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Original Research |

The Risk for Depression Comorbidity in Patients With COPD FREE TO VIEW

Lisette van den Bemt, MSc*; Tjard Schermer, PhD; Hans Bor; Renate Smink, MD; Evelyn van Weel-Baumgarten, MD, PhD; Peter Lucassen, MD, PhD; Chris van Weel, MD, PhD
Author and Funding Information

*From the Department of General Practice (Ms. van den Bemt, Mr. Bor, and Drs. Schermer, van Weel-Baumgarten, Lucassen, and van Weel) and Nursing Home Department (Dr. Smink), Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

Correspondence to: Lisette van den Bemt, MSc, Radboud University Nijmegen Medical Centre, Department of General Practice, (117) PO Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: L.vandenbemt@hag.umcn.nl

*Data are presented as No. (%), mean ± SD, or median (25th–75th percentile).

†p ≤ 0.01 for difference with COPD group.

‡For COPD and DM: time from diagnosis of chronic condition (ie, COPD or DM) until diagnosis of first depression. For control subjects: start of observation time until first diagnosis of depression.

*Data are presented as HR (95% CI).

†p ≤ 0.01.

‡Reference group: general practice 1.

§Reference group: low SES.

Ms. van den Bemt has no conflicts of interest to disclose. Dr. Schermer received grant money for research in the field of respiratory medicine from noncommercial organizations (Radboud University Nijmegen Medical Centre, the Netherlands Organization for Health Research and Development [ZonMw], and the Dutch Asthma Foundation), and from several pharmaceutical companies (Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline); Mr. Bor, Dr. Smink, and Dr. van Weel-Baumgarten have no conflicts of interest to disclose. Dr. van Weel's Department of General Practice, Radboud University Nijmegen Medical Centre, has received financial support for research from the university and unrestricted grants for research and education from the pharmaceutical industry.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Ms. van den Bemt has no conflicts of interest to disclose. Dr. Schermer received grant money for research in the field of respiratory medicine from noncommercial organizations (Radboud University Nijmegen Medical Centre, the Netherlands Organization for Health Research and Development [ZonMw], and the Dutch Asthma Foundation), and from several pharmaceutical companies (Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline); Mr. Bor, Dr. Smink, and Dr. van Weel-Baumgarten have no conflicts of interest to disclose. Dr. van Weel's Department of General Practice, Radboud University Nijmegen Medical Centre, has received financial support for research from the university and unrestricted grants for research and education from the pharmaceutical industry.

Ms. van den Bemt has no conflicts of interest to disclose. Dr. Schermer received grant money for research in the field of respiratory medicine from noncommercial organizations (Radboud University Nijmegen Medical Centre, the Netherlands Organization for Health Research and Development [ZonMw], and the Dutch Asthma Foundation), and from several pharmaceutical companies (Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline); Mr. Bor, Dr. Smink, and Dr. van Weel-Baumgarten have no conflicts of interest to disclose. Dr. van Weel's Department of General Practice, Radboud University Nijmegen Medical Centre, has received financial support for research from the university and unrestricted grants for research and education from the pharmaceutical industry.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(1):108-114. doi:10.1378/chest.08-0965
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Introduction:  Patients with COPD are believed to have a high risk for the development of depression. However, it remains unclear whether or not there is a temporal relation between COPD and depression, and if the higher risk for depression is a result of having a chronic disease, or is specific for COPD. The aim of this study is to compare the risk for physician-diagnosed depression in patients with COPD, patients with diabetes mellitus (DM), and control subjects without chronic conditions.

Methods:  The study was a prospective cohort study based on the Continuous Morbidity Registration database. Cox proportional hazards analysis was used to identify the risk of a first episode of depression in patients with COPD compared to patients with DM and matched control subjects without chronic conditions. The following covariates were added to the model: age, the general practice the patient was listed with, socioeconomic status, comorbidity, and gender. All patients with a diagnosis of depression preceding the date of first diagnosis of COPD or DM (dummy date in control subjects) were excluded.

