Anxiety and depression in patients with chronic obstructive pulmonary disease (COPD).

A review
RIE LAMBK MIKKELSEN, THOMAS MIDDELBOE, CHARLOTTA PISINGER, KURT BJERREGAARD STAGE

Mikkelsen RL, Middelboe T, Pisinger C, Stage K. Anxiety and depression in patients with chronic obstructive pulmonary disease (COPD). A review. Nord J Psychiatry 2004;58:65 /70. Oslo. ISSN 0803-9488. A review of the literature revealed high comorbidity of chronic obstructive pulmonary disease (COPD) and states of anxiety and depression, indicative of excess, psychiatric morbidity in COPD. The existing studies point to a prevalence of clinical significant symptoms of depression and anxiety amounting to around 50%. The prevalence of panic disorder and major depression in COPD patients is correspondingly markedly increased compared to the general population. Pathogenetic mechanisms remain unclear but both psychological and organic factors seem to play a role. The clinical and social implications are severe and the concurrent psychiatric disorders may lead to increased morbidity and impaired quality of life. Furthermore, the risk of missing the proper diagnosis and treatment of a concurrent psychiatric complication is evident when COPD patients are treated in medical clinics. Until now only few intervention studies have been conducted, but results suggest that treatment of concurrent psychiatric disorder leads to improvement in the physical as well as the psychological state of the patient. Panic anxiety as well as generalized anxiety in COPD patients is most safely treated with newer antidepressants. Depression is treated with antidepressants according to usual clinical guidelines. There is a need for further intervention studies to determine the overall effect of antidepressants in the treatment of anxiety and depression in this group of patients. Anxiety, Depression, Obstructive lung disease, Drug treatment, Psychology. Thomas Middelboe, Psychiatric Center Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark, E-mail: t.middelboe@dadlnet.dk; Accepted 9 October 2003.

or decades, the psychiatric morbidity of medically ill patients has been acknowledged. However, there has been relatively little focus on psychiatric disorders in patients with chronic obstructive pulmonary disease (COPD). COPD is a severe and treatment resistant pulmonary disease with varying impact on the patients general physical condition, functioning and quality of life. COPD is a disease with permanent pulmonary obstruction, producing permanent impairment of lung function; 80 /90% of COPD cases are caused by smoking. The clinical characteristics of the disorder are coughing, expectoration and progressive shortness of breath in exercise. Beside smoking cessation, treatment possibilities are limited. Pharmacological methods of treatment are few and non-curative. Smoking cessation is only effective in the early stages of COPD, and if the patient is unable to quit, the disease will progress to disability and finally death.

COPD patients constitute a substantial part of the medically ill patients, both in hospital wards and outpatients clinics, presenting a considerable challenge to the healthcare system. The association between COPD and psychiatric disorders, in particular generalized anxiety, panic anxiety and depression, has been acknowledged for many years. The prevalence of psychiatric comorbidity in these patients as well as the effect of treatment and the prognosis remains unsettled. The diagnostic procedure is complicated by an overlap or close association of somatic and psychiatric symptoms in COPD patients suffering from comorbid anxiety and depression. There is evidence that psychiatric comorbidity contributes significantly to the functional impairment of COPD patients (1) and that psychiatric treatment may improve not only psychiatric status but also pulmonary

# 2004 Taylor & Francis

DOI: 10.1080/08039480310000824

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function (2). The following review examines the comorbid panic anxiety, general anxiety and depression in COPD patients, in order to reveal the magnitude of this clinical problem and explore possible pathogenetic mechanisms. Furthermore, we have reviewed the studies and suggestions of the optimal treatment of psychiatric morbidity in this patient group. In the literature search, we used the Medline /PubMed , EMBASE and Psychlit databases. Key words used were depressive disorders, anxiety disorders, lung disease, obstructive and subheadings drug treatment, psychology and complications. Based on retrieved key articles, additional chain-search was conducted using the link related articles in PubMed .

studies contain no formal data analysis and only simple descriptive statistics. Finally, differences in the objective characteristics and severity of COPD may contribute to the variations in prevalence figures.

