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Anxiety in Health
Behaviors and Physical
Illness
Michael J. Zvolensky
University of Vermont
Burlington, Vermont, USA
Jasper A. J. Smits
Southern Methodist University
Dallas, Texas, USA
ISBN 978-0-387-74752-1
e-ISBN 978-0-387-74753-8
Preface
Research has been accumulating on the prevalence and nature of the cooccurrence between various forms of anxiety disorders and problematic health
behaviors as well as physical illness. This research has significant implications
for both those interested and affected by anxiety as well as physical health
factors. Yet, it is striking that there has been little systematic integration of this
health-oriented research in contemporary science and practice on anxiety and
its disorders. This relative neglect is unfortunate given that the co-occurrence of
anxiety and health problems is a major public health priority when measured
both in human and financial terms.
The overarching aim of this book is to provide a single resource that offers
current theoretical perspectives and cutting eZdge reviews of scientific research
on health behaviors and physical illness in relation to anxiety and its disorders.
A critical analysis of this emerging literature is needed to help move this field
forward, making this proposed volume timely. The specific objectives of this
edited book are to (1) provide a review of the literature on the link between
anxiety and certain health behaviors and processes as well as physical illness;
(2) present contemporary theories of their co-occurrence and interplay (e.g.,
onset, maintenance, and relapse); and (3) provide an analysis of recent research
in regard to therapeutic models for targeting these problems.
The book is organized into two general sections. In the first part of the book,
prototypical health behaviors smoking, alcohol, illicit substance use, exercise,
and sleep are discussed in relation to anxiety and its disorders. In the second
part of the book, the association between anxiety psychopathology and physical health conditions chronic pain, cardiovascular disease, asthma, HIV/
AIDS and their treatment are covered. In this same section, the potential
role of puberty and the menstrual cycle in the onset and maintenance of anxiety
psychopathology are discussed.
Inspection of the excellent and comprehensive works has yielded a number of
broad-based conclusions relevant to informing research and practice for anxiety disorders. First, there is consistent empirical evidence that medical problems
and poor health behaviors are overrepresented among persons with anxiety
disorders, and vice versa. Thus, there is a pressing need to marshal information
on anxiety-health processes to better serve this population. Second, as each
v
vi
Preface
contribution makes clear, there is uniform evidence that both health behaviors
and physical illness can, and do, affect the nature of anxiety psychopathology.
Yet, the exact nature of these associations depends on the specific disorder and
health factor in question. And finally, a variety of the chapters make clear that
persons suffering from anxiety psychopathology and poor health behaviors or
medical illnesses may need specialized interventions to prompt clinical change.
That is, traditional interventions may not be ideally suited or maximize clinical
benefit for this population.
For us, the present book offers the opportunity to appreciate the importance
and complexity involved with the study of anxiety disorders. For many years,
health behaviors and medical illnesses have been a neglected facet of anxiety
disorder research and practice. The contributions in this book help drive home
the message that such neglect is unwarranted, and that by working to better
understand the enigmas between health status and functioning and anxiety
psychopathology, significant clinically-relevant strides can likely be achieved.
We hope the present book helps move such work forward and bring a better
quality of life and reduced morbidity to persons with anxiety disorders in the
future.
We owe gratitude to many people who have helped us complete this project.
First among these are the experts who authored the chapters. We would like to
thank them for their hard work and dedication. We also appreciate the comments and suggestions of Dr. Martin Antony, the editor of the Series in Anxiety
and Related Disorders, and the assistance of Anna Tobias of Spinger with the
publishing of this book. Lastly, we continue to be appreciative of our respective
family members, Heidi and Jack Zvolensky and Jill and Stella Smits, for their
love and support.
April 2007
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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55
81
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Contents
Contributors
ix
Contributors
Contributors
xi
Part I
Recently, there has been increased effort to better understand linkages between
tobacco use and the anxiety disorders (Feldner, Babson, & Zvolensky, 2007;
Morissette, Tull, Gulliver, Kamholz, & Zimering, 2007; Morrell & Cohen,
2006; Zvolensky, Bernstein, Marshall, & Feldner, 2006; Zvolensky, Feldner,
Leen-Feldner, & McLeish, 2005; Zvolensky, Schmidt, & Stewart, 2003). These
efforts are theoretically and clinically important because substance use problems frequently co-occur with anxiety psychopathology, and anxiety-related
factors often play a role in tobacco use and dependence (Morissette et al.,
2007; Morrell & Cohen, 2006; Zvolensky, Bernstein et al., 2006). However, our
understanding of the explanatory nature of these comorbid relations is only
beginning to emerge. The purpose of the present chapter is to provide a current
review of extant empirical work pertaining to the inter-relations between
tobacco use and panic psychopathology. We expressly and specifically focus
on panic psychopathology, rather than anxiety disorders more broadly, as
most of the work on tobacco and anxiety relations to date has focused on
panic.
This chapter is organized into four sections. First, we briefly describe panic
psychopathology. Second, we review risk factor terminology developed by
Kraemer, Kazdin, and Offord (1997), in order to establish a nomenclature for
conceptualizing interrelations between tobacco and panic psychopathology.
Third, we describe tobacco use and common patterns of use. Fourth, we discuss
the nature of comorbidity between tobacco use and panic psychopathology and
review and evaluate the related empirical evidence. We focus both on the role of
tobacco use in the onset and maintenance of panic psychopathology, and the
role of panic factors and processes in the onset and maintenance of smoking.
Within each of these sections, we identify gaps in the existing literature and
highlight formative questions for future research.
Michael J. Zvolensky
University of Vermont, John Dewey Hall, Burlington, VT 05405-0134, Tel: 802-656-8994,
Fax: 802-656-8783
Michael.Zvolensky@uvm.edu
M. J. Zvolensky et al.
Panic Psychopathology
The term panic psychopathology is used in this chapter to denote panic
attacks, panic disorder, and agoraphobia (with or without panic disorder).
Panic attacks are a subjective sense of extreme fear or impending doom accompanied by an autonomic nervous system surge and a strong flight-or-fight
action tendency (Barlow, Brown, & Craske, 1994). Recent estimates of unexpected (out of the blue) panic attacks in representative samples suggest that
approximately 20% of individuals experience such attacks at one point in their
lives and 11.2% in the past 12-months (Kessler, Chiu, Jin, Ruscio, Shear, &
Walters, 2006). Thus, panic attacks are a relatively common psychological
experience and many people experience panic attacks without necessarily developing panic disorder (i.e., nonclinical panic attacks; Norton, Cox, & Malan,
1992). Typically, individuals who experience nonclinical panic attacks do not
experience these attacks as spontaneous or uncued (as is generally the case
in panic disorder), but rather in certain contexts such as stressful or threatening
social situations (Norton, 1989). Panic attacks also occur among those
with other types of psychopathology (i.e., beyond panic disorder; Bryant &
Panasetis, 2005). Panic attack onset can occur across the lifespan, but early
onset tends to first occur between the ages of 1213 years (Hayward et al., 1992;
Warren & Zgourides, 1988; please see Developmental Course section below
for further details).
Panic disorder involves recurrent unexpected panic attacks and anxious
apprehension about the possibility of experiencing future panic episodes
(American Psychiatric Association, 2000). Lifetime estimates of panic disorder
without agoraphobia are 3.7% and 1.1% for panic disorder with agoraphobia
(Kessler et al., 2006). Twelve-month estimates for panic disorder (with or
without agoraphobia) are approximately 2.8% (Kessler et al., 2006). Thus,
panic disorder is a relatively common psychiatric disorder both in terms of
lifetime and 12-month prevalence rates. This clinical condition is generally
regarded as a disorder of adulthood with a median age of onset of 24 (Burke,
Burke, Regier, & Rae, 1990), although emerging research has noted that
another possible peak onset period may be between ages 4554 years
(Burke et al., 1990). Panic disorder with and without agoraphobia is associated
with a chronic, fluctuating course and high rates of both psychiatric comorbidity and substance use disorders (Zvolensky, Bernstein et al., 2006).
Although not all persons with panic disorder will meet diagnostic criteria for
agoraphobia, individuals with panic disorder often show signs of avoiding
potentially threatening situations in which a panic attack might occur (Feldner,
Zvolensky, & Leen-Feldner, 2004). Agoraphobia reflects a pattern of behavior
characterized by consistent avoidance of threatening situations where a panic
attack or high anxiety is perceived to be likely (e.g., limited options to escape),
or experiencing marked emotional distress when in such situations. Avoidance
behavior can be multifaceted, with a wide range of stimuli that are perceived as
Vulnerability Nomenclature
Explicit delineation of terminology facilitates efforts to understand the nature
of associations between tobacco use and panic psychopathology. Led by the
work of Kraemer and colleagues, groundbreaking conceptual strides have
created a clearer understanding of various risk processes (Kazdin, Kraemer,
Kessler, Kupfer, & Offord, 1997; Kraemer et al., 1997; Kraemer, Lowe, and
Kupfer, 2005; Kraemer, Stice, Kazdin, Offord, & Kupfer, 2001). Specifically, as
is reviewed in this section, Kraemer and colleagues have worked to standardize
operational definitions for risk processes to increase the clarity and consistency
with which these factors are communicated across studies.