Results:  The hazard ratios for a first episode of depression in the COPD group compared to the DM group and healthy controls subjects were 1.80 (95% confidence interval [CI], 1.16 to 2.81) and 1.68 (95% CI, 1.20 to 2.35), respectively.

Discussion:  We found a temporal relation between COPD and physician-diagnosed depression. Patients with COPD are more likely to have depression diagnosed than patients with DM and control subjects without chronic conditions.

Figures in this Article

Depression is a mental health problem that results in reduced health-related quality of life, and increased mortality.13 Patients with chronic diseases in general and those with COPD in particular are believed to have a higher risk for depression compared to healthy individuals.4 Precise data of depression rate in patients with COPD are lacking: estimates range from 6 to 59%.512 As COPD is a leading cause of morbidity and the prevalence of COPD is increasing, concomitant susceptibility of patients to depression is of major concern.13 Most studies have used depression questionnaires in which COPD-related symptoms and those indicative of depression may well be entwined and unjustly be interpreted as a “depression.”6 More importantly, the temporal relation between depression and COPD remains unclear (ie, does COPD enhance the risk for a depression, or vice versa?). Moreover, it is not clear if depression in patients with COPD is a specific characteristic of this patient group, or is a more general feature of patients with a chronic illness. Patients with other common chronic conditions like diabetes mellitus (DM) are also assumed to be at higher risk for depression.14 Finally, the role of comorbid conditions on the relation between depression and COPD is unknown. For another chronic condition, DM type II, a larger number of coexisting chronic conditions significantly increased the risk of a concurrent diagnosis of depression.15 However, for COPD patients, comorbidity was not associated with significant higher risk for depression in one study.7 The objective of this study was to assess the incidence of first episodes of a physician's diagnosis of depression in patients with COPD and compare this with patients with DM and individuals without chronic conditions.

The design of this study was a historical cohort study based on the Continuous Morbidity Registration (CMR) database with a 35-year observation period. Details of the CMR database have been described elsewhere.16 Briefly, the CMR records since 1971 all new episodes of morbidity presented to general practitioners (GPs) in four general practices in the surroundings of Nijmegen, the Netherlands. The practices have a stable practice population of approximately 12,000 individuals.17 The turnover of patients in these general practices (because patients enter of leave the cohort) is low (< 5%/yr).17 All patients of the practices were informed of the use of the database for research and asked to provide written consent. Only anonymous information of the patients was used. Since only information already available in the CMR records was used, no approval of an internal review board was needed. The practice population is representative of the Dutch population in terms of age, gender, and social class.18 In the Netherlands, all inhabitants are listed with a general practice and receive all their medical care through this particular practice. As a consequence, a general practice has a complete overview of the patient's medical history.

Morbidity is registered by the GP at the time of diagnosis with a diagnosis-oriented classification. Diagnoses made after referral to other specialists are included in the database, as is cause of death for deceased individuals. When the course of the illness or additional testing changes the diagnostic interpretation, the diagnosis is corrected in the system. If a diagnosis is modified, only the current diagnosis is available in the database.

For each patient, sociodemographic information (age, sex, and socioeconomic status [SES], classified as low, middle, and high) and data on morbidity and mortality, if applicable, are available. SES is defined according to profession and education level based on the Dutch Standard Classification of Occupations, 1992.19 To classify morbidity, the Dutch translation of the Royal College of General Practitioners' E-book was introduced in 1971; at that time, this was the only general practice classification available.20 This classification has been maintained in the CMR database ever since, to preserve consistency of data over time. For the diagnostic categories, the criteria and definitions of the International Classification of Health Problems in Primary Care have been introduced in 1984.21 According to the International Classification of Health Problems in Primary Care, depression should be diagnosed if at least three of the following symptoms occur: depressed mood; decrease in interest; suicidal thoughts; indecisiveness; feeling worthlessness/sense of guilt; insomnia/morning tiredness; anxiety/irritability; and psychomotor agitation. It has been demonstrated that for the large majority of patients in the database, their diagnosis is in agreement with the diagnostic criteria, like the diagnosis of patients with DM in reference to the World Health Organization criteria,22 and patients with a GP diagnosis of depression in reference to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive disorder criteria.23 No information on the validity of the diagnoses of COPD in the CMR database is available.

