Psychology
2012. Vol.3, No.10, 878-882
Published Online October 2012 in SciRes (http://www.SciRP.org/journal/psych) http://dx.doi.org/10.4236/psych.2012.310132
878
The Impact of Anxiety on Chronic Obstructive
Pulmonary Disease
Hoda Mojazi Amiri, Khalid Monzer, Kenneth Nugent*
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, USA
Received July 9th, 2012; revised August 10th, 2012; accepted September 4th, 2012
Patients with COPD have chronic respiratory symptoms and significant physical limitations secondary to
abnormal pulmonary function. These patients often have significant comorbidity, including psychiatric
disorders such as anxiety and/or depression. The frequency of anxiety and generalized anxiety disorder
(GAD) in patients with COPD significantly exceeds the frequency in the general population. GAD re-
duces the quality of life in these patients and potentially contributes to acute flares in their chronic lung
disease. Most neurobiological models for anxiety involve the limbic system and amygdala. Stimulation of
these areas results in fear and anxiety. The sense of dyspnea (an unpleasant sensory perception of difficult
breathing) also stimulates the limbic system, including the amygdala. Consequently, episodes of dyspnea
could contribute to the development of anxiety in these patients through kindling phenomena. This could
evolve to the point that the patient has chronic anxiety which is maintained by the ongoing sense of dysp-
nea secondary to chronic lung disease. Pulmonary rehabilitation improves the overall quality of life in
these patients and reduces respiratory symptoms, including dyspnea. Patients who do not respond to pul-
monary rehabilitation or who have more severe GAD may need chronic medications, such as selective
serotonin re-uptake inhibitors. These patients will also benefit from psychological and psychiatric evalua-
tion and care.
Keywords: Generalized Anxiety Disorder; COPD; Acute Flare; Treatment
Introduction
Patients with chronic obstructive pulmonary disease (COPD)
have a chronic irreversible lung disease characterized by air-
flow limitation on spirometric testing. The pathological changes
typically include both chronic bronchitis and emphysema.
These patients have chronic respiratory symptoms, reduced
quality of life, physical limitations, disability, increased medi-
cal costs, frequent hospitalizations, and premature death. This
disease occurs worldwide and usually occurs in chronic ciga-
rette smokers. Patients frequently present after the age of 50
and are at risk for other chronic comorbidity, including cardiac
disease, hypertension, diabetes, and malignancy. Patient man-
agement should focus on smoking cessation, improvement in
lung function when possible, limiting the deterioration in lung
function, preventing acute exacerbations, and managing co-
morbidity. These patients frequently have anxiety and/or de-
pression, and some clinical literature suggests that anxiety in-
creases the frequency and/or severity of exacerbations. This
review will focus on the association between anxiety and
COPD.
Diagnostic Criteria for Anxiety
The diagnosis of anxiety in patients with COPD requires a
careful clinical assessment. Physicians can use checklists, such
as the Beck Anxiety Inventory (BAI), The Taylor Manifest
Anxiety Scale, or the Zung Self Rating Anxiety Scale, or struc-
tured clinical interviews. The Beck Anxiety Inventory has 21
categories which are rated 0 to 3, with 3 indicating that the
symptom “bothered the patient a lot” (Beck & Steer, 1996). The
scores are summed and the patient is placed into categories of
low, mild, moderate, or severe anxiety. This scale is frequently
used in clinical and population studies. Structured clinical in-
terviews make use of the Diagnostics and Statistics Manual for
Mental Disorders (DSM-IV) (American Psychiatric Association,
2000). The diagnosis of a General Anxiety Disorder (GAD)
based on the DSM-IV has strict diagnostic criteria, including
excessive anxiety and/or worry for at least six months, diffi-
culty in controlling the worry, and at least three of six listed
symptoms. This anxiety cannot be explained by another Axis 1
psychiatric disorder, by substance abuse, or by a general medi-
cal condition, and it must cause clinically significant distress or
impairment in social, occupational, or other areas of function-
ing. The use of structured interviews typically requires training
in either psychology or psychiatry, and these are not used by
most physicians in their routine practice. The BAI includes
somatic symptoms, such as dizziness, palpitations, shortness of
breath, and indigestion; the DSM-IV diagnostic criteria include
symptoms, such as restlessness, fatigue, difficulty concentrating,
irritability, muscle tension, and sleep disturbance. These so-
matic complaints and psychological symptoms may occur in
patients with COPD as a consequence of their underlying
chronic lung disease and/or treatment and might not necessarily
represent a separate diagnosis, such as GAD. Consequently,
deciding whether a patient with COPD has psychological dis-
tress as a consequence of underlying respiratory symptoms and
impairment or has a separate independent disorder is difficult
and warrants consideration when reviewing studies on the
*Corresponding author.