Risk factors. A risk factor is a variable that is related to, and temporally
precedes, an unwanted outcome (Kraemer et al., 1997). Causal risk factors
reflect variables that, when modified in some way (e.g., through an intervention), produce change (increase or decrease) in the dependent variable of
interest (Kraemer et al., 1997). Controlled research designs are necessary to
document causal effects because they can rule out competing alternative
explanations (e.g., confounding variables). Proxy risk factors are variables
that are related to an outcome of interest, but this association is due to the proxy
risk factors relation with another causal risk factor (Kraemer et al., 2001).
Thus, change in a proxy risk factor would not yield corresponding systematic
change in an outcome variable; accordingly, a proxy risk factor may mark
risk, but not explain or account for such risk.
Due to the importance of the ability to change a risk factor, both risk and
proxy risk factors often are further categorized on the basis of whether or not
they are malleable (i.e., can be changed or altered). When a risk factor cannot be
changed, it can be classified as a fixed marker, whereas when it can be changed,
it can be classified as a variable risk factor (Kraemer et al., 2005).
M. J. Zvolensky et al.
A risk factor also can be contrasted with a maintenance factor. A maintenance factor is a variable that predicts the persistence of an existing condition
over time among individuals already demonstrating the outcome (Stice, 2002).
In theory, the same categorization scheme could be applied to maintenance
factors in terms of whether or not they are causal or proxy maintenance factors
(Kazdin et al., 1997). Moreover, a risk factor also may subsequently function as
a maintenance factor.
Qualifying conditions for risk factor effects. Clarifying relations between
vulnerability processes and outcomes represents only the first step in a larger
process of risk factor research. That is, this step represents a focus on main
effects, but does not explicate how, when, or among whom a specified risk
process unfolds (see Zvolensky, Schmidt, Bernstein, & Keough, 2006). We do
not delve fully into these explanatory processes within the present chapter, as
extant work has largely focused on questions of main effects at this early
developmental stage of this area of study.
users in the U.S. and other regions of the world (e.g., India; ACS, 1999).
Epidemiological data in the U.S., for example, suggest that approximately
3% of individuals have used some form of smokeless tobacco either snuff
(finely ground, shredded tobacco) or chewing tobacco in the past month
(ACS, 1999). These rates of use are elevated among young Caucasian males
compared to females, and among those in southeastern and north central states
compared to other regions, as well as rural compared to urban settings
(Hatsukami & Severson, 1999). For example, past work suggests that the
highest rates of current use (16.6%) are among Caucasian males 1825 years
of age (CDC, 1994).
In general, rates of smokeless tobacco use are noteworthy because smokeless
tobacco contains carcinogens (e.g., tobacco-specific nitrosamines [TSNAs];
National Cancer Institute and National Institute of Health (NCI/NIH), 2006)
known to be causal agents in lung, oral, esophageal, liver, and pancreatic
cancer (About: Smoking Cessation, 2006b). In addition, smokeless tobacco
use is associated with greater nicotine absorption and for longer periods of
time (e.g., stays in the bloodstream for greater durations of time) than cigarette
smoking (ACS, 2006; NCI/NIH 2006b). Similar to cigarettes, smokeless
tobacco use can lead to increased rates of physical disease (e.g., oral cancer,
gum disease) and nicotine addiction (ACS, 1999). Whereas the risks associated
with cigarette use have become well-publicized in the U.S., public awareness
about the dangers of smokeless tobacco remains limited. Indeed, many perceive
smokeless tobacco as a risk-free alternative to cigarette smoking (CDC,
1994). Although as many as 50% of smokeless tobacco users report wanting
to quit (ACS, 2006a), as with cigarettes, rates of relapse remain high (Hatsukami, Jensen, Allen, Grillo, & Bliss, 1996). In a recent review of smokeless
tobacco treatment programs, Hatsukami and Severson (1999) estimated a 36
month abstinent rate of 12%30% with intensive behavioral treatments fairing
better than other intervention options. Thus, similar to cigarette use, smokeless
tobacco use is an addictive behavior that is difficult to quit and more intensive
care appears to yield relatively better outcomes.
M. J. Zvolensky et al.
Kandel, Huang, & Davies, 2001; Kandel et al., 1997; Merikangas et al., 1998;
Tilley, 1987). Although such work has importantly directed scientific attention
to tobacco-anxiety relations at the broadest level, it is limited in demarcating
specific rates of co-occurrence for (particular) disorders of interest, such as
panic. Thus, for the sake of explanatory specificity, we focus our summary on
investigations that expressly distinguished panic psychopathology from other
anxiety disorders.
Comorbidity prevalence. The majority of studies have focused on documenting rates of smoking among persons with panic psychopathology. The criteria
for smoking behavior has varied across investigations. Moreover, treatmentbased recruitment strategies have been most commonly employed, perhaps
making these data somewhat less generalizable to the overall smoking population. Nonetheless, among treatment-seeking adults, several studies have
reported that current daily smoking among patients with panic psychopathology
(either panic disorder or agoraphobia or both) ranged from 19% Panic
(Baker-Morissette, Gulliver, Wiegel, & Barlow, 2004) to 57% (Himle, Thyer, &
Fischer, 1988), with the vast majority of investigations falling between 30% to
50% (Amering et al., 1999; Lopes et al., 2002; McCabe et al., 2004; Pohl,
Yeragani, Balon, Lycaki, & McBride, 1992). These rates of daily smoking are
typically higher than comparison groups involving persons without psychiatric
problems and typically higher, or as high as, rates among persons with other
anxiety or mood disorders (McCabe et al., 2004). Thus, these data collectively
suggest that smoking is a relatively common unhealthy behavior among treatment-seeking individuals with panic psychopathology.
Studies focused on non-treatment seekers are currently limited. Of the
available work, one study focused on youth (Hayward, Killen, & Taylor,
1989; 95 9th graders in public schools) and the other on college students
(Valentiner, Mounts, & Deacon, 2004, n = 337). In both investigations, individuals with panic attacks, but not necessarily panic disorder or agoraphobia,
had higher rates of cigarette use on a regular basis (Hayward et al., 1989;
Valentiner et al., 2004). For example, Hayward et al. (1989) reported that of
those with a lifetime history of panic attacks, 77% had engaged in experimental or regular cigarette use compared with 48% of adolescents without a
lifetime history of panic attacks. These results, albeit highly limited in overall
scope, generally parallel those of the treatment-oriented investigations noted
earlier in terms of documenting elevated use prevalence among individuals with
panic problems.
Another set of investigations has utilized representative sampling methods to
explore the nature of tobacco use among those with panic psychopathology
(Covey, Hughes, Glassman, Blazer, & George, 1994; Farrell et al., 2001; Lasser
et al., 2000). In perhaps the most comprehensive and well-known of these
investigations, Lasser et al. (2000) examined smoking status according to
psychiatric diagnoses using data from the National Comorbidity Survey (NCS),
a nationally representative study that used structured clinical interviews to document mental illness (Kessler et al., 1994). Participants were 4,411 individuals aged
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M. J. Zvolensky et al.
In the only study to focus on cigarette and smokeless tobacco use, Goodwin
and colleagues (2007) found that among a representative sample from the U.S.,
rates of past-year panic attacks (with or without agoraphobia) were greatest
among smokers with nicotine dependence (6.7%), followed by cigarette use
with no dependence (2.2%), both of which were greater than among those with
no past year cigarette or smokeless tobacco use (1.5%). Being dependent on
smokeless tobacco (1.9%) was largely comparable to no past year tobacco use,
both of which were greater than smokeless tobacco use without nicotine
dependence (0.6%).
Overall, the extant literature suggests that heavier rates of cigarette use
(greater degrees of dependence) are associated with a greater rate of comorbidity with panic psychopathology. Although limited, this pattern of findings does
not yet seem to be apparent for smokeless tobacco use, suggesting that factors
related to the mode of administration may be an important domain to further
understand in tobacco-panic linkages.
Future directions. Though there are many avenues for future inquiry into the
nature of tobacco-panic comorbidity, here we highlight a few domains of
primary importance based upon the gaps in the existing literature. Before
specific recommendations are made, it is striking to point out that, to the best
of our knowledge, none of the past work focused on comorbidity issues has
been a priori oriented on tobacco-panic relations. Thus, it is, perhaps, not
surprising that some of the assessment approaches used in past work may not
be fully comprehensive or geared towards maximizing information about the
nature of the co-occurrence of these specific behavioral problems. As such, a
first-step in improving research in this domain would be to design evaluations
specifically focused on better understanding tobacco-panic comorbidity.
Beyond this general issue, there are at least three specific points within this
domain that would be particularly useful to address.
First, only one study has provided data on smokeless tobacco and panic
comorbidity. Thus, to foster further empirical knowledge in this domain, it is
necessary to complete investigations wherein multiple forms of tobacco use are
assessed to provide information on both cigarette use and smokeless tobacco.
