abstract: Depression and anxiety are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), and like COPD, they are often underrecognized. Both of these comorbidities can adversely affect the course of COPD. Anxiety, for example, is associated with more severe dyspnea, greater disability, and impaired functional status; it also is a significant predictor of hospitalizations for acute exacerbations of COPD. When evaluating depressive symptoms, it is important to rule out cognitive impairment, particularly in patients with severe COPD and hypoxemia. Treatment options include antidepressants and cognitive behavioral therapy. Participation in a pulmonary rehabilitation program also can help reduce anxiety and depressive symptoms in patients with COPD. (J Respir Dis. 2007;28(3):94-103)
Chronic obstructive pulmonary disease (COPD) is a health problem worldwide, and the impact is expected to increase in the next several decades.1 In the United States, COPD has been diagnosed in more than 10 million persons, and an additional 14 million show signs of the disease, although they have not yet received the diagnosis.2
The COPD death rate for women has more than doubled in the past 20 years--from 20.1 to 56.7 per 100,000--and the financial burden of COPD is significant: an estimated $14.7 billion annually for direct medical costs and an estimated $15.7 billion annually for indirect costs (such as loss of productivity and premature mortality).3 Despite the fact that COPD is the fourth leading cause of death in the United States, behind heart disease, cancer, and stroke, it is underrecognized and undertreated.4-6
Primary care physicians have a central role in managing the care of persons with COPD at all stages.7 First is their effort to support and facilitate the patient's and family's smoking cessation, which many of them do in the office setting.5 However, the lack of office spirometry equipment,8 concerns about appropriate timing of home oxygen therapy, and the high frequency of other major morbidities in patients with COPD may encourage the family physician or general internist to send such patients to pulmonary or cardiology specialists.9,10
While specialists are helpful in recommending certain types of therapy,generalists may be better able to provide help for mood disorders11,12--a group of chronic conditions that often negatively affect the course of COPD.13,14 Research shows that deterioration in patient-reported outcomes only weakly correlated with declines in physiological indices, such as forced expiratory volume in 1 second, but more strongly correlated with the presence and severity of mood disorders and the ability to sleep.13
Fatigue is one of the most common complaints of persons with COPD.15 Fatigue makes the activities of daily living difficult if not impossible and greatly decreases pleasure in any activity.15,16 Health care professionals often become so focused on the dyspnea and decline in lung function associated with COPD that they neglect the functional symptoms that are most important to the patient and his or her family.13 Kapella and colleagues17have developed a model that focuses on fatigue in persons with COPD and places dyspnea in the context of the many other concomitant causes of fatigue.
In this 2-part article, we review the 3 major nonpulmonary components of fatigue and COPD: depression, anxiety, and sleep disorders. The objective is to provide primary care physicians with effective tools to address the poor quality of life experienced by many of their patients with COPD.18
DEPRESSION AND COPD
Few physicians are surprised by or unaware of the connection between COPD and depression.16,19,20 In fact, we may believe that depression is a normal part of the grief reaction to the diagnosis of COPD and fail to formally diagnose and treat this serious comorbidity.14 Depression is diagnosable and treatable even in patients with chronic life-threatening conditions.
The diagnosis of COPD is usually made only after patients present with significant symptoms associated with a change in lifestyle and a reduction in quality of life.21 Such lifestyle changes often result in isolation from productive endeavors and from family and friends, which might be expected to be depressing. However, recent work suggests that the association between depression and COPD goes beyond a reaction to required life changes.
In a study of older adults with a variety of chronic conditions, including diabetes with complications, cancer, and COPD, the overall medical burden was most powerfully associated with depression, and this was largely independent of functional status. This suggests that in general primary care populations, the relationship of illness to depression may be multimodal or may involve shared pathobiological or psychosocial mechanisms.15
Inflammation may be one such shared mechanism. Inflammation is a central factor in the pathophysiology of COPD, and recent research suggests that depression may also be linked to inflammation and inflammatory mediators in the brain.22,23 At present, this is only a fascinating possible association between pulmonary and brain inflammation, but in the future, it may prove to be of value when selecting treatments for both COPD and depression.