We selected patients with DM type 1 or type 2 as a reference group of patients with another common chronic disease. Comorbidity was defined as the coexistence of one or more recorded chronic conditions with a prevalence > 2% in the CMR population in a patient with an index disease (COPD, DM). Long-term conditions included the following: hypertension, sinusitis, migraine, stomach ulcer, duodenum ulcer, malignant neoplasms, stroke, Parkinson disease, psychiatric disorders, arteriosclerosis, decompensation, cordis, asthma, myocardial infarction, angina pectoris, claudication intermittens, DM type 1 and type 2 (excluded as comorbidity for patients with DM), and arthritis (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and polyarthritis).

Selection of Patients With COPD, DM, and Control Subjects Without Chronic Conditions

This study was based on all data of the CMR database until January 2006. All patients with COPD and DM diagnosed since 1971 with at least 1 month of follow-up were considered for this study. They were identified in the CMR database. For COPD, this required a diagnostic code of chronic bronchitis (diagnostic code 2480) after the age of 40 years.20 For DM, this was diagnostic codes 0911 (type 1) or 0919 (type 2).20 Patients with depression diagnosed prior or at the same time the diagnoses of COPD or DM were assigned by the GP were excluded. DM patients with a diagnosis of nonatopic asthma after the age of 40 years or a diagnosis of COPD at any time during their life were also excluded. These patients were excluded to ensure that no patients with COPD who had been misclassified as having asthma would be included in the DM population. Moreover, patients were excluded if information on at least one of the covariates (ie, SES, gender, age, or general practice) was missing.

Patients with a COPD diagnosis were matched to control subjects drawn from the CMR cohort. These control subjects were free of any of the long-term conditions listed above at the start of the observation period. We used “greedy” propensity matching scoring, balancing the covariates SES, gender, age, and general practice in the propensity score model, with a variable number (1, 2, or 3) of control subjects for each patient with COPD.24 In other words, for each patient with COPD, a maximum of three control subjects were selected, who had the same risk of depression based on the aforementioned covariates. For each control subject, a dummy “date of diagnosis” was defined that equaled the date of diagnosis of matched COPD patients. Thus, the observation time of matched control subjects started at the same point in time as the observation time for the matched COPD patients. In the propensity-matching procedure, control subjects with a diagnosis of depression before the dummy date could not be matched to a patient with COPD. Best matches were defined as those with the highest digit match (0.00001) on the propensity score. The algorithm proceeded sequentially to matches with lower agreement in propensity score between COPD patients and control subjects. The lowest allowable digit match was 0.1. Control subjects could have chronic medical conditions develop during the observation period, with the exception that individuals with a diagnosis of nonatopic asthma after the age of 40 years or a diagnosis of COPD at any time during their life were excluded from the control group prior to the matching procedure. Again, these individuals were not included in the study to guarantee that no patients with COPD were included in the control group.

Statistical Analysis

Characteristics of the COPD group were compared to the DM and control groups and analyzed using χ2 tests and unpaired Student t test (ie, rate of diagnosed with depression, time to newly diagnosed depression, gender, age, SES, comorbid diseases, observation time, and general practice). Cox proportional hazards analysis (ie, survival analysis) was used to identify the risk of a first episode of GP-diagnosed depression in patients with COPD compared to the DM and control groups. Hazard ratios (HRs) are presented with 95% confidence intervals (CIs). An HR is broadly equivalent to relative risk but takes the unequal observation time per subject into account. The following covariates were added to both models (ie, COPD vs DM and COPD vs control subjects): age, gender, SES, general practice, and comorbidity. Comorbidity does not fulfill the proportional hazards assumptions, and therefore we added comorbidity as a categorical time-dependent covariate in the model (ie, months of follow-up with comorbidity compared to months of follow-up without comorbidity); p values used in all analyses were two tailed; p ≤ 0.05 was considered statistically significant.