Aside from providing much needed data on smokeless tobacco and
psychopathology, this type of work would help to define the parameters of
tobacco-panic relations more generally. In this same context, it would be
advisable to clarify the extent to which the observed co-occurrence rates
between tobacco use and panic psychopathology are similar to, or different
from, other health behaviors (e.g., alcohol use, physical exercise). In general,
research suggests smoking is strongly positively related to alcohol and other
substance use and negatively related to exercise (Zvolensky & Bernstein, 2005).
This work is necessary because it would further explicate the degree to which
tobacco use is or is not unique to the co-occurrence of panic psychopathology.
As the present book illustrates, research in the health-anxiety linkage is only
now emerging.
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M. J. Zvolensky et al.
Studies examining the typical age of onset for panic attacks also suggest that
such problems often first occur in adolescence. For example, Goodwin and
Gotlib (2004) reported that the mean age of panic attack onset was 13.4 years
(n = 1,285; age range 917). Other studies based on community or school
samples have found similar results, with the modal age of onset of panic attacks
being 12 years old (Hayward et al., 1992; Warren & Zgourides, 1988), and
clinical samples report a slightly younger age of panic attack onset (Alessi &
Magen, 1988; Black & Robbins, 1990). These data suggest that, across studies,
panic attack onset tends to first occur between the ages of 1213 years. One
important interpretative caveat to these investigations is that they focus
exclusively on youth and expressly do not sample from a larger age range.
Thus, it is possible that the average age of onset of panic attacks may be
different if the sampling strategy incorporated adults.
Based on available indirect data from smoking and panic attack age of onset
studies, it appears that in many instances the typical age of onset of panic
attacks precedes the typical age of onset of smoking. However, retrospective
reports of smokers with active panic problems are not entirely consistent with
this perspective. For example, Amering and colleagues (1999) examined 102
consecutive panic disorder patients with or without agoraphobia attending an
academic treatment clinic in Austria. Participants were diagnosed using the
SCID-III-R (First, Spitzer, Gibbon, & Williams, 1995) and interviewed about
their smoking status. Individuals presenting with severe somatic illness
and comorbid depression and other psychiatric illnesses were excluded
from the study. Amering and colleagues (1999) reported that the onset of
smoking preceded the onset of panic disorder (cf. panic attacks) by 12.3 years
(SD = 9.4) in a community sample of individuals with the condition (n = 102).
Bernstein, Zvolensky, Schmidt, and Sachs-Ericsson (2007) directly evaluated
onset patterns among 4,409 adults (Mage = 33.1, SD = 10.7, females = 2,221)
from the NCS (Kessler et al., 1997). Results indicated that among cases with a
lifetime history of comorbid daily smoking and panic attacks (n = 167), the
onset of daily smoking (M = 16.0 years, SD = 3.0) preceded the onset of panic
attacks (M = 27.8 years, SD = 7.6) in the majority, but not among all, of the
comorbid cases (63.7%, n = 106). A relatively large minority of comorbid cases
(33%; n = 55) reported that panic attacks (M = 11.4 years, SD = 5.2) preceded
the onset of daily smoking (M = 18.2 years, SD = 4.7). The concurrent (same
year) onset of these two problems appeared rarely (3.3%, n = 6). Also, as the
pattern of ages of onset above illustrate, daily smoking demonstrated a relatively consistent mean age of onset (mid to late adolescence) across comorbid
sub-samples and the uni-morbid sub-sample of smokers (age 18.5 years). In
contrast, the mean ages of onset of panic attacks differed markedly between the
comorbid sub-samples and the uni-morbid sub-sample of nonsmokers with
panic attacks (age 20.3 years). Overall, while data focused expressly on developmental course and smoking-panic psychopathology is limited, extant studies
suggest that the majority of cases may involve smoking preceding panic attacks.
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M. J. Zvolensky et al.
panic-relevant cues even among those with panic disorder. Less attention has
been focused on determining the relation between smoking rate and level of
affective distress or impairment. Yet, a number of studies, some involving
prospective measurement (discussed in greater detail below), have found that
smoking rate is related to greater degrees of panic-specific emotional symptoms
(e.g., panic-relevant avoidance; Breslau & Klein, 1999; Goodwin, Lewinsohn, &
Seeley, 2005; Johnson et al., 2000; McLeish, Zvolensky, & Bucossi, 2007;
Zvolensky, Kotov, Antipova, & Schmidt, 2003). Thus, there is empirical
evidence that both smoking status and rate are related to increased risk for
panic-relevant emotional vulnerability.
Cross-sectional tests also have helped to clarify factors that may affect the
smoking-panic relation. In one study of epidemiologically-defined (i.e., representative) adult residents of Moscow (n = 95 daily smokers from a larger
sample of about 400 persons; Zvolensky, Kotov et al., 2003), anxiety sensitivity
moderated the effects of cigarettes smoked per day (m = 15) on level of
agoraphobic avoidance. This significant interaction accounted for approximately 10% of unique variance after controlling for their respective main effects
and the theoretically-relevant factors of problematic alcohol use and negative
affectivity. No interaction, however, was found for panic attacks, potentially
due to the fact that assessment of this factor was restricted to the past (most
recent) week to enhance the validity of panic reports (but probably truncating
variability). Similar moderating effects have been evident for perceived health
among young adult daily smokers (McLeish, Zvolensky, Bonn-Miller, &
Bernstein, 2006), and for neuroticism among a representative sample of adult
smokers (Zvolensky, Sachs-Ericsson, Feldner, Schmidt, & Bowman, 2006).
Overall, these findings suggest smokers are not a homogeneous group in regard
to their risk for panic problems and that individual differences in anxiety
sensitivity (or other cognitive-affective factors like perceived health or neuroticism) may be key factors in accounting for such differences.
Moderating effects for anxiety sensitivity also have been evident in
between-group tests involving smokers and nonsmokers. For example, the
combination of high levels of anxiety sensitivity and a positive current smoking
status predicted panic symptoms and somatic complaints, but not depressive
symptoms in a biological challenge test (Leen-Feldner et al., 2007). Again, such
findings suggest that anxiety sensitivity (and possibly other factors) may moderate the relation between smoking and prototypical panic psychopathology
variables (panic attacks and somatic complaints) even after controlling for
gender and negative affectivity. Moreover, these associations are specific to
panic-relevant processes. In a re-analysis of the Russian epidemiological study
reported earlier, Zvolensky and colleagues extended this smoking and anxiety
sensitivity effect (Zvolensky, Kotov, Bonn-Miller, Schmidt, & Antipova, in
press). Here, anxiety sensitivity, again, moderated the association of smoking
status with indices of anxiety symptoms; effects were evident after controlling
for the variance accounted for by alcohol use problems, environmental stress
(past month), and gender.
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M. J. Zvolensky et al.
later in the chapter. More recently, Goodwin and colleagues (2005) replicated
the results of Breslau and Klein (1999), Johnson et al. (2000), and Isensee et al.
(2003) by finding that daily smoking during adolescence was associated with an
increased risk for panic attacks and panic disorder in young adulthood.
Moreover, the observed effects were no longer evident after controlling for
parental smoking and anxiety disorder status, suggesting that these family
history characteristics may be formative in the linkages between smoking and
panic psychopathology.
Prospective tests examining moderating factors in the tobacco use-panic
relation are very limited. In the only study to date on this topic, McLeish
and colleagues (2007) evaluated the moderating role of anxiety sensitivity in
the relation between smoking rate and panic vulnerability variables among a
community-based sample of 125 daily smokers (60 females; Mage =
26.02 years). Findings indicate that the interaction between anxiety sensitivity and smoking rate significantly predicted concurrent agoraphobic avoidance (3.2% of unique variance) and change in levels of anticipatory anxiety
about bodily sensations during the 3-month follow-up period (4.7% unique
variance). Smokers high in anxiety sensitivity who also smoked at greater
rates reported the highest levels of avoidance and greatest increase in anticipatory anxiety. These data, in accord with cross-sectional findings (LeenFeldner et al., 2007; Zvolensky, Kotov et al., 2003), once again suggest that
anxiety sensitivity is an important individual difference factor that, when
coupled with higher rates of smoking, is associated with greater levels of
avoidance and anticipatory anxiety among daily smokers, both of which
contribute to the development of panic psychopathology.
Overall, research co-addressing smoking and panic psychopathology
suggests that smoking can be considered a variable risk factor for panic
problems. Indeed, existing work provides evidence regarding relations with
panic problems based on cross-sectional and prospective studies, but it is
noteworthy that this work is rarely multi-method in its approach. To have
more confidence in smoking-panic psychopathology relations, the incorporation of multi-method assessment protocols would be an important next
research step. Additionally, evidence from cross-sectional, and to a lesser
extent, prospective studies indicates that fears of internal sensations (anxiety
sensitivity) and perhaps other affect-amplifiers (e.g., perceived health,
neuroticism) may moderate smoking-panic processes.
Future directions. There is a rapidly developing empirical literature on
tobacco-use and panic psychopathology relations. Such scientific interest in
this work underscores its public health relevance and potential clinical implications (see Zvolensky, Bernstein, Yartz, McLeish, & Feldner, in press, for an
expanded discussion of treatment implications of tobacco-panic relations). At
the same time, this literature remains relatively under-developed and there are a
number of key areas in need of future study.