H. M. AMIRI ET AL.
prevalence of anxiety in COPD. In addition, this distinction has
implications for both treatment and outcome.
Anxiety Prevalence in COPD
Several studies have reported a high prevalence of anxiety in
patients with COPD, but the rates vary widely in these studies
(Di Marco et al., 2006; Eiser et al., 1997; Kunik et al., 2005).
The prevalence of moderate to severe anxiety ranges from 2% -
96% (Hynninen et al., 2005; Hill et al., 2008; Brenes, 2003).
This variation may reflect differences in methodologies and
criteria used to diagnose anxiety, such as self-report vs struc-
tured clinical interviews. The lowest prevalence (2%) was re-
ported by Light et al. who used State Trait Anxiety Inventory
and considered scores two standard deviations above the mean
as positive (Light et al., 1985). The highest prevalence (96%)
was reported by Borak et al who used self-reports based on the
Taylor Manifest Anxiety Scale in COPD patients with chronic
respiratory failure (CRF) (Borak et al., 1991). Kunik et al. re-
ported the largest study on the prevalence of anxiety disorder in
patients with COPD (Kunik et al., 2005). These authors first
used the Primary Care Evaluation of Mental Disorders
(PRIME-MD) screening questions to screen 1334 patients with
a chronic breathing problem for anxiety and/or depression.
Nine-hundred and ninety-five (75%) patients tested positive for
anxiety. The authors then used DSM-IV based structured inter-
views to confirm the presence of anxiety or depression in pa-
tients with COPD who tested positive on PRIME-MD. Two
hundred and four patients underwent DSM-IV interviews, and
103 (50.5%) had GAD.
Recent review articles have reported the prevalence of GAD
is 10% - 15.8% in COPD patients compared to 3.6% - 5.1% in
the general public (Brenes, 2003). The prevalence of panic
disorder is 8% - 67% in patients with COPD (Hynninen et al.
2006). The 12 month and lifetime prevalence of panic disorder
in the general public in the United States is 2.7% and 4.7%,
respectively (Kessler et al., 2005). These studies confirm that
anxiety disorders are more common in COPD patients than the
general population. In addition, the reverse situation is also true.
Zandbergen reported that the lifetime prevalence of respiratory
disorders in patients with panic disorder is 47%, which is sig-
nificantly higher than in patients with obsessive-compulsive
disorders (13%) or eating disorders (13%) (Zandbergen et al.,
1991). These studies suggest that COPD and anxiety have an
unusual linkage, that COPD contributes to the pathogenesis of
GAD, or that the symptom profile in COPD leads to misdiag-
nosis of GAD.
Ferguson and coworkers addressed this issue in a study
which involved 202 military veterans with COPD (Ferguson et
al., 2006). These veterans completed BAI, BDI, and Mini-
Mental state examinations. They then underwent structured
interviews using DMS- IV criteria to determine whether or not
they had anxiety or depression. Eighty-six percent of the par-
ticipants exceeded the cut-off score for depression based on the
BDI, and 77% exceeded the cut-off score for anxiety based on
the BAI. Based on structured clinical interviews, 30.2% met
diagnostic criteria for depressive disorder, and 31.7% met crite-
ria for an anxiety disorder. Confirmatory factor analysis sug-
gested that a two factor model which included depression and
anxiety best fit the data. Therefore, these authors concluded that
somatic symptoms in patients with COPD were good indicators
of depression and/or anxiety. However, they did not exclude the
possibility that these diagnoses represented a mood disorder
associated with a general medical condition. Making this dis-
tinction remains quite difficult even in a study like this and
probably requires evaluations by both a psychiatrist and a pul-
monary physician to determine whether or not the mood disor-
der symptoms represent an independent medical disorder. How-
ever, the main conclusion from this study is that mood disorder
symptoms are quite common in these patients and potentially
have important effects on disease course and quality of life.
Association with Acute Flares
Most patients with COPD have episodic increases in their
symptoms which are referred to as acute exacerbations of
COPD. These patients typically have increased cough, in-
creased sputum production, and increased shortness of breath.
They often require changes in their management, hospitalize-
tion, and occasionally mechanical ventilation for respiratory
failure. Viral infections, bacterial infections, environmental
pollution, and other acute medical disorders, usually cause
acute flares in COPD. A few studies have examined the effect
of psychiatric disorders on the risk of COPD exacerbation, and
these are reviewed in this section.