Clinical and social implications

The clinical and social implications of comorbid anxiety and depression in COPD patients are only scarcely investigated. In the study by Yellowlees et al. (15), the authors compared COPD patients with and without comorbid psychiatric disorders. Patients with psychiatric comorbidity were spending twice as long time in hospital as the comparison group. McSweeny et al. (10) found that the quality of life of the COPD patients was impaired in all dimensions compared to healthy controls. High impact was seen both on ambulation, mobility, sleep and rest. If COPD patients are further suffering from comorbid psychiatric disorder, this will add to the psychosocial dysfunction. Additionally, substantial marital problems are reported by patients and attributed to their illness (15). Furthermore, the role of medication side-effects should be considered. Many COPD patients are taking several medications. In the Yellowlees study (15), the average number of daily medications was five (range 2 / 9). Gift et al. (18) found in a study of 40 patients with severe COPD that 20 patients receiving steroids were significantly more depressed than a group of 20 patients not receiving steroids. This association is well known and stresses that the emotional status of COPD patients in steroid treatment needs psychiatric monitoring.

Prevalence and comorbidity

The prevalence of anxiety symptoms in COPD patients varies from 2% to more than 50% (3 /5). The prevalence of depressive symptoms varies correspondingly. In a recent review article on comorbid depression in the COPD patients, Van Ede et al. (6) found a prevalence of depression, ranging from 6% to 42%. Only four of 34 studies used control groups (7 /10). In these four studies, the prevalence of depression was higher in the study groups, but only in two studies (8, 10) was the difference significant. Two of the latest prevalence studies identified clinically significant depressive symptoms in 42 /57% of COPD patients (11, 12). The major comorbidity studies are summarized in Table 1. In comparison, Robins et al. (13) found a lifetime prevalence for panic anxiety of 1.5% in an US study of the general population. Lifetime prevalence for anxiety in the general population amounted to 15% and for single depressive episodes 5%. Our review of comorbidity discloses a substantial overrepresentation of anxiety and depression in COPD patients, both regarding occurrence of significant symptoms and psychiatric diagnoses. Although there are large variations in prevalence figures, even the latest studies confirm earlier reports of clinical depression amounting to over 40% in this population (12, 14), i.e. eight times the life time prevalence in the background population. Levels of morbid anxiety are equally elevated in some studies (5, 15, 16) The high prevalence rates are found in studies from western countries as well as from a developing country (17). Furthermore, both inpatients and outpatients have excess psychiatric morbidity, and studies of the elderly make no exception to this trend (12). The explanation for these very differing results can be several. Many studies are performed on small samples and are lacking control groups. The way the psychiatric diagnoses are obtained also varies. Some studies utilize established diagnostic criteria; other studies only use clinical assessments or self-reported symptoms. Most

Psychological and physiological explanatory models

Dyspnea and hyperventilation are frequent symptoms in patients with COPD as well as patients with panic anxiety. Due to this symptom overlap, three different explanatory models have been put forward to explore possible, common pathophysiology. The hyperventilation model assumes that dyspnea and panic arise from the same clinical presentation, namely the hyperventilation syndrome. Thus, patients with COPD and with panic anxiety tend to have dysfunctional breathing patterns that may be associated with hyperventilation. The following hypocapnia may in turn be responsible for various symptoms of anxiety and for dyspnea as well, in this way producing an aggravation of symptoms. The paper bag rebreathing technique used to treat acute panic attacks is based on this model. The carbon dioxide hypersensitivity model is based on the finding that lactate can produce panic attacks in about two-thirds of patients suffering from panic disorder (19). The pathophysiological mechanism
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Table 1. Summary of comorbidity studies: Prevalence of psychiatric comorbidity in chronic obstructive pulmonary disease (COPD) patients.
Author McSweeny et al. (1982) Prigatano et al. (1984) Reference Sample/control group (10) (8) Psychiatric assessment methods Findings Depression 42% in COPD vs. 9% in HC No prevalence figures. POMS anxiety and depression score significantly higher in COPD group Panic anxiety 24%, generalized anxiety 10%, depression 12% Anxiety disorders 16%, mood disorders 8% Depression, men 26% vs 18%; depression, women 33% vs 20%, differences non-significant Depression 7% vs 1%, anxiety 13% vs 6%, differences significant Clinical depression in 42%, 2/3 of these patients moderately depressed (MADRS) Depression 28%, anxiety 50% Depressive symptoms 57% Depression 16.7% anxiety 10% in COPD group, significantly less in control groups Depression and/or anxiety 47.3%. Prevalence 19 /26% in control group, differences significant Major depression 33%, mild depression 14%

203 COPD, nocturnal Self-report: MMPI, POMS, SIP oxygen treatment, 73 HC 985 COPD outpatients, Self-report: POMS, SIP 25 HC