First, as in the area of comorbidity prevalence studies reviewed earlier, there
is a dearth of data on smokeless tobacco-panic relations. Virtually no scientific
17
data exists on this important topic, making it a fertile area for future exploration. Second, available data suggest daily smoking tends to precede the onset of
panic attacks in the majority of cases, although direct evaluations with panic
disorder and agoraphobia have not been completed. Given that smoking can be
changed via intervention (Abrams et al., 2003), there is evidence of its potential
malleability, and hence, possible application to prevention programs for panic
psychopathology. Overall, then, evidence that changing cigarette smoking rate
or smoking cessation will alter the future risk of panic psychopathology from a
preventative standpoint is lacking. Thus, it is currently not clear if smoking
represents a variable marker or a variable causal risk factor for panic psychopathology. To clarify this issue, it is important for future research to examine
changes in smoking prospectively following experimental manipulation
(e.g., smoking cessation intervention; Zvolensky, Schmidt, Bernstein, &
Keough, 2006). Third, research has yet to examine the possibility that shared
or common risk factors may further explain the development of comorbid
tobacco use and panic. It is theoretically possible that certain biological,
psychological, and social factors may partially underlie the etiology and
maintenance of these behavior problems. And finally, while there is a growing
literature on moderating factors, there has been little scientific attention to
mediators of smoking-panic associations and therefore almost no empirical
knowledge exists pertaining to the putative causal mechanisms of interest.
Intensifying the focus on mediators of smoking-panic relations is a clinicallyrelevant and timely task. Specifically, clarification of key mechanisms through
which smoking achieves its panicogenic effects will stimulate the development
of targeted interventions focused on therapeutic processes, and help to establish
such processes (e.g., emotional reactivity) as important in the etiology and/or
maintenance of panic-related problems. Only Breslau and Klein (1999)
conducted exploratory analyses of possible mediators by evaluating the
role of lung disease. Although medical illness is one useful process to better
understand, other factors such as perceived health, affect tolerance, various
trajectories of emotional distress (e.g., delayed recovery), withdrawal
symptoms, and avoidance-oriented smoking patterns are all examples of
theoretically-relevant factors deserving of future study (see Zvolensky &
Bernstein, 2005, for an expanded discussion).
Current knowledge regarding the relation between panic psychopathology.
pre-morbid panic risk variables, and tobacco use. Although much of the most
highly publicized work on smoking and panic psychopathology pertains to the
potential role of smoking in the onset or maintenance of panic problems, panic
vulnerability characteristics, broadly encompassing both pre-morbid variables
and full-blown panic problems, may conversely impact smoking behavior
(Zvolensky & Bernstein, 2005). Work in this domain has focused on empirical
evidence related to smoking cessation outcome, expression of withdrawal
symptoms, and motivational and cognitive processes related to smoking
behavior (e.g., outcome expectancies). A major strength of work in this domain
is that study of smoking has involved measurement of various facets of
18
M. J. Zvolensky et al.
19
20
M. J. Zvolensky et al.
21
among high anxiety sensitive compared with low anxiety sensitive youth. Using a
sample of panic disorder patients, Zvolensky and colleagues (2005) also found
that smokers with panic disorder reported higher levels of smoking to reduce
negative affect than their counterparts without such a history. These
cross-sectional studies are not capable of elucidating the direction of the effects.
Theoretically, coping-oriented smoking motives may have bi-directional effects,
influencing, and being influenced by, affective vulnerability. An initial investigation exploring this possibility was consistent with such an account (Gregor,
Zvolensky, Bernstein, Marshall, & Yartz, 2007), reporting that coping-oriented
motives were incrementally related to a variety of negative affective and cognitive
factors.
Overall, there are a variety of separate, but related, lines of inquiry indicating
panic psychopathology and a select number of pre-morbid risk factors are
meaningfully related to smoking behavior. These lines of work differ in their
focus, but broadly indicate that panic factors (full blown disorders and certain
pre-morbid risk factors) are related to abstinence duration during smoking
cessation outcome expectancies related to smoking, perceived barriers and
reasons for quitting, nicotine withdrawal symptom severity, and motivational
bases for smoking. Thus, it is most appropriate to conceptualize many of the
studied variables (e.g., anxiety sensitivity) as variable risk factors. Although
definitive prospective work has not been conducted to firmly establish temporal
precedence in many, if not most, of the investigations, theoretically, panic
variables would precede the smoking factors. It also is theoretically possible
that panic and panic-relevant risk factors may not necessarily developmentally
precede smoking, but nevertheless meaningfully influence the course and nature
of smoking behavior over time via many of the processes described throughout
this chapter. Further prospective work will delineate the possibility that these
panic-smoking relations may be transactional over development.
Future directions. As in the earlier sections of this chapter, a first observation
and recommendation for future research is to better understand the relations
between panic psychopathology and smokeless tobacco use. There is no empirical work completed in this domain to the best of our knowledge, leaving this
facet of the tobacco-panic linkage undocumented. Second, essentially all of the
existing work on panic psychopathology (and related factors) and smoking
behavior is focused on main effects. This approach seems appropriate given
the currently limited knowledge in the area, but represents only a first step in a
larger scientific effort. Future work is needed to increase understanding about
linkages among these factors beyond main effects by including moderational
and mediational tests of theoretically relevant variables. Similarly, the possibility that shared or common risk factors may underlie panic problems,
panic-relevant risk factors, and these smoking-related problems and processes
has received little theoretical or empirical evaluation. Third, the generalizability
of panic psychopathology and smoking research is limited in that it has focused
largely on adults from the U.S. Furthermore, there is very little information on
the nature of these relations among youth. Given the early age of onset of these
22
M. J. Zvolensky et al.
behaviors and their health relevance, as well as the international scope of this
public health problem, research development in these domains is needed.
Finally, little research has directly targeted panic vulnerability factors in smoking cessation interventions. Similarly, there is little work addressing smoking in
the context of panic-related treatments. Given the consistent empirical evidence
of bi-directional associations between these often comorbid behavioral problems, it is important to develop specialized treatments, as generic interventions
may not target the affective vulnerability processes functioning to maintain
smoking in this population. For example, it may be useful to integrate interoceptive exposure, cognitive restructuring, and psychoeducation exercises
developed for panic prevention and treatment programs with standard smoking
cessation strategies and nicotine replacement therapy. These therapeutic tactics
may be most effective when they target theoretically-relevant panic risk factors
like anxiety sensitivity in order to facilitate cessation. As a second illustration, it
may be useful to target smoking cessation as part of evidence-based panicproblem treatment strategies. While there have been some inroads made in this
domain, with successful case reports and pilot studies now being reported
(Zvolensky, Bernstein et al., in press; Zvolensky, Lejuez, Kahler, & Brown,
2003; Zvolensky, Schmidt et al., 2006), much work is yet to be addressed in this
domain.
Summary
The present chapter provides an updated review of extant empirical work
pertaining to the inter-relations between tobacco use and panic psychopathology. Although a relatively nascent area of research, a recent spate of empirical
evidence indicates that theoretically and clinically important associations exist
between tobacco use and panic psychopathology. Although promising, there
are a multitude of critical gaps in the research literature that need to be
addressed in future studies. We hope that such ongoing research may help
translate knowledge about basic processes to the development and dissemination of powerful clinical intervention strategies for tobacco users with
panic-related vulnerabilities or psychopathology.
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Zvolensky, M. J., Schmidt, N. B., Antony, M. M., McCabe, R. E., Forsyth, J. P., Feldner, M. T.,
et al. (2005). Evaluating the role of panic disorder in emotional sensitivity processes involved
with smoking. Journal of Anxiety Disorders, 19, 673686.
Zvolensky, M. J., Schmidt, N. B., Bernstein, A., & Keough, M. E. (2006). Risk-factor research
and prevention programs for anxiety disorders: A translational framework. Behaviour
Research and Therapy, 44, 12191239.
Zvolensky, M. J., Schmidt, N. B., & McCreary, B. T. (2003). The impact of smoking on panic
disorder: An initial investigation of a pathoplastic relationship. Journal of Anxiety
Disorders, 17, 447460.
Zvolensky, M. J., Schmidt, N. B., & Stewart, S. H. (2003). Panic disorder and smoking.
Clinical Psychology: Science and Practice, 10, 2951.
Zvolensky, M. J., Vujanovic, A. A., Bonn-Miller, M. O., Bernstein, A., Yartz, A. R.,
Gregor, K. L., et al. (2007). Incremental validity of anxiety sensitivity in terms of motivation to
quit, reasons for quitting, and barriers to quitting among community-recruited smokers.
Nicotine and Tobacco Research, 9, 965975.