The flowchart in Figure 1 summarizes the selection procedure of patients and control subjects in the study. Of the patients with COPD, 5.5% were excluded because depression had been diagnosed prior or at the same time of the diagnosis of COPD, or the date of first depression was unknown. For patients with DM, this was also 5.5%.

Figure Jump LinkFigure 1 Flowchart of the selection procedure of patients with COPD, DM, and control subjects without chronic conditions. *Potential controls: no COPD ever, no morbidity at the time the patient registered at the general practice, and no morbidity with an unknown start date (eg, the first registered episode of a disease is not coded as a new episode of an existing disease)Grahic Jump Location

Table 1 shows the characteristics of the selected COPD, DM, and control groups. Patients with COPD had depression diagnosed almost twice as often by their GP, compared to patients with DM and control subjects without chronic conditions. The mean time to a first diagnosis of depression was 7.7 years (95% CI, 5.8 to 9.6 years) for patients with COPD. Time to a first depression did not significantly differ between COPD patients and DM patients (5.9 years; 95% CI, 4.0 to 7.7 years) or control subjects (7.3 years; 95% CI, 5.8 to 8.7 years).

Table Graphic Jump Location
Table 1 Characteristics of Patients With COPD, Patients With DM, and Control Subjects Without Chronic Conditions*

*Data are presented as No. (%), mean ± SD, or median (25th–75th percentile).

†p ≤ 0.01 for difference with COPD group.

‡For COPD and DM: time from diagnosis of chronic condition (ie, COPD or DM) until diagnosis of first depression. For control subjects: start of observation time until first diagnosis of depression.

Table 2 shows that for a first diagnosis of depression in the COPD group compared to the DM group, and for a first diagnosis of depression in the COPD compared to control subjects, HRs are 1.80 (95% CI, 1.16 to 2.81) and 1.68 (95% CI, 1.20 to 2.35), respectively. Figure 2 visualizes the survival curve (time until first episode of depression) in patients with COPD and control subjects. Figure 3 shows the survival curve for patients with COPD and patients with DM. The figures show that patients with COPD have a higher probability of a first episode of depression at any time during the observation time compared to patients with DM and control subjects.

Table Graphic Jump Location
Table 2 Cox Proportional Hazards Regression Models on Depression of Patients With COPD Compared to Patients With DM and Control Subjects Without Chronic Conditions*

*Data are presented as HR (95% CI).

†p ≤ 0.01.

‡Reference group: general practice 1.

§Reference group: low SES.

Figure Jump LinkFigure 2 Survival curve (time until first episode of depression) in patients with COPD and control subjects. Cum = cumulative.Grahic Jump Location
Figure Jump LinkFigure 3 Survival curve for patients with COPD and patients with DM. See Figure 2 legend for expansion of abbreviationGrahic Jump Location

The objective of this study was to determine the incidence of GP-diagnosed initial episodes of depression in patients with COPD, and to compare the risk of depression with patients with DM and with control subjects without chronic conditions. In total, 5.5% of the COPD population and DM group were not selected for this study because depression had been diagnosed at the same time or prior to the diagnosis of COPD or DM. Our study showed that the risk for a depression was approximately 1.7- to 1.8-times higher for patients with COPD compared to DM patients, as well as for control subjects without chronic conditions.