Yellowlees et al. (1987) Karajgi et al. (1990) Isoaho et al. (1995)

(15) (4) (7)

50 COPD inpatients with Psychiatric interview: DSM-III exacerbation diagnoses 50 COPD outpatients Psychiatric interview: DSM-III diagnoses 82 COPD community Self-report: Zung Depression Scale sample, 246 HC (self-rating) 68 COPD in- and outpatients, 89 HC 137 COPD outpatients Self-report: HADS

Engstrm et al. (1996)

(9)

Yohannes et al. (2000)

(12)

Dowson et al. (2001) Lacasse et al. (2001) Aghanwa & Erhabor (2001)

(5) (11) (17)

Aydin & Ulusahin (2001)

(37)

79 COPD inpatients 109 COPD, home care 30 COPD outpatients, 30 hypertensive patients, 30 HC 38 COPD inpatients, 120 tuberculosis patients 49 COPD outpatients

Psychiatric interview and self-report: MADRS, Geriatric Mental Health Scale Self-report: HADS Self-report: SF-36, GDS Self-report and interview: GHQ-30, PSE Self-report: GHQ-12

Stage et al. (2002)

(14)

Psychiatric interview: ICD-10 diagnoses, Hamilton Rating Scales for anxiety and depression

HC, healthy controls; MMPI, Minnesota Multiphasic Personality Inventory; POMS, Profile of Mood States; SIP, Sickness Impact Profile; HADS, sberg Depression Rating Scale; GDS, Geriatric Depression Scale. Hospital Anxiety and Depression Scale; MADRS, Montgomery /A

remains unclear, but abnormally sensitive brain stem chemoreceptors seem to elicit a suffocation false alarm (20). The cognitive behavioural model is based on the idea that patients fear and misinterpretation of bodily experiences arising from dyspnea and hyperventilation are catalysing a panic reaction (19). It is hypothesized that persons with panic disorder interpret threats as more dangerous due to a higher awareness of interoceptive cues like dyspnea and tachycardia. This leads to catastrophic cognitions. The pathogenetic mechanisms of comorbid depression in COPD patients are also complex. The focus has mainly been on four biological factors: Hypoxia, smoking, excacerbations of COPD and untreated chronic depression, all of which factors may in turn lead to comorbid depression and neurocognitive dysfunction in COPD patients. Hypoxia is known to induce not only psychomotor slowing and memory impairment but also depressed mood. Both smoking and COPD generates hypoxia, leading to neuropsychiatric disturbances in these patients.
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Several pathogenetic mechanisms are suggested, ranging from direct damage of the white matter in the brain to vascular endothelial damage or simply increased oxidative stress. A correlation between cognitive dysfunction and blood gas abnormalities is described, resulting in particularly impaired memory and attention functioning (21). Accordingly, Brorson et al. (22) suggest that depression and neurocognitive impairment are two different clinical manifestations of the same pathophysiological brain disturbances in COPD patients. Smoking in COPD patients is considered to have both anxiolytic and anxiogenic effect, and in a large community sample, Breslau (23) found that smokers who met the criteria for nicotine dependence had elevated lifetime rates of anxiety disorders. Further, patients with a history of depressive and anxiety disorders report more severe nicotine withdrawals symptoms (24) and may experience greater difficulty in smoking cessation. Smoking thus seems to play a pathogenetic role in several ways.

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General factors such as weight loss, fatigue and lack of mobility, together with the psychological and social losses associated with COPD, may also trigger depressive reactions. The resulting impairment in patients quality of life is associated with loss of activities of daily living functions and a worsened emotional status (25).

Despite having anxiolytic effect, beta-blockers are contraindicated in this patient group due to their potential risk of bronchoconstriction.

Non-pharmacological treatment
In general, the non-pharmacological treatment of depression in COPD is limited to patients with mild depression and here multidisciplinary rehabilitation, as well as cognitive /behavioural therapy (CBT), appears effective (22). CBT for this group of patients includes increasing the patients body awareness by exercises in relaxation and breathing. The cognitive element of the treatment is aimed at identifying automatic thoughts and promoting a more adaptive cognitive style. Graduated exposure and desensitizing is then attempted, to reduce fears of symptoms as well as alleviating the panic reactions. Eiser (34) found that six sessions of CBT resulted in sustained improvement in exercise tolerance in patients suffering from severe COPD and anxiety. In a recent randomized clinical trial (35), a single 2-h session of group CBT and weekly calls in 6 weeks reduced both depressed mood and anxiety. The effect was significantly better than in the control group (2 h education and weekly calls). There was no improvement in physical functioning in either group. Pulmonary rehabilitation programmes have also been described for COPD patients for comorbid anxiety. By means of progressive exercise, training of respiratory function and psycho-education, patients obtained better exercise tolerance, less dyspnea and better quality of life (36).