The relationship between anxiety and alcohol use is a topic of great theoretical
and practical interest for both scientists interested in the nature and causes of
psychopathology and practitioners working with anxious and/or alcohol abusing clients. Although it has been clearly established that anxiety disorders and
alcohol use disorders are highly comorbid or co-occurring conditions (e.g., see
Kushner, Abrams & Borchardt, 2000a for a review), the relationship between the
symptoms or behaviors involved in each disorder (e.g., feelings of anxiety and
levels of alcohol use) has not been as extensively reviewed. This chapter will
review recent empirical evidence linking anxiety and alcohol at both the behavioral and disorder level to determine if similar conclusions can be derived
regarding their relationship from data at both of these levels of enquiry. We
will first briefly describe epidemiological studies linking anxiety disorders and
alcohol use disorders. Then we will examine some of the etiological theories of
the relationship between anxiety and alcohol use and their disorders, with a
review of the empirical evidence supporting each theory. Next, some specific
factors moderating and mediating the relationship between anxiety and alcohol
use will be explored, with an emphasis on individual differences and specific
processes involved in the relationship. A brief discussion of the differences
between factors affecting onset, maintenance, and relapse in the anxiety and
alcohol relationship will follow. The latest empirical evidence and thoughts
about treating both alcohol use and anxiety related problems will also be
reviewed. Finally, we conclude the chapter with some remarks about where the
field stands and directions that future research in this area might profitably take.
Brigitte C. Sabourin
Department of Psychology, Life Sciences Center, Dalhousie University, Halifax, Nova
Scotia, Canada, B3H 4J1, Tel: +902 494 3793, Fax: +902 494 6585
brigitte.sabourin@dal.ca
29
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B. C. Sabourin, S. H. Stewart
31
Alcohol abuse is characterized by recurrent and significant adverse consequences related to the repeated use of alcohol (p. 198), whereas alcohol dependence must include evidence of tolerance, withdrawal, or compulsive behavior
related to alcohol use (p.214). Alcohol dependence is considered more severe
than alcohol abuse and always overrides the latter diagnosis. As was mentioned
earlier, consumption levels are not considered in the diagnosis of either alcohol
abuse or dependence. On the other hand, for anxiety disorders, both symptom
levels (e.g., repeated panic attacks in the case of panic disorder) and/or negative
consequences of the symptoms (e.g., distress about having another panic attack
in the case of panic disorder) are considered in making a diagnosis.
32
B. C. Sabourin, S. H. Stewart
disorder (2.6 and 1.1, respectively), panic disorder with agoraphobia (3.6 and
1.4) and without agoraphobia (3.4 and 0.8), social phobia (2.5 and 0.9), a
specific phobia (2.2 and 1.1), and generalized anxiety disorder (3.1 and 0.9).1
The NCS (Kessler et al., 1997) also examined sex differences in comorbidity
between alcohol use disorders and anxiety disorders. Anxiety disordered women
and men do not differ significantly in their risk of developing alcohol dependence;
however, women with social phobia, simple phobias or post traumatic stress disorder
hive higher ORs of abusing alcohol than men with these anxiety disorders. Similarly,
the NESARC (Smith et al., 2006) reported ORs of alcohol use disorders and anxiety
disorders by race/ethnicity. Across all races/ethnic groups, there were significant ORs
of any anxiety disorder with alcohol dependence but not with alcohol abuse. However, the pattern of comorbidity across specific anxiety disorders reveals significant
racial/ethnic effects. For Whites and Blacks, the ORs for alcohol dependence and
anxiety disorders were significant across almost all anxiety disorders. The only
exception was that the OR for panic disorder with agoraphobia was significant for
alcohol abuse but not for alcohol dependence among Blacks. On the other hand, for
Native Americans and Hispanics, only a few of the anxiety disorders were significantly associated with alcohol dependence and none with alcohol abuse.
Two general conclusions can be made from the data reported across these
large-scale community surveys. First, the relationship between anxiety disorders
and alcohol dependence appears to be much stronger than between anxiety
disorders and alcohol abuse, with the ORs for dependence much more likely to
be significant than those for abuse. In other words, having a comorbid anxiety
disorder increases the chances of displaying the more severe type of alcohol use
disorder (dependence) moreso than the less severe type (abuse), suggesting a
gradient of effect relationship. . Second, the relationship between alcohol use
disorders and anxiety disorders differs between sexes and racial/ethnic groups.
Although alcohol use is generally more common among men than women (Paavola, Vartiainen, & Haukkala, 2004), alcohol abuse and anxiety disorders are
more closely related for women than for men. Furthermore, it appears that for
Whites and Blacks, anxiety and alcohol dependence are more closely associated
than for Native Americans and Hispanics. The following sections cover etiological models of the relationship between alcohol and anxiety, their maintenance,
and their relapse, in an attempt to explicate the high level of comorbidity between
anxiety disorders and alcohol use disorders observed in the epidemiologic surveys.
33
are three main hypotheses that have been put forward, with some evidence
supporting each hypothesis. First, there is some evidence that the associations
between anxiety and alcohol arise from common underlying variables, such as
common genetic or environmental factors, that cause both anxiety symptoms
and problematic alcohol use. Second, some believe that certain aspects of
problematic alcohol use, such as repeated experiences with alcohol withdrawal,
cause anxiety symptoms and ultimately an anxiety disorder. Finally, others
argue that anxiety symptoms cause alcohol misuse, culminating in an alcohol
use disorder. Evidence examining these three hypotheses is presented below.
34
B. C. Sabourin, S. H. Stewart
Second, results from some prospective studies suggest a possible common third
variable contribution to the alcohol anxiety relationship. For example, Zimmerman et al. (2003) found that remitted panic disorder and social phobia were as
important as current panic/social phobia diagnoses in predicting future alcohol
outcomes. That is, even individuals who were not currently experiencing sufficient
symptoms to receive any anxiety disorder diagnosis were at higher risk of developing
alcohol problems if they had ever been diagnosed with either panic or social phobia in
the past. These findings can be interpreted to suggest that a third underlying factor
(such as a common personality vulnerability or genetic predisposition) was driving
both the alcohol problem and the past or current anxiety disorder.
A 21-year longitudinal study (Goodwin, Fergusson, & Horwood, 2004)
found that once other factors were controlled (i.e., prior substance dependence,
concurrent major depression, and affiliations with deviant peers), the ability of
anxiety disorders to predict the development of alcohol dependence was no
longer significant. The study points to a number of possible third variables
including prior substance dependence which could contribute both to the
development of anxiety disorder (see Norton, Norton, Cox, & Belik, in press)
and of alcohol dependence (e.g., alcohol is consumed in larger quantities when
combined with other substances; Barrett, Darredeau, & Pihl, 2006). Unfortunately the study did not test which of these factors was most important in
explaining the link between anxiety and alcohol dependence.
Some factors that have emerged as possible contributors to the increased
vulnerability of developing comorbid anxiety and alcohol use problems include
either common genetic pre-dispositions (e.g., anxiety sensitivity), biological environment risk factors (e.g., fetal alcohol syndrome), or non-biological environmental
risk factors (e.g., disruptive familial environment; Merikangas, Stevens, & Fenton,
1996). Unfortunately, no research has yet confirmed one or more of these candidate
factors. More research needs to be conducted exploring these additional underlying
mechanisms before one can make conclusions about their influence.
35
with frequent and excessive alcohol use over time such that repeated alcohol
withdrawals actually sensitize this withdrawal-induced anxiety (Breese, Overstreet, & Knapp, 2005). This has often been referred to as the kindling-stress
hypothesis; that is, repeated withdrawals from chronic heavy drinking are
thought to worsen, or kindle withdrawal-induced anxiety.
A number of studies have also demonstrated increased norepinephrine
activity as well as hyperexcitability of the central nervous system, especially of
limbic structures, during alcohol withdrawal (Kushner et al., 2000a; Marshall,
1997). These are the same neural systems that have been implicated in panic
attacks and panic disorder, providing a possible physiological explanation for
the link between panic disorder and alcohol use disorders (Marshall, 1997).
A final area of research supporting the hypothesis that alcohol problems
cause anxiety involves prospective studies. One such study by Kushner, Sher,
and Erickson (1999), for example, found that a diagnosis of alcohol dependence
at baseline quadrupled the risk of developing an anxiety disorder three to six
years later. Prospective studies have also examined the relationship between
PTSD and alcohol abuse to ascertain whether heavy alcohol use can be a risk
factor for developing PTSD. It has been hypothesized that physiological and
neurochemical changes due to prolonged heavy alcohol use and/or past reliance
on alcohol to deal with life stressors at the expense of developing other coping
mechanisms may increase an individuals susceptibility of developing PTSD
after a traumatic experience (Brown & Wolfe, 1994; Stewart et al., 1998).
A prospective study by Acierno, Resnick, Kilpatrick, Saunders, and Best
(1999) found that a history of alcohol abuse increased the risk of developing
PTSD in rape victims almost three-fold (OR = 2.65) when compared to the
absence of this factor.
36
B. C. Sabourin, S. H. Stewart
& Carrigan, 2003; see also Kushner, et al., 2000a for a review). In addition,
Thomas and colleagues (2003) found that socially anxious individuals not only
reported that they drank to feel more comfortable in social situations, but that
they would actually avoid social situations if alcohol were unavailable.