The exact percentage of persons with COPD and depression is unknown, primarily because COPD is often unrecognized. However, in those with diagnosed COPD, the rate of depression ranges from 20% to 50%16,24 and has varied little over the past 20 years. The rates of depression associated with COPD do not appear to vary by sex but do vary by the person's use of coping skills.25
Depression is often associated with anxiety, and the combination of the two can amplify the adverse effects of COPD. For example, persons with COPD and depression walk shorter distances in 12 minutes than those with comparable lung impairment without depression.26 Felker and associates27 suggest that 11% to 18% of the variance in physical functioning in COPD can be attributed to depressive symptoms. In patients who require home oxygen therapy, rates of anxiety and depression are as high as 62%,28 and fewer than two thirds of these patients receive therapy for depression.29
Poorer quality of life and decreased rates of compliance with treatment are also more common in COPD patients who are depressed than in those who are not depressed.26 In fact, depression often affects the patient's desire for any treatment for COPD.30 The depressed patient is also more likely to perceive a lack of support from family, friends, and the medical community.26
Recognition of depression
There are many screening tools for depression in adults. One of the newest--the Patient Health Questionnaire (PHQ)-9--has become one of the most commonly used in primary care practices. The PHQ-9 can serve as a screening and follow-up tool. It translates directly to the established DSM-IV criteria for depression, and the results have been shown to improve as a person's depression improves. A score of greater than 5 indicates the need for further evaluation, and a drop of 4 to 5 points is considered evidence of successful therapy with an anticipated return to near-normal status over several months.31-33
No screening test should be considered diagnostic. The person with a high score still requires at least a short diagnostic interview to identify other potential causes, seek a history of previous depression, and assess suicidal thoughts. The diagnostic evaluation can be done by a generalist physician familiar with the diagnostic criteria for depression (Table 1).
No depression screening program should be started without first establishing a system of follow-up. To identify an illness without having a system to treat, monitor, or assess the impact of treatment is irresponsible. This is one of the reasons why general internists' and family physicians' offices can be excellent sites for screening for and diagnosing depression in patients with COPD as well as for treating or referring and monitoringthese patients.13,18 Patients who have more complex problems, are at high risk for suicide, or have substance abuse problems should be referred for specialty mental health care.34
Cognitive impairment must be ruled out when evaluating depressive symptoms in patients with severe COPD, especially those with hypoxemia. In a small study, the incidence of depression was not higher in patients with severe COPD than in age-matched controls, but more than three quarters of the patients had subjective and objective evidence of cognitive disturbance and were classified as having possible mild dementia.35 The patients with COPD had significant symptoms and functional impairments that were not attributable to depression.35
Treatment of depression
In patients with COPD, the first-line treatment of depression remains antidepressants and cognitive behavioral therapy (CBT).36 Pulmonary rehabilitation is an important adjuvant treatment. COPD patients who have completed pulmonary rehabilitation have shown improvements in self-concept and decreased depressive symptoms.37 Withers and associates38 demonstrated that the gain in exercise capacity was greater for those who were more anxious at the outset of pulmonary rehabilitation and that depression scores were improved.39
There is no evidence for or against the use of a simple graded exercise program when formal pulmonary rehabilitation is not available. The very limited risk and the potential benefit suggest that such a programmay be worth trying.
All types of antidepressants, including the older tricyclic antidepressants (TCAs) as well as the newer selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, can improve depression in persons with COPD (Table 2).36 TCAs have been shown to be safe even in those with severe COPD.40 Most antidepressants have adverse effects that can be minimized by a few simple strategies (Table 3). All medications must be used very cautiously in patients who have marked hypoxia and end-stage COPD.
Adherence is a major problem with the use of antidepressants.41 Many persons stop taking their medication because of adverse effects in the first few days or weeks and before they begin to improve. Beginning the medications slowly and providing regular follow-up through visits and telephone calls can improve adherence in depression management and can improve patient outcomes.12
Brief CBT can effectively treat depression and may decrease the sensation of dyspnea as well as anxiety. A single session of CBT--as short as 2 hours--can make a difference.42 Follow-up visits are recommended at 2 weeks and at 4 to 6 weeks, then at least every 2 to 3 months to monitor the course of the depression. These visits can serve to manage both the COPD and the depression.
In summary, depression is a common comorbid condition in patients with COPD. Treatment with pulmonary rehabilitation, antidepressant medications, and CBT is effective. However, currently we are not doing well treating depression in these patients. Even when depression is recognized and treatment initiated, patients with COPD are about one third less likely to have adequate treatment in the first 3 months after the diagnosis of depression, compared with patients with other chronic conditions, including coronary heart disease, diabetes mellitus, and osteoarthritis (odds ratio, 0.67; 95% confidence interval, 0.47 to 0.96).41
ANXIETY AND COPD
Although anxiety and depression often coexist, anxiety alone is also common. The prevalence of clinical anxiety in patients with COPD is significantly higher than in the general population. Estimates for specific anxiety disorders range from a 3- to 10-fold increase in COPD; the highest rates are for panic disorder, which may occur in as many as one third of COPD patients.43-45
The diagnostic criteria for anxiety disorders for patients with COPD are the same as for those without COPD, but special care must be taken to avoid misdiagnosis. The DSM-IV criteria for panic disorder require the presence of one or more noncued panic attacks--that is, panic attacks that do not occur in the presence of an identifiable trigger. For example, a patient who has panic attacks only in the context of an exacerbation of COPD would not meet criteria for panic disorder.