The prevalence of depression in patients with COPD has been studied before. Reported prevalence rates range from 6 to 59%.512 Although prevalence rates provide information on the cross-sectional association between COPD and depression, it does not provide crucial information on the temporal relation between COPD and depression. In other words, it remains unclear whether or not COPD causes a higher risk of depression. Only two longitudinal studies on depression in patients with various medical conditions have been published that also concerned patients with COPD4 or “chronic lung disease” (asthma and COPD).25 Both studies4,25 collected information on depression based on self-reported questionnaire scores like the Center for Epidemiologic Studies Depression Scale. Using such questionnaires to determine depressive disorders can result in higher scores based on the nature of the underlying chronic disease and is not the same as a clinically verified event.6 Physical symptoms (fatigue, sleeplessness/insomnia, poor appetite) are an integral part of depression questionnaires, but it is not possible to distinguish between “depression-generated” and “physical condition-generated” symptoms. This may result in overreporting of depression. Our study was based on a clinical diagnosis of depression by GPs, in a research practices' database with high diagnostic specificity compared to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.23 This high specificity had also been found in other studies.26 In our study, working from a clinical diagnosis made it possible to avoid the limitations depression questionnaires have in patients with chronic conditions. However, it is likely that depression is underrepresented in general practice because not all patients seek treatment when depressed or the GP may record it other than depression. This particularly applies to patients with less severe depression. As a consequence, our findings might reflect more serious or chronic episodes of depression in patients with COPD. Despite the differences between our study and previous studies, the cumulative incidence rate of depression in our study was more or less comparable with the findings reported by Patten4 (ie, 6.7%). Bisschop et al25 do not report on the incidence of depression.

We found that the mean time elapsed between the date of diagnosis of COPD and the first episode of depression was 7.6 years. Unfortunately, this could not be compared with these two aforementioned studies because these studies had follow-up periods of 2 years and 6 years, respectively, and did not use longitudinal data collection like our study.4,25

The CMR database with its longitudinal design is an important strength of our study because we were able to investigate the temporal direction in which COPD and depression are related. The CMR database consists of information that is systematically recorded by GPs in daily routine care. Therefore, it enabled us to restrict the study sample to subjects who were free of diagnosed depression until the start of the observation period. Survival analysis adjusts for censored data, so no eligible subjects dropped out because of death or leaving the CMR practice, which resulted in a sufficiently large sample of COPD patients and sufficiently large reference groups. A limitation of the CMR database is the absence of objective data on the lung function of the patients with COPD diagnosed and information on smoking status.

There are many mechanisms that could be responsible for the higher risk of depression in patients with COPD. First of all, patients with chronic respiratory disease have worse physical functioning than patients with other chronic diseases, and it has been shown that the level of functional impairment itself is related to a higher rate of depression.27,28 However, in one study25 the physical limitations did not seem to play a mediating role on the relation between chronic lung disease and depression. The lack of control on the course of the disease experienced by the patient could be a second mechanism that results in depressive symptoms.25 Moreover, the hypoxic nature of severe COPD can result in an organic depression, and dyspnea can cause much distress and higher depression rates in patients with COPD.10 In addition, COPD is a disease that primarily occurs in patients with advanced age, and low SES, and the nature of the disease can result in social isolation, feeling useless, and immobility, all factors associated with depression.29

Comorbidity is a well-established phenomenon that was found in 85% of the patients with COPD in this study but did not result in higher risk for depression in patients with COPD compared to healthy control subjects and DM patients. This result is comparable with the findings of Mulsant et al,30 who examined the relationship between various variables and the risk for depression in COPD patients and found that comorbidity was no significant determinant for the level of depression in patients with COPD. It might be that the overlap between symptoms of depression and somatic diseases complicates the recognition of depression. This finding warrants further investigation. We included psychiatric diseases in the list of comorbid conditions. The HR for a first episode of diagnosed depression for patients with COPD compared to DM and healthy control subjects were calculated based on the same Cox proportional hazard model with the exception of psychiatric comorbidity. Only negligible differences with the results in Table 2 were found. Therefore, the psychiatric comorbidity did not have an important effect on our findings.