As introduced earlier in this chapter, one possible criterion for establishing
causation (Chilcoat & Breslau, 1998) is a dose response, or gradient of effect
relationship: if anxiety causes alcohol use, one would expect that higher levels of
anxiety would be associated with higher levels of alcohol use. Studies have
found positive correlations between severity of PTSD arousal symptoms and
severity of alcohol use disorder symptoms (McFall, Mackay, & Donovan, 1992;
Stewart et al., 1998). Because correlation does not determine causation, one
must rely on laboratory-based studies, such as a study by Abrams, Kushner,
Medina, and Voight (2002), for evidence that induction of anxiety symptoms
causes heavier drinking. The study found that participants with social phobia
consumed more alcohol following an anxiety provoking activity (speaking in
front of a group) than a control activity (reading a book), presumably in an
effort to dampen the anxious feelings caused by the anxiety provoking activity.
Prospective research on non-clinical populations also supports a doseresponse relationship between anxiety and alcohol use. In a diary-based study
by Swendsen and colleagues (2000), moderate drinkers documented their daily
drinking and mood states for a one-month period. The study revealed that only
anxious feelings and not sadness or other negative affective states preceded and
predicted increased alcohol consumption. As can be observed above, findings
from correlational, laboratory-based experimental, and diary-based prospective research conducted with both clinical and non-clinical populations
converge to provide some evidence for a relationship between anxiety symptoms and alcohol use where anxiety precedes and contributes to increased
alcohol use.
Social anxiety appears to have a more complicated relationship with alcohol
use than do other types of anxiety, however. Specifically, some studies examining the relationship between social anxiety and alcohol consumption show a
positive relationship, whereas other studies show either no linear relationship or
even a negative relationship (Ham & Hope, 2005; Stewart, Morris, Mellings, &
Komar, 2006; Tran, Haaga, & Chambless, 1997). The negative relationship
between social anxiety and alcohol consumption may exist because socially
anxious individuals actually avoid the types of social situations that involve
drinking because of their social anxiety, thus leading to lower levels of alcohol
consumption (Stewart et al., 2006). Nonetheless, social anxiety has been found
to predict alcohol dependence, as well as problems caused by alcohol (Gilles,
Turk, & Fresco, 2006; Stewart et al., 2006). Thus, social anxiety does appear
related to alcohol-related consequences, even if it does not always predict
increased alcohol use.
Another criterion discussed by Chilcoat and Breslau (1998) as necessary for
causation is temporality. If anxiety causes increased or problematic alcohol use,
then anxiety symptoms should predate alcohol-related problems, and anxiety
37
38
B. C. Sabourin, S. H. Stewart
other variables (Baron & Kenny, 1986). A mediator variable, on the other hand,
explains how or why the relationship between a predictor and given criterion
(e.g., between anxiety and alcohol use) exists. That is, the mediator actually
accounts for the relationship between the two variables (Baron & Kenny).
Alcohol expectancies. A potential moderator variable between anxiety and
problematic alcohol use includes certain alcohol outcome expectancies (i.e.,
beliefs about the consequences of drinking alcohol). For anxious individuals
who self-medicate to avoid anxiety, an important aspect of the self-medication
hypothesis involves the notion that self-medicators anticipate anxiety, and that
they expect that alcohol will actually decrease their feelings of anxiety (e.g.,
Kushner, Sher, Wood, & Wood, 1994; Tran et al., 1997). Studies have shown
that tension reduction expectancies predict drinking frequency and quantity in
non-alcoholic drinkers with panic disorder (Kushner et al., 2000b) and comorbid problem drinking in women with PTSD (Ullman, Filipas, & Townswend,
2005). These results support the role of tension reduction alcohol expectancies
as a moderator: increased or problematic drinking occurs among anxiety disorder patients only when tension reduction alcohol expectancies are present.
Another methodology that has been employed to investigate the role of
alcohol outcome expectancies in the anxiety alcohol relationship is the experimental manipulation of expectancies via the placebo-controlled design. If
expecting alcohol were to induce a cognitive or placebo-induced anxiety reducing effect among anxious individuals, such an effect would provide additional
evidence for the contribution of alcohol expectancies in explaining the anxiety
alcohol relationship. The empirical evidence provided thus far has found mixed
results for this placebo anxiolytic effect. Some studies have found that the belief
that one was consuming alcohol, even when one was actually consuming a
placebo, was enough to lower feelings of anxiety among anxiety-disordered
patients (Abrams, Kushner, Lisdahl, Medina, & Voight, 2001; Lehman, Brown,
Palfai, & Barlow 2002). On the other hand, research by MacDonald, Stewart,
Hutson, Rhyno, and Loughlin (2001) conducted with participants high in
anxiety sensitivity did not support a cognitively-mediated tension reduction
effect of alcohol. The researchers actually found a reverse placebo effect,
where high AS participants in a placebo condition, who had expectations of
alcohol-induced tension reduction, but did not benefit from alcohols physiological tension-reduction properties, appeared to have even higher levels of
anxiety than participants in a control condition where they neither received
nor expected alcohol. Regardless of the direction of the placebo effect, all of
these findings do suggest a role for cognitive expectancy variables in accounting
for the effects of alcohol among anxious individuals.
A number of studies have examined specific aspects of alcohol expectancies
in individuals with social anxiety. For people high in social anxiety, expecting
that alcohol would decrease social anxiety or increase social assertiveness was
associated with both higher self-reported drinking quantities (Tran et al., 1997)
and higher alcohol consumption in a laboratory setting (Kidorf & Lang, 1999).
More general tension reduction expectancies, on the other hand, had no effect
39
40
B. C. Sabourin, S. H. Stewart
41
42
B. C. Sabourin, S. H. Stewart
increase the rate of anxiety disorders above the rate associated with alcohol use
only (Kandel, Huang, & Davies, 2001).
A diagnosis of an anxiety disorder combined with a drug use disorder
constitutes a significant risk factor for developing alcohol dependence (lifetime
OR =5.81; Kessler et al., 1997). This increased risk appears to be even higher
than the risk associated with being diagnosed with an anxiety disorder alone
(i.e. without a drug use disorder; lifetime OR = 1.85). Unfortunately, like many
epidemiological surveys, the National Comorbidity Survey does not break drug
use disorders down by drug type/class, which could further elucidate the drug
anxiety alcohol relationship. One possible explanation for this elevated risk
for alcohol dependence among those with comorbid anxiety drug use disorders is that problematic drug use, through the drugs potentially anxiogenic
effects, exacerbates the need to self-medicate with alcohol, resulting in increased
risk for alcohol dependence relative to those with non-comorbid anxiety
disorders.
43
feelings caused by PTSD may naturally remit with time. Thus, when individuals
drink in an attempt to numb or avoid these feelings, they may be preventing this
natural recovery from taking place, leading to maintenance of the anxiety
symptoms in the long run (Stewart et al., 1998).
44
B. C. Sabourin, S. H. Stewart
45
46
B. C. Sabourin, S. H. Stewart
47
Conclusion
Although there is ample evidence supporting the existence of a strong relationship between anxiety and its disorders, and alcohol use and its disorders, much
remains unknown regarding the nature of the relationship. More research
examining particular circumstances in which anxious individuals are more
48
B. C. Sabourin, S. H. Stewart
likely to self-medicate needs to be conducted, with a focus on potential differences in high-risk drinking situations across the various anxiety disorders. In
addition, there has been little research about protective factors that can
decrease anxious individuals needs to self-medicate their anxiety symptoms.
For example, a few studies have explored the role of self-efficacy in heavy
drinking among individuals with anxiety disorders (Burke & Stephens, 1997;
Gilles et al., 2006). Initial results suggest that it might be beneficial for treatments to incorporate specific strategies to increase anxious individuals feelings
of self-efficacy, especially about avoiding heavy drinking in particular high risk
situations (e.g., those involving anxiety). Increased knowledge about this and
other potential protective factors may be useful when designing specific treatments for comorbid populations (Burke & Stephens, 1997).
It has also been found that alcohol expectancies, drinking motives, and
anxiety sensitivity all moderate or mediate the relationship between anxiety
and alcohol use/abuse. In addition, these three variables have been found to
interact with or intervene with each other when explaining reasons and circumstances for increased and problematic alcohol use in anxious individuals (e.g.,
Stewart et al., 2001). More research exploring the interplay between these and
other moderating and mediating variables would provide deeper and more
complete understanding of the precise mechanisms through which anxiety
and alcohol use affect one another.
Finally, although research on treating and preventing comorbid anxiety
disorders and alcohol use disorders is still in relatively early stages, promising
approaches are emerging in this growing clinical research area. For example, in
prevention/early intervention, recent studies have shown promising results for
targeting personality risk factors directly (e.g., AS) in attempts to reduce both
emergent problematic drinking (Conrod et al., 2006; Watt et al., 2006) and
emerging anxiety disorder symptoms (Castellanos & Conrod, 2006). Recent
research aimed at developing truly integrated treatments for comorbid patients
that consider the interplay between anxiety symptoms and drinking behaviors
(Kushner et al., 2006) has also provided positive preliminary results. Treatment
research efforts should continue exploring ways to address the factors discussed
in this chapter (e.g., moderating and/or mediating factors) linking anxiety and
problematic alcohol use to improve the efficacy of treatments we have available
for comorbid patients.