Anxiety symptoms are very common in COPD patients,26,38,46-49 exceeding those of patients with other chronic medical conditions, such as heart failure and cancer.50 Anxiety has a significant effect on the course and impact of COPD. It is associated with decreased quality of life, more severe dyspnea, greater disability, and impaired functional status,14,27 even after controlling for lung function, baseline levels of dyspnea, and the presence of other chronic diseases.26,51 Anxiety is also a significant predictor of the frequency of hospitalizations for acute exacerbations of COPD.52
Many primary care physicians are less familiar and comfortable with the tools for the screening and diagnosis of anxiety than they are with those for depression. Compared with depression, the screening for anxiety disorders in medical clinics has received relatively little attention. Means-Christensen and coworkers53 were not exaggerating when they stated recently, ". . . there is little controversy surrounding the issue of screening for anxiety [in primary care] because guidelines, or even suggestions, for screening for anxiety are almost nonexistent." Nonetheless, there are some data, as well as expert consensus, that can be used to guide efforts to screen for and treat anxiety disorders in medical settings.
A number of different instruments have been used for screening for anxiety and depression. Effective screening tools need not be time-consuming. The Anxiety and Depression Detector is a 5-item screening instrument with good sensitivity and specificity in screening for anxiety and depressive disorder in primary care settings.53 Another 5-item instrument taken from the larger PHQ also has demonstrated effectiveness in screen-ing for anxiety and depression in COPD patients.54
To our knowledge, there are no published randomized controlled studies of treatments for anxiety disorders in patients with COPD. However, a number of studies report decreased anxiety symptoms in COPD patients after they received pharmacological therapy, CBT, and exercise therapies (including pulmonary rehabilitation). In 2 small randomized controlled studies, nortriptyline39 and buspirone55 were shown to significantly reduce anxiety symptoms in COPD patients who were not assessed for the presence of anxiety disorders.
In 2 series of case studies,56,57 sertraline was also shown to significantly reduce anxiety symptoms in patients with COPD. In one study,57 3 of 6 COPD patients had a diagnosed panic disorder; all reported improvement in anxiety when they were treated with sertraline.
CBT has been shown to reduce anxiety and disability in many, but not all, published trials. For example, Kunik and colleagues42 reported significant reductions in anxiety following a single 2-hour session that included education about anxiety, relaxation training, cognitive modification strategies, information on exposure, and home practice materials. Two other small studies58,59 found no significant impact of CBT interventions on anxiety in COPD patients. However, in both studies, the choice of anxiety outcome measures and small sample sizes may have limited the ability to detect real treatment effects.
Participation in comprehensive pulmonary rehabilitation programs has been shown to reduce anxiety symptoms in patients who have COPD. In a series of studies, Emery and colleagues60-62 reported improvement in anxiety in those who participated in programs that included exercise, education, and stress management components. Others have found similar bene- fits following pulmonary rehabilitation.38,63-65 Finally, de Godoy and de Godoy65 found that adding psychotherapy to a standard pulmonary rehabilitation program further reduced anxiety and depressive symptoms compared with pulmonary rehabilitation alone.
World Health Organization. The GOLD global strategy for the management and prevention of COPD. 2001. Available at: www. goldcopd.com. Accessed February 7, 2006.
Wilt TJ, Niewoehner D, Kim C, et al. Use of spirometry for case finding, diagnosis and management of chronic obstructive pulmonary disease (COPD).
Evid Rep Technol Assess (Summ)
Mannino D, Holguin F. Epidemiology and global impact of chronic obstructive pulmonary disease.
Respir Med: COPD Update
Ward MM, Javitz HS, Smith WM, Bakst A. Direct medical cost of chronic obstructive pulmonary disease in the USA.
Global Initiative for Chronic Obstructive Lung Disease.
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report.
Bethesda, Md: National Institutes of Health National Heart, Lung, and Blood Institute; 2006.
Strassels SA, Smith DH, Sullivan SD, Mahajan PS. The costs of treating COPD in the United States.
Yawn BP. A US national agenda for COPD in primary care.
