoking status ,.001 Anxiety ,.001 Depression ,.01 TDI % predicted, smoking status ns Anxiety ,.01 Depression ,.001 SF-36 physical summary score % predicted, smoking status Anxiety ,.05 Depression ,.05 SF-36 mental summary score % predicted, smoking status ns Anxiety ,.001 Depression ,.001 Results from hierarchic multiple regression analyses that control for age, sex, lung function, and smoking status in step one, include anxiety in step two and depression in step three (after controlling for anxiety). For brevity, only regression coefficients from step two (anxiety) and step three (depression) are presented. See Tables 2 and 3 for expansion of abbreviations. Conclusions In summary, the present study demonstrates that anxiety and depression are significantly associated with increased dyspnea and reduced functional performance and QoL in patients with COPD. These negative associations remain stable over the course of PR, even when improvements in these outcomes are achieved during rehabilitation. Therefore, the detection and treatment of anxiety and depression in patients with COPD is of considerable clinical importance. Acknowledgments Author contributions: Dr von Leupoldt: contributed to development of the study design, data collection, statistical analyses, and writing of the manuscript. Dr Taube: contributed to development of the study design, data collection, and writing of the manuscript. Ms Lehmann: contributed to development of the study design, data collection, and writing of the manuscript. Dr Fritzsche: contributed to development of the study design, data collection, statistical analyses, and writing of the manuscript. Dr Magnussen: contributed to development of the study design and writing of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The German Research Society (Deutsche Forschungsgemeinschaft), as sole funding source, had no impact on the study design, collection/analysis/interpretation of the data, and preparation of or decision to submit the present manuscript. References 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global strategy for diagnosis, management, and prevention of COPD. GOLD Web site. com. Accessed September 9, O Donnell DE, Banzett RB, Carrieri-Kohlman V, et al. Pathophysiology of dyspnea in chronic obstructive pulmonary disease: a roundtable. Proc Am Thorac Soc ; 4 ( 2 ): Decramer M, Rennard S, Troosters T, et al. COPD as a lung disease with systemic consequences clinical impact, mechanisms, and potential for early intervention. COPD ;5(4): Yohannes AM, Willgoss TG, Baldwin RC, Connolly MJ. Depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease: prevalence, relevance, clinical implications and management principles. Int J Geriatr Psychiatry ;25(12): Mikkelsen RL, Middelboe T, Pisinger C, Stage KB. Anxiety and depression in patients with chronic obstructive pulmonary disease (COPD). A review. Nord J Psychiatry ;58(1): Maurer J, Rebbapragada V, Borson S, et al ; ACCP Workshop Panel on Anxiety and Depression in COPD. Anxiety and depression in COPD: current understanding, unanswered CHEST / 140 / 3 / SEPTEMBER,

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