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Illicit Drugs
The term illicit drug is used here in reference to any substance that is illegal,
with the distinction of illegal being specific to the United States.1 Such drugs,
as recognized by the Diagnostic and Statistical Manual of Mental Disorders,
Matthew T. Tull
Department of Psychology, University of Maryland, College Park, MD 20742, Tel: 301-4053281, FAX: 310-405-3223
MTull@psyc.umd.edu
1
Due to space limitations we do not consider legal drugs used in an illegal manner (e.g., pain
medications used without a prescription).
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Due to space limitations, only data pertaining to drug use disorders in general will be
presented. Readers interested in data pertaining to rates of drug abuse or dependence
separately across the anxiety disorder diagnoses are referred to Conway et al. (2006).
61
prevalence rates pertaining to specific illicit drug use disorders were not examined. Among respondents who met 12-month criteria for a DSM-IV anxiety
disorder of PD with agoraphobia, 10.58% also exhibited a 12-month drug use
disorder (4.65% drug abuse and 5.94% drug dependence). Rates of 12-month
drug use disorders for other anxiety disorders were: 6.32% (2.17% drug abuse
and 4.16% drug dependence) for PD without agoraphobia, 5.52% (2.59% drug
abuse and 2.94% drug dependence) for SAD, 4.08% (2.13% drug abuse, 1.95%
drug dependence) for specific phobia, and 8.06% (2.82% drug abuse, 5.24%
drug dependence) for GAD.
Finally, data from the NESARC has been used to examine differences in
racial/ethnic background across comorbid anxiety and drug use disorders.
Specific to abuse, Smith et al. (2006) found significant 12-month associations
between drug abuse and all anxiety disorders (with the exception of PD without
agoraphobia). No other significant 12-month associations between drug abuse
and anxiety disorders were found for any other racial/ethnic group, with the one
exception of a significant 12-month association between drug abuse and specific
phobia among Native American respondents. A greater number of significant
associations were found when examining the relationship between drug dependence and specific anxiety disorders across racial/ethnic groups. Significant
associations were found for drug dependence and all anxiety disorders examined (PD with and without agoraphobia, SAD, specific phobia, GAD) among
White respondents. Significant associations were found for drug dependence
and all anxiety disorders with the exception of specific phobia for Black/African
American respondents. Among Native American respondents, significant associations were found for PD without agoraphobia and SAD. Asian/AsianAmerican respondents demonstrated significant associations between drug
dependence and PD without agoraphobia, SAD, and GAD, and Latino respondents exhibited significant associations between drug dependence and PD with
agoraphobia, SAD, specific phobia, and GAD.
As mentioned previously, the NESARC is the first to provide comprehensive
data on the co-occurrence of specific anxiety disorders and illicit drug use
disorders. In general, though, limited data is available that examines drug use
within specific anxiety disorders. The one exception, however, may be PTSD, as
a number of studies have examined the co-occurrence of PTSD and illicit drug
use (for a review, see Chilcoat & Menard, 2003). We now move to a review of
this literature, followed by a review of the literature pertaining to drug use
within other anxiety disorders besides PTSD.
Posttraumatic stress disorder. Data from the ECA found that compared to
men and women without a diagnosis of PTSD, men with PTSD were 5 times
more likely to also exhibit a drug use disorder and women with PTSD were
1.4 times as likely to exhibit a drug use disorder (overall odds ratio of 2.2; Helzer
et al., 1987). In the NCS, Kessler, Sonnega, Bromet, Hughes, and Nelson (1995)
found that compared to men and women without a diagnosis of PTSD, men
with PTSD were approximately 2.97 times as likely and women 4.46 times as
likely to exhibit a drug use disorder. Giaconia and colleagues (1995, 2000)
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collected data from 384 18-year-olds as part of The Early Adulthood Research
Project (EARP) and found that compared to individuals without a history
of traumatic exposure, individuals with a lifetime diagnosis of PTSD were
8.8 times as likely to also meet criteria for a lifetime drug dependence diagnosis
and 14.14 times as likely to meet criteria for past year drug dependence.
Calhoun et al. (2000) assessed drug use among a sample of 341 veterans with
PTSD seeking treatment for PTSD. Opiate and marijuana use was reported by
the largest number of patients (23% and 20% respectively). Benzodiazepine use
was reported by 11% of patients, cocaine use by 8% of the patients, barbiturates by 5% of the patients, amphetamines by 3% of the patients, psilocybin by
3% of the patients, LSD by 1% of the patients, and PCP by 1% of the patients.
Other studies have produced similar findings in regard to the use of specific
drugs. For example, Saxon et al. (2001) found that incarcerated veterans with
PTSD were more likely to report a greater degree of cocaine and heroin use as
compared to individuals without a PTSD diagnosis. Tarrier and Sommerfield
(2003) assessed 120 civilians seeking treatment for chronic PTSD on their drug
use histories. Of the 120 participants, 17 used marijuana, 6 used sedatives, 4
used stimulants, 2 used a psychedelic, and 1 used cocaine. Further, in regard to
rates of drug use disorders among younger individuals with PTSD, Kilpatrick,
et al. (2000) collected data from a national sample of 4,023 adolescents (between
the ages of 12 and 17). They found that PTSD was significantly associated with
illicit drug use, including marijuana abuse and dependence and harder drug
abuse and dependence (e.g., stimulants).
Panic disorder and panic disorder-related symptoms. Moving beyond PTSD, a
number of studies have examined illicit drug use among individuals with PD or
PD-related symptoms, such as the experience of non-clinical panic attacks.
Biederman et al. (2005) examined the rates of comorbid disorders among 23
individuals with PD and found that 8% exhibited a comorbid psychoactive
substance use disorder. Among individuals with PD and major depression, 21%
exhibited a comorbid psychoactive substance use disorder. Further, Zvolensky,
Bernstein et al. (2006) examined lifetime associations between marijuana use,
abuse, and dependence and panic attacks in a representative sample of 4,745
individuals. They found a positive association between lifetime panic attack
occurrence and marijuana use, even when controlling for the effect of polysubstance use, alcohol abuse, and demographic variables (e.g., age, gender, etc.).
Bonn-Miller, Bernstein, Sachs-Ericsson, Schmidt, and Zvolensky (2007) also
examined the relationship between psychedelic (e.g., PCP, LSD, mescaline,
peyote, psilocybin, DMT) use, abuse, and dependence and lifetime panic attack
history within this same sample. Psychedelic abuse and dependence (although
not use) were significantly associated with a heightened risk for the experience
of lifetime panic attacks, controlling for demographic variables, polysubstance
use, alcohol abuse, and a history of major depressive disorder.
Deacon and Valentiner (2000) examined the relationship between panic
attacks and substance use within a sample of 279 college students. Students
with non-clinical panic attacks (n = 25) were significantly more likely than
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students without panic (n = 222) to report the use of drugs, such as sedatives
(not alcohol), cocaine, and stimulants. Further, among non-clinical panickers,
sedative use was not found to be related to distress about panic attacks, panic
attack frequency, the occurrence of unexpected attacks, or general anxiety or
depression symptoms. Valentiner, Mounts, and Deacon (2004) also investigated the relationship between panic attacks and illicit drug use in a sample of
399 incoming college freshman. Similar to Deacon and Valentiner (2000), they
found that non-clinical panickers (n = 47), compared to non-panickers
(n = 290), were significantly more likely to report lifetime use of sedatives,
stimulants, and opioids, but not tobacco, alcohol, cocaine, or hallucinogens. In
regard to specific rates of drug use among panickers, 12.8% reported lifetime
use of sedatives (not alcohol), 6.4% reported lifetime use of cocaine, 55.3%
reported lifetime use of marijuana, 34% reported lifetime use of stimulants,
21.3% reported lifetime use of opioids, and 23.4% reported lifetime use of
hallucinogens. Additional analyses were conducted by Valentiner et al. (2004)
to determine whether the relationships between panic and substance use differed as a function of gender or racial/ethnic background. Gender only served
as a moderator in the relationship between panic and cocaine use. In particular,
male panickers were significantly more likely to use cocaine than males without
panic. In addition, among non-clinical panickers, substance use was not due to
the number of panic attacks in the past year, panic attack symptom severity,
and the experience of unexpected panic attacks.
Other anxiety disorders. There is a dearth of studies on the relationship
between specific drug use disorders with SAD, GAD, OCD, and specific
phobia. More research is needed, especially given extant evidence that these
anxiety disorder diagnoses may be associated with heightened risk for the
development of illicit drug use disorders. For example, using data from the
ECA Study, Reiger et al. (1990) found that 18.4% of respondents with lifetime
OCD also exhibited a lifetime drug use disorder (11% for drug dependence and
7.4% for drug abuse). Further, this rate was significantly greater than what was
found among individuals without a diagnosis of OCD.
In regard to SAD, Kessler et al. (1996), in examining data from the NCS,
found that respondents with SAD were significantly at greater risk to exhibit a
12-month co-occurrence of drug dependence (OR = 3.2) and lifetime drug
dependence (OR = 2.6). Kessler et al. (1996) also provide data on GAD and
specific phobia. Respondents with GAD were at significantly greater risk to
exhibit lifetime drug dependence (OR = 3.8). Respondents with specific phobia
were at significantly greater risk to exhibit co-occurring 12-month (OR = 1.8)
or lifetime (OR = 2.5) drug dependence. Fewer studies have specifically examined the relationship between specific drug use and SAD; however, of note,
several studies have also found evidence of an association between SAD and
marijuana use (Buckner, Mallott, Schmidt, & Taylor, 2006; Buckner, Schmidt,
Bobadilla, & Taylor, 2006; Lindquist, Lindsay, & White, 1979; Lynskey et al.,
2002).