Pharmacological treatment
Only a few studies have been conducted on the pharmacological treatment of anxiety and depression in COPD patients.

Antidepressants
The tricyclic antidepressants have been tested in a few studies of depression in COPD patients (26, 27) and the results are contradictory. There are some suggestions that imipramine and amitriptyline relieve symptoms of depression as well as improve pulmonary function in this patient group (27), but a placebo-controlled study (28) turned out negatively. For treating anxiety in COPD patients, the newer generations of antidepressants offer an alternative to the benzodiazepines, due to the restricted number of sideeffects. However, no scientific evidence exists for such a treatment strategy. It has been suggested that the serotonergic effect of clomipramine decreases CO2 sensitivity in patients with panic disorder, and that this may be one of the ways that SSRIs can relieve symptoms of panic (20). However, it is reported that SSRIs are well tolerated by COPD patients (29, 30), but compliance may be poor (31).

Benzodiazepines
Benzodiazepines have anxiolytic effect in COPD patients (19), but may cause respiratory depression. Therefore, the drugs should only be considered, if other anxiolytic agents have proved without effect and if the patients do not suffer from clinical significant respiratory depression due to the pulmonary disease.

Conclusions
Many studies have documented excess psychiatric morbidity in COPD patients that frequently suffer from anxiety disorders and depression. The comorbid, psychiatric disturbances are frequently overlooked or regarded as a natural feature of the lung disease. The relationship between COPD and the neuropsychiatric disorders is very complex, comprising organic, psychological and social factors. Very careful assessment of the patients physical symptoms should be made before the psychiatric diagnosis is settled. A comorbid, psychiatric disorder is possible to treat, and successful treatment leads to improved quality of life and less restricted general functioning. The treatment of comorbid depression should follow the usual clinical guidelines, and in case of major depression, a pharmacological approach should be made. When clinically significant anxiety is present, psychotropic medication is indicated. The newer lines of antidepressants, such as the SSRIs, seem well tolerated
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Other drugs
As an alternative to benzodiazepines, the partial 5HT1A-receptor agonist buspirone has been tested on COPD patients. One study has proved the effect on anxiety and dyspnea in these patients (32), a result that could not be replicated in the study by Sing et al. (33). It is our clinical experience that some centres use lowpotency antipsychotics in very small dosages, reporting good effect in the treatment of anxiety in these patients. However, antipsychotics have no specific anti-panic effect, and the potential neurological and cardiovascular side-effects in particularly medically ill patients render this group of drugs relatively contraindicated.

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in COPD patients with comorbid anxiety disorders. The research evidence for pharmacological treatment is, however, limited. CBT seems an effective non-pharmacological alternative in patients with only minor to moderate psychiatric comorbidity and in patients with elevated risk of adverse drug effects or interactions. There is still a need for valid differentiation between non-specific depressive symptoms and the presence of major depression in this group of patients. A closer cooperation between specialists in pulmonary medicine and psychiatrist could facilitate the process of settling the correct diagnosis and treatment of the psychiatric morbidity in COPD patients. Further intervention studies are needed to illuminate the pathogenetic mechanisms and treatment effects in these patients, so that treatment guidelines can be set up.

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37. Aydin IO, Ulusahin A. Depression, anxiety comorbidity, and disability in tuberculosis and chronic obstructive pulmonary disease patients: Applicability of GHQ-12. Gen Hosp Psychiatry 2001;23:77 /83. Rie Lambk Mikkelsen, M.D., Psychiatric Center, Gentofte University Hospital, DK-2900 Hellerup, Denmark. Thomas Middelboe, M.D., Ph.D., Psychiatric Center, Gentofte

University Hospital, DK-2900 Hellerup, Denmark. Charlotta Pisinger, M.D., Center for Preventive Medicine, Glostrup University Hospital, DK-2600 Glostrup, Denmark and Department of Medicine Y, Gentofte University Hospital, DK-2900 Hellerup, Denmark. Kurt Bjerregaard Stage, M.D., Ph.D., Department of Psychiatry, Odense University Hospital, DK-5000 Odense C, Denmark.

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