In a meta-analysis of nine prospective studies, Laurin et al.
reported patients with anxiety had a higher risk for out of hos-
pital treated COPD exacerbations (RR: 1.23; 95%CI: 1.03 -
1.47) (Laurin et al., 2012). However, anxiety had no effect on
risk for in-patient treated COPD exacerbations (RR: 1.05
95%CI: 0.92 - 1.19). They suggested that fear and increased
symptom awareness in patients with anxiety caused “early in-
terventions” in these patients and prevented exacerbation pro-
gression which would require in-patient treatment. Xu et al.
measured depression and anxiety with the Hospital Anxiety and
Depression Scale (HADS) at baseline in 491 patients with sta-
ble COPD (Xu et al., 2008). These patients were then followed
for 12 months to determine the frequency of COPD exacerba-
tion and hospitalizations. Patients with probable anxiety
(HADS anxiety score > 11) were more likely to have a longer
duration of event-based (≥1 symptom worsening plus >1
change in regular medications) exacerbations than patients
without anxiety (HADS score < 7). Also, patients with anxiety
were more likely to have symptom-based (worsening of >1 key
symptom) exacerbations than those without anxiety, but the
number of hospitalizations was not significantly different be-
tween the two groups. Conversely, Yohannes et al. reported that
anxiety score is independently associated with frequency of
hospitalization in a group of elderly patients with COPD (Yo-
hannes, Baldwin, & Connolly, 2000). Variation in study meth-
ods, including the definition of COPD exacerbation, criteria
used to diagnose anxiety, and different patient populations,
likely influenced the results in these studies.
Laurin suggested that the relationship between anxiety and
COPD exacerbation was explained by activation of hypotha-
lamic-pituitary-adrenal pathway axis and increased systemic
inflammatory response, by low self-confidence which in turn
causes worse coping and self-care behavior, and by fear and
worry which could increase the awareness of symptoms and
symptom reporting (Laurin et al., 2012). In summary, anxiety
appears to increase the risk of acute exacerbations in patients
with COPD. Early diagnosis and treatment of anxiety in pa-
tients with COPD could reduce somatic symptoms and possibly
decrease the frequency of exacerbations.

H. M. AMIRI ET AL.
COPD and Anxiety-Neuroendocrine and
Drug Effects
Patients with GAD have greater sensitivity to bodily sensa-
tions than control patients, and this contributes to their exag-
gerated responses to stress. Patients with COPD and hypoxemia
have marked peripheral sympathetic activation, and this activity
decreases after the correction of the hypoxemia with supple-
mental oxygen (Andreas et al., 2005; Wennlund & Carlstrom,
2000; Heindl et al., 2001). These patients also have impaired
autonomic heart rate control, probably explained by cardiac
sympathetic nerve activation, and an activated rennin-angio-
tensin system. During acute flares they have increased levels of
norepinephrine. In summary, patients with COPD have chronic
sympathetic activation with increased responses during acute
changes in disease status. This stress causes somatic symptoms,
contributes to cardiovascular morbidity, and would increase
symptoms in patients with comorbid anxiety.
Patients with COPD usually take bronchodilators and anti-
inflammatory drugs. Beta agonist bronchodilators are used in
patients with COPD for both acute symptom relief and chronic
symptom management. These drugs frequently cause tachycar-
dia, palpitations, nervousness, tremor, and dizziness (Salpeter,
Ormiston, & Salpeter, 2004). Theophylline (a weak bronchodi-
lator) has a similar side effect profile and can cause tremor,
irritability, restlessness, tremor, and insomnia. Systemic corti-
costeroids are used during acute flares for anti-inflammatory
effects and cause insomnia, nervousness, and mood swings.
Therefore, these drugs have frequent side effects which mimic
the somatic symptoms associated with GAD and could increase
the severity of non-respirtory symptoms in these patients. Con-
sequently, patients with COPD and GAD need careful medica-
tion reviews to determine whether or not some somatic symp-
toms reflect potentially avoidable drug side effects. Both sym-
pathetic stress associated with acute flares and drug side effects
could contribute to the development of anxiety through kin-
dling which is discussed below in the pathogenesis section.
