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Anxiety and Depression in Patients With Pulmonary Hypertension

From the Department of General Internal and Psychosomatic Medicine, University of Heidelberg, Medical Center, Heidelberg, Germany (B.L., K.G., C.U., W.H.); the Regenstrief Institute, Indiana University School of Medicine, Indianapolis, Indiana (B.L., K.K.); and the Department of Cardiology, Angiology, and Pulmonology, University of Heidelberg, Medical Center, Heidelberg, Germany (E.G., M.M.B.).

Address correspondence and reprint requests to Bernd Löwe, MD, PhD, Department of General Internal and Psychosomatic Medicine, University of Heidelberg, Medical Center, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. E-mail: bernd.loewe{at}med.uni-heidelberg.de

	ABSTRACT

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OBJECTIVE: This is the first study that investigates the prevalence and actual treatment of anxiety, depression, and other mental disorders in patients with pulmonary hypertension (PH). The prevalence of mental disorders in patients with PH was compared with parallel groups of primary care patients and patients with inflammatory rheumatic diseases, and the relationship between functional status and prevalence of mental disorders was determined.

METHODS: The patient group with PH (70.1% female; mean age, 47.8 ± 12.7 years) and the two comparison groups, which were matched by age and sex, consisted of 164 patients each. Patients completed self-administered instruments, including the Patient Health Questionnaire for the diagnosis of mental disorders. New York Heart Association (NYHA) functional class was assessed in all patients with PH.

RESULTS: Thirty-five percent of the patients with PH suffered from mental disorders, with the most common being major depressive disorder (15.9%) and panic disorder (10.4%). Both panic disorder and panic attacks were significantly more prevalent in patients with PH than in either patients with inflammatory rheumatic diseases or primary care patients. The prevalence of mental disorders in patients with PH increased significantly with functional impairment, from 17.7% (NYHA class I) to 61.9% (NYHA class IV). Only 24.1% of the patients with PH with mental disorders were receiving psychopharmacological or psychotherapeutic treatment.

CONCLUSIONS: Anxiety and depression are frequent in patients with PH and increase as the severity of disease progresses. Given the fact that safe and efficacious treatments of mental disorders are available, greater importance should be attached to the diagnosis and treatment of these conditions in patients with PH.

Key Words: pulmonary hypertension, • depressive disorders, • anxiety disorders, • panic, • diagnosis, • prevalence.

Abbreviations: PH = pulmonary hypertension;; IRD = inflammatory rheumatic disease;; PC = primary care;; PHQ = Patient Health Questionnaire;; NYHA = New York Heart Association;; OR = odds ratio;; CI = confidence interval.

	INTRODUCTION

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Pulmonary hypertension (PH) is an alarming, incurable disease with a poor prognosis (1). Patients with PH often report that they suffer from the uncertainty of the disease, manifested by anxiety and depression. In patients with other severe chronic medical conditions such as coronary artery disease or chronic obstructive pulmonary disease, depression is strongly associated with functional impairment, increased health care costs, and higher mortality (2–4). There appears to be a higher than predicted comorbidity of anxiety, particularly panic disorder and panic attacks, with pulmonary disease (5–8). Respiratory symptoms, such as breathlessness at rest and after activity, are associated with both anxiety and depression (9). Given the sensation of dyspnea and impending suffocation that patients with PH often experience, elevated rates of anxiety and depressive disorders are expected in this patient group. In addition, some medications for PH might cause anxiety in patients with PH. Although psychological side effects have not been described in the original randomized trials (10–12), there is limited evidence that prostanoids potentially induce anxiety (13).

However, until now, the prevalence of anxiety and depressive disorders in patients with PH has not been investigated, either in patients with primary pulmonary hypertension or in patients with pulmonary hypertension related to other etiologies. Because efficacious psychosocial and pharmacological treatments are available for medical patients with anxiety or depression (5,14–16), recognition and management of these disorders in patients with PH could improve clinical outcomes, functional status, personal well-being, drug adherence, and health care costs (17,18).