Some interventions for patients with COPD, like comprehensive pulmonary rehabilitation, appear to result in a decline of depressive symptoms.31 Moreover, treatment and recovery for depression are difficult but achievable.32 A stepped-care approach for the treatment of depression in a primary care population was found to be effective and might be suitable for patients with COPD as well.33 Therefore, the negative effect that a depressive disorder can have on the life and health of patients with COPD may be prevented or reduced. Physicians need to be aware of the higher risk of depression in COPD patients to attain early detection and start early treatment.

In conclusion, we found that patients with COPD have a higher risk of physician-diagnosed depression than patients with DM and control subjects without relevant chronic conditions. Therefore, a temporal relation between COPD and diagnosis of depression seems to exist. Moreover, it seems that the increased risk of depression is not the result from having a chronic disease in general but is specific for COPD. For daily care, these results imply that physicians involved in the management of COPD need to be aware of the increased risk of depression in these patients.

CI

confidence interval

CMR

Continuous Morbidity Registration

DM

diabetes mellitus

GP

general practitioner

HR

hazard ratio

SES

socioeconomic status

The authors thank the GPs and practice nurses of the CMR practices for the collecting of data for so many years. Moreover, we are very grateful to Reinier Akkermans for his help with advanced Cox proportional hazard modeling.

The authors thank the GPs and practice nurses of the CMR practices for the collecting of data for so many years. Moreover, we are very grateful to Reinier Akkermans for his help with advanced Cox proportional hazard modeling.

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Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72:227-236. [PubMed] [CrossRef]
 
Lenze EJ, Rogers JC, Martire LM, et al. The association of late-life depression and anxiety with physical disability: a review of the literature and prospectus for future research. Am J Geriatr Psychiatry. 2001;9:113-135. [PubMed]
 
Patten SB. Long-term medical conditions and major depression in a Canadian population study at waves 1 and 2. J Affect Disord. 2001;63:35-41. [PubMed] [CrossRef]
 
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Figures

Figure Jump LinkFigure 1 Flowchart of the selection procedure of patients with COPD, DM, and control subjects without chronic conditions. *Potential controls: no COPD ever, no morbidity at the time the patient registered at the general practice, and no morbidity with an unknown start date (eg, the first registered episode of a disease is not coded as a new episode of an existing disease)Grahic Jump Location
Figure Jump LinkFigure 2 Survival curve (time until first episode of depression) in patients with COPD and control subjects. Cum = cumulative.Grahic Jump Location
Figure Jump LinkFigure 3 Survival curve for patients with COPD and patients with DM. See Figure 2 legend for expansion of abbreviationGrahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Characteristics of Patients With COPD, Patients With DM, and Control Subjects Without Chronic Conditions*

*Data are presented as No. (%), mean ± SD, or median (25th–75th percentile).

†p ≤ 0.01 for difference with COPD group.

‡For COPD and DM: time from diagnosis of chronic condition (ie, COPD or DM) until diagnosis of first depression. For control subjects: start of observation time until first diagnosis of depression.

Table Graphic Jump Location
Table 2 Cox Proportional Hazards Regression Models on Depression of Patients With COPD Compared to Patients With DM and Control Subjects Without Chronic Conditions*

*Data are presented as HR (95% CI).

†p ≤ 0.01.

‡Reference group: general practice 1.

§Reference group: low SES.

References

Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58:221-227. [PubMed] [CrossRef]
 
Cuijpers P, Smit F. Excess mortality in depression: a meta-analysis of community studies. J Affect Disord. 2002;72:227-236. [PubMed] [CrossRef]
 
Lenze EJ, Rogers JC, Martire LM, et al. The association of late-life depression and anxiety with physical disability: a review of the literature and prospectus for future research. Am J Geriatr Psychiatry. 2001;9:113-135. [PubMed]
 
Patten SB. Long-term medical conditions and major depression in a Canadian population study at waves 1 and 2. J Affect Disord. 2001;63:35-41. [PubMed] [CrossRef]
 
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