Kaminsky DA, Marcy TW, Bachand M, Irvin CG. Knowledge and use of office spirometry for the detection of chronic obstructive pulmonary disease by primary care physicians.
Bellamy D, Bouchard J, Henrichsen S, et al. International Primary Care Respiratory Group (IPCRG) Guidelines: management of chronic obstructive pulmonary disease (COPD).
Prim Care Respir J
Schermer T, Smeenk F, van Weel C. Referral and consultation in asthma and COPD: an exploration of pulmonologists' views.
Neth J Med
Culpepper L, Judd CR, Moller MD, et al. Clinicians on the front line: active management of depression and anxiety in primary care.
Rost K, Nutting P, Smith JL, et al. Managing depression as a chronic disease: a randomised trial of ongoing treatment in primary care.
. 2002; 325:934.
Oga T, Nishimura K, Tsukino M, et al. Longitudinal deteriorations in patient reported outcomes in patients with COPD.
Cully JA, Graham DP, Stanley MA, et al. Quality of life in patients with chronic obstructive pulmonary disease and comorbid anxiety or depression.
. 2006;47: 312-319.
Lyness JM, Niculescu A, Tu X, et al. The relationship of medical comorbidity and depression in older, primary care patients.
Yohannes AM. Depression and COPD in older people: a review and discussion.
Br J Community Nurs
Kapella MC, Larson JL, Patel MK, et al. Subjective fatigue, influencing variables, and consequences in chronic obstructive pulmonary disease.
Gensichen J, Beyer M, Muth C, et al. Case management to improve major depression in primary health care: a systematic review.
. 2006; 36:7-14.
Van Ede L, Yzermans CJ, Brouwer HJ. Prevalence of depression in patients with chronic obstructive pulmonary disease: a systematic review.
Mikkelsen RL, Middelboe T, Pisinger C, Stage KB. Anxiety and depression in patients with chronic obstructive pulmonary disease (COPD). A Review.
Nord J Psychiatry.
Hajiro T, Nishimura K, Tsukino M, et al. Comparison of discriminative properties among disease-specific questionnaires for measuring health-related quality of life in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med
. 1998; 157:785-790.
Johannsen A, Rylander G, Soder B, Asberg M. Dental plaque, gingival inflammation, and elevated levels of interleukin-6 and cortisol in gingival crevicular fluid from women with stress-related depression and exhaustion.
Leonard BE, Myint A. Inflammation and depression: is there a causal connection with dementia?
Breslin E, van der Schans C, Breukink S, et al. Perception of fatigue and quality of life in patients with COPD.
Unger DG, Jacobs SB. Couples and chronic obstructive airway disease: the role of gender in coping and depression.
Kim HF, Kunik ME, Molinari VA, et al. Functional impairment in COPD patients: the impact of anxi- ety and depression.
Felker B, Katon W, Hedrick SC, et al. The association between depressive symptoms and health status in patients with chronic pulmonary disease.
Gen Hosp Psychiatry
Mishima M, Oku Y, Muro S, et al. Relationships between dyspnea in daily life and psycho-physiologic state in patients with chronic obstructive pulmonary disease during long-term domiciliary oxygen therapy.
Lacasse Y, Rousseau L, Maltais F. Prevalence of depressive symptoms and depression in patients with severe oxygen-dependent chronic obstructive pulmonary disease.
J Cardiopulm Rehabil
. 2001; 21:80-86.
Stapleton RD, Nielsen EL, Engelberg RA, et al. Association of depression and life-sustaining treatment preferences in patients with COPD.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure.
J Gen Intern Med
Stage KB, Middelboe T, Pisinger C. Measurement of depression in patients with chronic obstructive pulmonary disease (COPD).
Nord J Psychiatry
Lowe B, Kroenke K, Herzog W, Grafe K. Measuring depression outcome with a brief self-report instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9).
J Affect Disord
. 2004;81: 61-66.
Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ. A proposed algorithm for improved recognition and treatment of the depression/anxiety spectrum in primary care.
Prim Care Companion J Clin Psychiatry
Ozge C, Ozge A, Unal O. Cognitive and functional deterioration in patients with severe COPD.
Lacasse Y, Beaudoin L, Rousseau L, Maltais F. Randomized trial of paroxetine in end-stage COPD.
Monaldi Arch Chest Dis
Kersten L. Changes in self-concept during pulmonary rehabilitation, Part 2.
Withers NJ, Rudkin ST, White RJ. Anxiety and depression in severe chronic obstructive pulmonary disease: the effects of pulmonary rehabilitation.