Hence, the primary objective of our study was to examine the prevalence of anxiety disorders, depression, and other mental disorders in patients with PH. To investigate whether these disorders were more frequent in patients with PH, rates were compared with a matched patient group with another chronic medical condition and a matched sample of consecutive primary care patients. Secondly, this study aimed to assess the association between mental disorders and the degree of functional limitation in patients with PH. We also investigated whether prostanoid treatment was associated with anxiety and depression in patients with PH and whether patients with primary and nonprimary PH differed with respect to the prevalence of mental disorders. Finally, to determine whether mental disorders in patients with PH were adequately treated, the proportion of affected patients receiving either psychotherapeutic or psychopharmacological treatment was assessed in all patient groups.

	METHODS

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Patients and Study Design
The patients with PH investigated in this study were members of the patient organization Pulmonary Hypertension from Germany, Switzerland, and Austria. This nonprofit association meets approximately once yearly, and its major task is to provide information on PH to patients, their dependents, and physicians. Inclusion criteria for this study were written informed consent, diagnosis of PH, and age 16 years or older. The Pulmonary Hypertension patient organization mailed the patient questionnaire, including the diagnostic instrument, a letter explaining the study, and a postage-paid envelope to each of its 250 members. Subjects mailed the completed questionnaires to the principal investigator (B.L.) at the University of Heidelberg, Medical Center. No payment was provided for participation. A second letter was sent to the 125 patients who did not respond to the initial letter within 8 weeks. A total of 177 patients returned completed questionnaires, for a response rate of 71%. From this sample, 13 patients were excluded because they had undergone lung transplantation, heart-lung transplantation, or pulmonary endarterectomy and therefore did not have the diagnosis of PH at the time of the study. Thus, the final sample consisted of 164 patients with PH.

Patients in the comparison groups were matched with patients with PH by age and sex, because these two demographic factors are strongly associated with mental comorbidity (19). As a comparison group with another chronic medical condition, patients with inflammatory rheumatic diseases (IRDs) were recruited in the rheumatology outpatient clinic of the University of Heidelberg, Medical Center. Patients with IRDs were chosen as controls because we aimed to compare the prevalence of mental disorders between patients with PH and patients with another chronic disease without symptoms of dyspnea or impending suffocation. On predetermined days, consecutive patients were approached and invited to complete a self-report questionnaire during their waiting time. Three hundred fifty-six patients with IRDs diagnosed by their physicians gave informed consent and participated in this study (participation rate, 76%). From this sample, the 164 patients with IRDs who best met the matching criteria were selected as the first comparison group for this study. The total sample of 356 patients with IRDs is described in detail elsewhere (20).

The second comparison group included consecutive primary care (PC) patients from 12 family practices in Heidelberg and the general internal medicine outpatient clinic of the University of Heidelberg, Medical Center. The assessment method was similar to that of the patient group with IRDs. Medical diagnoses were extracted from the medical records of the patients. Four hundred seventy-four primary care patients gave informed consent and filled out the patient questionnaire (participation rate, 79%). The 164 patients who best met the matching criteria of age and sex constituted the PC comparison group. Participation rates were not significantly different among the three patient groups. The study protocol was approved by the ethics committee at the Medical Faculty of the University of Heidelberg.