Pathogenesis of Anxiety
Patients with chronic anxiety have exaggerated responses to
life stresses. This likely reflects abnormal function in regions of
the brain associated with the detection and response to external
dangers and involves both biological and social-environmental
factors (Jetty, Charney, & Goddard, 2001). These regions either
respond to stress with increased stimulation of the limbic sys-
tem (i.e., have a low activation threshold), or have an excessive
response to potential danger, or both. Eventually this arousal
state in GAD becomes chronic and is either autonomous or
sensitive to very mild stresses. These responses involve the
limbic system in the central nervous system, and this includes
both cortical structures (the hippocampus, the insular cortex,
the orbital frontal cortex, and other regions) and subcortical
structures (the hypothalamus, the amygdala, and other nuclei).
The limbic system is involved in both fear and anxiety re-
sponses and in emotional memory. There are several neurobio-
logical models which potentially explain anxiety and generate
clinical hypotheses about its pathogenesis. The fear circuitry
model is centered in the amygdala (Jetty, Charney, & Goddard,
2001). Animals, including humans, need to be able to sense
danger; sensory inputs into the limbic system activate this sys-
tem when danger is present. This results in the behavioral
changes and physiologic changes associated with fear. These
physiologic responses largely involve the autonomic nervous
system and the endocrine system. The amygdala has an impor-
tant role in this system since it coordinates behavioral, auto-
nomic, and endocrine responses to environmental stimuli, espe-
cially those that have emotional content, through connections to
the hypothalamus, brainstem, and cerebellum. Lesions in
amygdala reduce responses to stress; stimulation of the amyg-
dala produces behavioral arousal and can produce rage reac-
tions. The fear circuitry model explains some of the symptoms
associated with the generalized anxiety disorder, including
hyperarousal, increased motor tension, stress sensitivity, and
avoidance behavior, and offers approaches to treatment.
Multiple neurotransmitters are potentially involved in the
generation of anxiety (Jetty, Charney, & Goddard, 2001). Glu-
tamate receptors mediate excitatory neurotransmission, and
stress activates glutamate transmission in cortical and limbic
regions in the CNS. Glutamate receptor antagonists reduce
anxiety in animal models. The gamma amino butyric acid
(GABA) neurotransmitter is the main inhibitor in the central
nervous system and low levels or receptor dysfunction would
facilitate arousal. Serotonin has a role in anxiety in animal, but
human studies are unclear. Partial agonists such as buspirone
and receptor blockers both have clinical benefits in GAD. Cor-
ticotrophin releasing factor injection in the CNS in animals
causes physiological and behavioral responses similar to stress.
Studies with these neurotransmitters and others provide the
basis for clinical treatment trials.
Acute flares in COPD frequently cause significant psycho-
logical distress secondary to the uncertainty about the course
and the severe shortness of breath and could contribute to the
development of anxiety through the process referred to as kin-
dling. This kindling model arose from animal studies which
demonstrated that progressively smaller amounts of electrical
current could induce seizures in mice (Post, Fleming, & Kap-
czinsk, 2012; Bender & Allow, 2011). In other models using
stimulants such as cocaine it was noted that animals have a
progressive increase in behavioral responses associated with the
stimulant drug. Therefore, kindling represents functional and/or
structural change in neural activity associated with electrical
stimuli (animal models), stress, or drugs and has been used to
help understand unipolar depression, bipolar disorder, anxiety,
and chronic alcoholism. Patients with COPD with acute exac-
erbations associated with increased respiratory symptoms, es-
pecially dyspnea, often have increased psychological distress
(anxiety). If they have repeated exacerbations, they may have a
kindling phenomenon in which smaller changes in respiratory
distress result in similar or larger changes in anxiety. Dyspnea
has both quantitative characteristics (intensity) and behavioral
features (unpleasantness) (Parshall et al., 2012). Studies with
T-weighted magnetic resonance imaging demonstrate that ex-
perimental dyspnea activates the sensorimotor cortex and the
supplemental motor area (Von Leupoldt et al., 2008). Dyspnea
with unpleasant features activates the right insular cortex and
the amygdala. The amygdala has a chemosensor which re-
sponds to carbon dioxide and acidosis and initiates fear re-
sponses in animals (Ziemann et al., 2009). Activation of these
respiratory pathways may also trigger fear and anxiety which in
turn amplify the dyspnea. Since these patients typically have a
chronic shortness of breath independent of any acute exacerba-
tions, they may eventually have chronic anxiety associated their
880

H. M. AMIRI ET AL.
baseline shortness of breath. This is one potential mechanism in
which patients with COPD develop a higher prevalence of
anxiety. In addition, some medications used in the management
of COPD, such as beta-agonists, theophylline, and corticoster-
oids, cause somatic symptoms secondary to side effects. Finally,
patients with COPD often have sleep disturbance which can
disrupt circadian rhythms and contribute to development of
abnormal psychological responses associated with both internal
and external stimuli.