J Cardiopulm Rehabil
Garuti G, Cilione C, Dell'Orso D, et al. Impact of comprehensive pulmonary rehabilitation on anxiety and depression in hospitalized COPD patients.
Monaldi Arch Chest Dis.
Borson S, McDonald GJ, Gayle T, et al. Improvement in mood, physical symptoms, and function with nortriptyline for depression in patients with chronic obstructive pulmonary disease.
Pirraglia PA, Charbonneau A, Kader B, Berlowitz DR. Adequate initial antidepressant treatment among patients with chronic obstructive pulmonary disease in a cohort of depressed veterans.
Prim Care Companion J Clin Psychiatry
Kunik ME, Braun U, Stanley MA, et al. One session cognitive behavioural therapy for elderly patients with chronic obstructive pulmonary disease.
Karajgi B, Rifkin A, Doddi S, Kolli R. The prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease.
Am J Psychiatry
. 1990; 47:200-201.
Moore MC, Zebb BJ. The catastrophic misinterpretation of physiological distress.
Behav Res Ther
Yellowlees PM, Haynes S, Potts N, Ruffin RE. Psychiatric morbidity in patients with life-threatening asthma: initial report of a controlled study.
Med J Aust
Borak J, Chodosowska E, Matuszewski A, Zielinski J. Emotional status does not alter exercise tolerance in patients with chronic obstructive pulmonary disease.
Eur Respir J
Engstrom CP, Persson LO, Larsson S, et al. Functional status and well being in chronic obstructive pulmonary disease with regard to clinical parameters and smoking: a descriptive and comparative study.
Prigatano GP, Wright EC, Levin D. Quality of life and its predictors in patients with mild hypoxemia and chronic obstructive pulmonary disease.
Arch Intern Med
Yohannes AM, Baldwin RC, Connolly MJ. Depression and anxiety in elderly outpatients with chronic obstructive pulmonary disease: prevalence, and validation of the BASDEC screening questionnaire.
Int J Geriatr Psychiatry
Kvaal K, Macijauskiene J, Engedal K, Laake K. High prevalence of anxiety symptoms in hospitalized geriatric patients.
Int J Geriatr Psychiatry
. 2001;16: 690-693.
Beck JG, Scott SK, Teague RB, Perez FI. Correlates of daily impairment in COPD.
Dahlen I, Janson C. Anxiety and depression are related to the outcome of emergency treatment in patients with obstructive pulmonary disease.
Means-Christensen AJ, Sherbourne CD, Roy-Byrne PP, et al. Using five questions to screen for five common mental disorders in primary care: diagnostic accuracy of the Anxiety and Depression Detector.
Gen Hosp Psychiatry
Kunik ME, Roundy K, Veazey C, et al. Surprisingly high prevalence of anxiety and depression in chronic breathing disorders.
Argyropoulou P, Patakas D, Koukou A, et al. Buspirone effect on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease.
Papp LA, Weiss JR, Greenberg HE, et al. Sertraline for chronic obstructive pulmonary disease and comorbid anxiety and mood disorders.
Am J Psychiatry
Smoller JW, Pollack MH, Systrom D, Kradin RL. Sertraline effects on dyspnea in patients with obstructive airways disease.
. 1998;39: 24-29.
Eiser N, West C, Evans S, et al. Effects of psychotherapy in moderately severe COPD: a pilot study.
Eur Respir J
Lisansky DP, Clough DH. A cognitive-behavioral self-help educational program for patients with COPD. A pilot study.
. 1996; 65:97-101.
Emery CF. Effects of age on physiological and psychological functioning among COPD patients in an exercise program.
J Aging Health
Emery CF, Schein RL, Hauck ER, MacIntyre NR. Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease.
. 1998; 17:232-240.
Emery CF, Shermer RL, Hauck ER, et al. Cognitive and psychological outcomes of exercise in a 1-year follow-up study of patients with chronic obstructive pulmonary disease.
. 2003; 22:598-604.
Guell R, Resqueti V, Sangenis M, et al. Impact of pulmonary rehabilitation on psychosocial morbidity in patients with severe COPD.
Kayahan B, Karapolat H, Atyntoprak E, et al. Psychological outcomes of an outpatient pulmonary rehabilitation program in patients with chronic obstructive pulmonary disease.
. 2006;100: 1050-1057.
de Godoy DV, de Godoy RF. A randomized controlled trial of the effect of psychotherapy on anxiety and depression in chronic obstructive pulmonary disease.
Arch Phys Med Rehabil
American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders.
4th ed. Arlington, Va: American Psychiatric Association; 2000.