Measures
The patient questionnaire was identical in the three patient groups and assessed sociodemographic characteristics, work disability, history of the disease, limitations of physical activity, physical symptoms, psychopharmacological medication, and psychotherapy. A standardized self-administered diagnostic instrument, the Patient Health Questionnaire (PHQ; 21–24), was also included. The PHQ was specifically developed for use in primary care and other nonpsychiatric settings. For diagnosis, the PHQ offers categorical algorithms for depressive, anxiety, eating, and alcohol disorders based on modified criteria of DSM-IV-TR (19). Excellent operating characteristics have been demonstrated for the American (21) and the German versions of the PHQ (22–24). It has been shown that the PHQ diagnostic algorithms are not overinclusive, but result in realistic estimates of base rates for major depressive disorder, panic disorder, and panic attacks (25). To be certain that the diagnosis of panic disorder was not biased by dyspnea or other physical symptoms, a coding algorithm for the PHQ panic module was used that was independent from the presence of physical symptoms, and that was validated in medical outpatients, including patients with pulmonary, cardiovascular, or circulatory diseases (24). This coding algorithm requires a positive response to each of the first four items of the panic module from the PHQ that refer to the psychological but not to the physical symptoms of anxiety. With reference to a gold standard interview of mental disorders, the sensitivity of the PHQ classification for major depressive disorders is 83%, and specificity is 90% (22); for panic disorder, sensitivity is 86%, and specificity is 91% (24). The prevalence of panic attacks, the cardinal symptom of full-blown panic disorder, was investigated using the first item from the PHQ panic module. To assess the degree of functional limitation, patients with PH were classified according the modified New York Heart Association (NYHA) functional classification. Patients were assigned to one of the four NYHA functional classes based on their reports of dyspnea and fatigue at different levels of physical activity.

Statistical Analysis
Differences between the three patient groups were tested using ² tests for categorical variables and one-way analysis of variance according to the general linear model for continuous variables. Statistical significance was based on two-sided tests evaluated at the .05 level of significance. Age and sex as potential confounders of the group comparisons were controlled by the matching of the three patient samples.

However, as matching might result in overmatching, attenuating potential differences between patients with PH and the two comparison groups, we performed additional logistic regression analyses adjusted for age and sex using the total nonmatched comparison groups (patients with IRDs, N = 356; PC patients, N = 474). The findings from these adjusted analyses were used to investigate whether the unadjusted results from the matched patient groups were subject to selection bias. Corresponding to the analyses in the matched patient groups, the diagnosis of a specific mental disorder was the dependent variable in each adjusted analysis.

Logistic regression analyses were also used to investigate the potential impact of prostanoids and PH subtype on the prevalence of anxiety and depression. To control for potential confounding variables, these analyses were adjusted for age, sex, and NYHA class.

	RESULTS

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Patient Characteristics
As shown in Table 1, 70% of the patients were female and the mean age was 48 years in each patient group. The patient groups were well matched with respect to age, sex, educational level, and nationality. However, work disability was reported by 45% of patients with PH, which was significantly higher than the two comparison patient groups. According to the classification system proposed at the 1998 World Symposium on Pulmonary Hypertension (26), 103 of the patients with PH (62.8%) were diagnosed as having primary pulmonary hypertension and 25 (15.2%) as having pulmonary arterial hypertension related to collagen vascular disease, congenital systemic-to-pulmonary shunts, porto-pulmonary hypertension, human immunodeficiency virus infection, or drugs or toxins. Sixteen patients (9.8%) reported a pulmonary hypertension because of chronic thromboembolic disease, 6 patients (3.7%) a pulmonary hypertension associated with disorders of the respiratory system, and 1 patient (0.6%) a pulmonary venous hypertension; 13 patients (7.9%) with pulmonary hypertension were not able to give enough information to classify the subtype. Distribution of NYHA classes I, II, III, and IV was 10.5%, 25.3%, 51.2%, and 13.0%, respectively. With regard to specific treatment of PH, 53.3% of the patients were on inhaled, 9.7% on oral, and 6.5% on intravenous prostanoids. Sildenafil was taken by 4.9% of the patients, and 40.6% were treated with long-term oxygen therapy. Endothelin-1 receptor antagonists were not available in Europe at the time of the study.

Prevalence of Mental Disorders
Mental disorders as diagnosed by the PHQ are detailed in Table 2. One or more mental disorders were diagnosed in 35.4% of the patients with PH, 27.4% of the patients with IRDs, and 24.4% of the PC patients. However, the differences achieved statistical significance only when comparing patients with PH with PC patients. Among patients with PH, the most common disorders were major depressive disorder (15.9%), and panic disorder (10.4%). One fourth of patients with PH (25.6%) reported having had panic attacks during the last 4 weeks. Panic disorder and panic attacks were significantly more common in PH compared with both patients with IRDs and PC subjects. No differences were found in the frequency of depressive disorders, other anxiety disorders, eating disorders, or alcohol abuse or dependence.