Consequences
The development of anxiety and GAD can occur in any
COPD patient independent of the reduction in pulmonary func-
tion and is not preferentially observed in patients with severe
disease. Patients with COPD and GAD have more somatic
complaints and psychological distress than patients with just
COPD. GAD clearly decreases their quality of life and may
interfere with chronic medical care. GAD may increase the
frequency of acute flares which put patients at immediate risk
for mortality and usually cause deterioration in lung function in
surviving patients. In addition, there is increased mortality in
the year following an acute flare in patients with GAD. Finally,
anxiety increases sympathetic activation which can increase
cardiovascular morbidity.
Anxiety Treatment
Patients with GAD frequently have concomitant depression.
Therefore, therapeutic decisions must consider the possibility
that depression is the more important psychiatric disorder.
Treatment approaches to GAD include both medication and
psychotherapy (Fricchione, 2004). Tricyclic antidepressants
have benefit in patients with GAD but are infrequently used
now because of their side effect profile. Selective serotonin
reuptake inhibitors such as paroxetine provide significant bene-
fit in patients with GAD. An eight week randomized placebo
controlled trial demonstrated that patients on paroxetine had
higher response rates (72%) than patients on placebo (56%).
The remission rate increased and the relapse rate (11% in those
on active therapy vs 41% on placebo) decreased when the trial
was extended 24 weeks in patients who responded to paroxetine
(Fricchione, 2004). Serotonin-norepinephrine reuptake inhibi-
tors also provide significant benefit in these patients. The re-
sponse rates were 58% at eight weeks and 66% at six months in
patients on active therapy and 36% and 39% in those on pla-
cebo (Fricchione, 2004). The optimal treatment duration is
uncertain but probably should be extended to at least 6 months
of treatment. Benzodiazepines are frequently used for acute
management, but their long term use should be limited because
of side effects and dependence. Patients with GAD also im-
prove with psychotherapy. In particular, cognitive behavioral
therapy provides significant benefit within three months, and
approximately 40% of patients improve within six months. In
comparison control patients in this study had no benefit at six
months. Applied relaxation therapy appears to provide the same
benefit as cognitive behavioral therapy.
Anxiety Treatment in COPD
The management of GAD in patients with COPD is poten-
tially more complicated. These patients are older, often have
significant comorbidity, and frequently are on multiple medica-
tions. These patients have been treated with selective serotonin
reuptake inhibitors with modest benefit. Several studies have
suggested that pulmonary rehabilitation improves both anxiety
and depression (Coventry, 2009; Cafarella et al., 2012). Coven-
try recently reviewed this literature and did a meta-analysis on
six studies which evaluated responses to rehabilitation (Coven-
try, 2009). He concluded that rehabilitation significantly im-
proved both anxiety and depression in COPD patients. It is
uncertain as to which component of the pulmonary rehabilita-
tion provides this benefit. In addition, it is uncertain as to
whether or not patients with severe GAD respond to just pul-
monary rehabilitation. Finally, it is unclear as to how long this
benefit persists after the completion of pulmonary rehabilitation.
However, in general it would seem that the best initial approach
to managing GAD in patients with COPD involves comprehen-
sive pulmonary rehabilitation. This should include patient edu-
cation and, if possible, patient psychotherapy. Patients who stay
in maintenance programs should maintain the initial benefits in
the reduction of GAD. Patients discharged to home programs
can maintain benefit with self-help programs. Patients who
have severe GAD who do not respond to pulmonary rehabilita-
tion might benefit from the addition of selective serotonin re-
uptake inhibitors. This decision may require input from a psy-
chiatrist or psychologist. In addition, physicians need to in-
crease treatment efforts to reduce respiratory symptoms, espe-
cially the shortness of breath. Finally, all medications should be
reviewed to identify medications causing important side effects,
and sleep habits and sleep quality should be reviewed.
Conclusion
In summary, patients with COPD frequently have GAD.
These psychological symptoms decrease the quality of life and
potentially contribute to the development of acute flares. There
is likely a complex interaction between the symptom of dysp-
nea and the development of anxiety, and this process involves
the limbic system and the amygdala. Medical management
should focus on measures which reduce dyspnea and prevent
acute flares. Comprehensive pulmonary rehabilitation can re-
duce anxiety symptoms, but in patients with severe GAD
medication may be necessary. This decision probably requires
input from a psychologist and/or psychiatrist; the drug of
choice is a selective serotonin reuptake inhibitor started at a low
dose.
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