Functional Impairment
As illustrated in Figure 1, the prevalence of mental disorders for patients with different levels of functional impairment was 17.7% (NYHA I), 31.7% (NYHA II), 32.5% (NYHA III), and 61.9% (NYHA IV), with significant differences between the NYHA classes (df = 3; ² = 9.4; p = .02). The prevalence of major depressive disorder and panic disorder also increased significantly as NYHA functional class declined.

View larger version (23K): [in this window] [in a new window]   Figure 1. Relationship between frequency of mental disorders and functional limitation according to New York Heart Association (NYHA) functional class in 164 patients with pulmonary hypertension.

Treatment of Mental Disorders
Of the 58 patients with PH who had a mental disorder diagnosed by the PHQ, only 14 patients (24.1%) reported receiving any type of psychiatric treatment. Specifically, eight patients with PH had received psychopharmacological medication only, two psychotherapy only, and four combination therapy. The treatment rates of patients with IRDs and PC patients with mental disorders did not differ significantly from the treatment rates of the patients with PH.

	DISCUSSION

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The results of this cross-sectional study in a large sample of patients with PH suggest that at least one third of patients suffer from a common and potentially treatable mental disorder, with the most common being major depressive disorder (15.6%) and panic disorder (10.4%). Another important finding was the high prevalence of panic attacks among the patients with PH (25.6%). These prevalence rates were 4 to 6 times greater than national rates for major depressive disorder (3.8%), panic disorder (1.8%), and panic attacks (4.5%; 25), which were drawn from a population-based sample which, like our study, used the PHQ as the diagnostic instrument.

Panic attacks and full-blown panic disorders were significantly more frequent in patients with PH than in IRDs and PC patients, respectively. These findings are strengthened by additional adjusted logistic regression analyses and satisfactory participation rates in all patient groups. Although our findings suggest that the prevalence rates of panic disorder and panic attacks in patients with pulmonary hypertension are higher compared with other chronic conditions not causing dyspnea, PH prevalence rates are comparable with those reported in other pulmonary diseases (5,7,8).

The prevalence of major depression, panic disorder, and overall psychiatric comorbidity was strongly associated with the level of functional limitation as determined by NYHA class. Work disability in nearly half of the patients with PH and other limitations regarding personal well-being, daily activities, and family life may also contribute to the development of mental disorders. On the other hand, our findings suggest that prostanoid treatment is not associated with panic attacks or panic disorder. Altogether, pulmonary hypertension, particularly in the advanced stages, may be a risk factor for the development of panic disorder.

Seventy percent of the patients with PH were receiving prostanoids, and 41% were on long-term oxygen therapy as treatment of their physical illness. In contrast, treatment rates for mental illnesses were as low as 24%. This is a disturbing finding, considering that safe and efficacious treatments for major depressive disorder, panic disorder, and other mental disorders in medical patients are available. Although sedating medications such as benzodiazepines should be used with caution in patients with pulmonary disease to avoid respiratory depression, selective serotonin reuptake inhibitors and cognitive-behavioral approaches are effective treatments that have relatively little potential for significant adverse effects for both depressive and panic disorder (5,14–16). In patients with PH who seek treatment with symptoms of anxiety or panic, it may be difficult to decide whether these symptoms are caused by psychological conditions or hemodynamic instabilities. However, independent from their original cause, anxiety symptoms have an adverse effect on dyspnea, exercise tolerance, and quality of life in patients with respiratory disease (5,9) and thus require attention and, in many cases, treatment.

According to the suffocation false alarm theory (29), patients with panic disorder have an increased sensitivity to CO₂, resulting in physiological misinterpretation of rising CO₂ as a harbinger of asphyxia and consequently in panic attacks. Studies in patients with pulmonary disease and healthy subjects are supportive of this theory (5,30). However, there is only limited evidence suggesting that episodic hypoxia also causes panic attacks (31), even though suffocation is associated both with high levels of arterial CO₂ (hypercapnia) and low levels of arterial O₂ (hypoxia). In contrast with chronic obstructive pulmonary disease (COPD) and end-stage interstitial lung disease, hypercapnia is extremely rare in PH. Typically, there is mild hypocapnia. Therefore, we do not think that the suffocation false alarm theory applies to patients with PH. Although this has never been studied systematically, we have never experienced bouts of hypoxia associated with (inappropriate) panic reactions. In any case, appropriate treatment of the pulmonary disease is probably an important prerequisite for effective treatment of psychological problems in patients with PH.

This study did not investigate why the treating physicians, mostly cardiologists, pulmonologists, or primary care physicians, failed to initiate treatment for mental problems in the large majority of the affected patients. It may be that, as with other medical populations, only 15% to 40% of the patients with anxiety and depression were identified (22,24). Moreover, even among those whose mental disorders may have been recognized, this may have not necessarily resulted in the initiation of an adequate treatment. The undertreatment of anxiety and depression we discovered in patients with PH is similar to that in other chronic, debilitating medical conditions (20,32). Multiple barriers to diagnosis and treatment of mental disorders in medical patients have been previously described (33,34).

This study has several limitations. One is the reliance on patient self-report. The use of self-administered questionnaires was necessary because the participating patients with PH were spread over Germany, Austria, and Switzerland. However, the psychiatric diagnostic instrument used has been shown to have excellent criterion validity with reference to gold standard measures of mental disorders (21–24), thus assuring valid diagnoses of mental comorbidity. Further, to ensure that panic disorder and panic attacks were more likely caused by an anxiety condition than pulmonary hypertension-induced hemodynamic instability, we used a validated, modified screening algorithm independent of physical symptoms that could be caused by either PH or panic. Clearly, self-report scales cannot replace clinical or structured interviews in either clinical research or medical care. Therefore, the use of validated interviews for establishing psychiatric diagnosis and NYHA class is recommended for future studies. Measurement bias was prevented by administering the same questionnaires to all three patient groups, which were also matched for age and sex. In contrast, sampling bias cannot entirely be excluded, because the patients with PH were recruited from a PH patient association. As a result of data protection rights, it was not possible to gather information about the nonparticipating patients with PH; thus, it remains unclear whether they differ from the participating patients in terms of sex, age, and illness severity. However, our PH patient group was similar to other PH study samples with respect to age, sex, and PH etiology (10–12). Finally, the subgroup analyses, using data from the PH group only (NYHA class, prostanoid treatment, PH subtype), must be interpreted with caution, because these analyses were powered to detect only medium or large differences between patient subgroups. Thus, smaller subgroup differences might have been missed.

	CONCLUSIONS

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Although patients with pulmonary hypertension frequently have anxiety and depression, only a minority receive adequate psychopharmacological or psychotherapeutic treatment. Future research is needed to improve medical care for patients with PH with anxiety and depression. Screening questionnaires like the PHQ (21) or simple diagnostic questions (35) can help identify and monitor mental disorders in medical patients (36,37). Particularly, their use is recommended in patients with high levels of functional impairment who appear to be at the greatest risk of developing conditions like major depression or panic disorder. At present, better recognition and treatment of mental disorders in patients with pulmonary hypertension remains an important goal for patients, physicians, and other health care providers.

	ACKNOWLEDGMENTS

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This study was supported by a research grant of the patient organization Pulmonary Hypertension, Rheinstetten, Germany.

We greatly appreciate the cooperation with Bruno Kopp, chairman of Pulmonary Hypertension, and we thank the patients who participated in this study. We would also like to express our thanks to Caroline Carney Doebbeling, MD, MSc, Regenstrief Institute, Indiana University School of Medicine, Indianapolis, for her very valuable contributions to this manuscript. There is no conflict of interest in connection with this article.

Received for publication January 30, 2004.

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