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Anxiety and illicit drug use disorder comorbidity in the context of a mood
disorder. It is important to recognize that anxiety disorders are also likely to cooccur with other disorders, especially mood disorders. Therefore, it will be
important for future studies to begin to examine the impact of mood-anxiety
disorder comorbidity on drug use behavior. Speaking to this potential impact of
mood-anxiety disorder comorbidity on drug use, Goodwin et al. (2002) examined the relationship between anxiety and drug use disorders among a sample of
130 individuals with a severe affective disorder (recurrent major depression,
bipolar disorder) to examine whether the presence of a comorbid anxiety
disorder diagnoses increases risk for the presence of a drug use disorder. They
found that, in general, among individuals with a severe affective disorder,
having an anxiety disorder was associated with a significantly increased risk
of a cocaine, sedative, stimulant, or opioid use disorder. In examining specific
anxiety disorders, they found that a) the experience of panic attacks increased
the likelihood of having a cocaine, sedative, stimulant, or opioid use disorder; b)
the presence of an OCD diagnosis increase the likelihood of stimulant use
disorder; c) a diagnosis of SAD increased risk for a sedative use disorder; and
d) and a specific phobia diagnosis was associated with increased risk for a
cocaine, sedative, stimulant, and opioid use disorder.
It is of note that a fourth possibility also exists. Specifically, anxiety disorder and drug use
disorder diagnoses may develop through a completely independent process. Goldenberg et al.
(1995) examined 181 participants in the Harvard Anxiety Research Project who had a history
of substance use disorders and anxiety disorders in order to test hypotheses pertaining to the
chronology of substance use-anxiety disorder comorbidity. They found, among individuals
with a primary anxiety disorder diagnosis, the anxiety disorder diagnosis was present for, on
average, 11.6 years before the onset of the substance use disorder. Further, substance use
tended to occur a mean of 9.6 years before the onset of a secondary anxiety disorder diagnosis.
Given the amount of time between the onset of the diagnoses, the authors concluded that there
is not an etiological connection between the disorders, but instead, the onset of these disorders
are guided by independent processes.
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Additional support for the hypothesis that the presence of an anxiety disorder increases risk for illicit drug use comes from findings of Lopez et al. (2005)
who found that, within their sample of 1747 young adults, the mean age of onset
for an anxiety disorder diagnosis was consistently lower than that for substance
dependence. In addition, an anxiety disorder diagnosis tended to occur before
the onset of substance dependence 80% of the time.
Common Third Variables that may Underlie Both Illicit Drug Use
and Anxiety Disorders
Much less research has examined the third hypothesis of third variables that
may function as a common underlying mechanism for both anxiety disorders
and illicit drug use, especially in regard to the identification of common neurobiological and psychological mechanisms for the relationship between anxiety
and drug use disorders. Two variables that are worthy of strong consideration
are neurobiology and individual difference variables, which we will review
below. First, however, it is also important to note that another important
third variable for future consideration is gene by environment interactions.
Although no current research has directly examined shared genetic transmission of anxiety and illicit drug use disorders, this is likely an important area for
further pursuit. Specifically, the interaction between life stress and a polymorphism in the regulatory region of the serotonin transporter gene may be a
particularly promising area of study. Indeed, although the preponderance of the
work in this area has focused on the development of depression, some emerging
research has separately identified the role of this interaction in the development
of anxiety (Kendler, 1996) and illicit drug use (see Kreek, Nielsen, Butelman, &
LaForge, 2005).
Neurobiology. One aspect of neurobiology that may be potentially relevant
to the development and maintenance of both anxiety disorders and illicit drug
use involves the hypothalamic-pituitary-adrenal (HPA) axis, which controls the
secretion of hormones for the pituitary and adrenal cortex. The HPA axis plays
a central role in mediating the bodys response to stress and anxiety and is
extremely sensitive to inputs from the limbic system and prefrontal cortex, two
brain areas that are important in modulating reinforcement and motivational
processes. The activity of the HPA axis is reflected in changes in serum or
salivary cortisol levels (de Kloet & Reul, 1987), and has been found to account
for differences in stress reactivity to physical and psychological laboratory
challenges (Kaye et al., 2004; Wetherell et al., 2006). Neurobiological models
of drug addiction hypothesize that dysregulated HPA axis functioning contributes to a state of chronic deviation of the regulatory system from its normal
operating level, resulting in increased reinforcing effects of illicit drugs (Koob &
Le Moal, 2001). More specifically, the HPA and brain stem stress circuits are
hypothesized to be recruited in feed forward loops during response to stress,
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such that the corticotrophin releasing factor (CRF) in the extended amygdala
drives norepinephrine systems in the pons-medulla of the brain stem, which in
turn drives CRF in the extended amygdala. The extended amygdala is thus
hypothesized to play a key role in regulating the HPA axis (i.e., stress response)
and subsequent recruitment of negative reinforcement behavior (Koob &
Le Moal, 2006), which may be especially relevant if substances are used for
self-medication of anxiety symptoms. As much of this work is focused more on
the relationship between stress and illicit drug use, as opposed to anxiety
disorders specifically, it will be important for additional work to target the
relationship between anxiety disorders and illicit drug use specifically. It is
important to note, though, that dysregulation of the HPA axis has been
found to play a role in the anxiety disorders (for a review, see Risbrough &
Stein, 2006) and especially in PD (e.g., Erhardt et al., 2006) and PTSD (e.g., de
Kloet et al., 2006; Yehuda, 2001) two anxiety disorders that have been found
to frequently co-occur with illicit drug use, suggesting that dysregulated functioning of the HPA axis may be common pathway at least for PD or PTSD and
illicit drug use. However, further research is needed to test this hypothesis.
Anxiety sensitivity. Anxiety sensitivity (AS) is an individual difference variable representing the tendency to fear anxiety-related sensations (e.g., increased
heart rate, shortness of breath) due to beliefs that they will have negative
somatic, cognitive, or social consequences (Reiss, 1991). Reiss (1991) originally
proposed AS as a predisposing personality factor for the pathogenesis of the
anxiety disorders, and research supports this, as demonstrated through the
finding of elevated levels of AS across the anxiety disorders, with the exception
of specific phobia (see Cox, Borger, & Enns, 1999). Although AS was originally
proposed as a vulnerability factor for the anxiety disorders in general, its role as
a specific vulnerability factor for PD has been examined most extensively.
Studies consistently find higher levels of AS among individuals with PD,
compared to individuals with other anxiety disorders (with the exception of
PTSD) and healthy controls (see Cox et al., 1999). Further, AS has been
predictive of the later development of spontaneous panic attacks (e.g., Schmidt,
Lerew, & Jackson, 1997, 1999), as well as fearful responding to biological
challenge tasks, such as hyperventilation and CO2 inhalation (Donnell &
McNally, 1990; Harrington, Schmidt, & Telch, 1996; Rapee & Medoro, 1994;
Schmidt & Telch, 1994; Telch, Silverman, & Schmidt, 1996; see also Zvolensky
& Eifert, 2001, for a review). Similarly, successful treatment of PD has been
found to be associated with corresponding reductions in AS following a
cognitive behavioral group for PD (Telch et al., 1993) and individual cognitive
behavior therapy (CBT) for anxiety medication discontinuation (Bruce,
Spiegel, Gregg, & Nuzzarello, 1995).
Research exploring AS as an underlying vulnerability for psychopathology
in general has also been conducted, producing evidence that AS may underlie
other psychiatric conditions as well, including depression (e.g., Otto, Pollack,
Fava, Uccello, & Rosenbaum, 1995; Taylor, Koch, Woody, & McLean, 1996;
Tull & Gratz, in press; Tull, Gratz, & Lacroce, 2006), borderline personality
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disorder (Gratz, Tull, & Gunderson, in press), and certain types of drug use
patterns (see Lejuez, Paulson, Daughters, Bornovalova, & Zvolensky, 2006;
Otto, Safren, & Pollack, 2004; Stewart & Kushner, 2001; Zvolensky & Schmidt,
2004). In regard to AS and drug use in particular, across the substance use
disorders, McNally (1996) predicted that those individuals high in AS should
specifically be at risk for drugs that include anxiolytic or depressive psychopharmacological effects as opposed to those with arousal properties (i.e.,
stimulants). However, research examining the role of AS in drug use is in its
infancy, and across substances, alcohol and tobacco use have been most extensively studied (see chapters in this book; for reviews, see also Stewart, Samoluk,
& MacDonald, 1999; Zvolensky et al., 2003). Few studies have been conducted
that specifically examine the relationship between AS and other drug use.
However, there is some evidence to suggest that elevated levels of AS may be
associated with certain drug classes (besides tobacco and alcohol).
Consistent with the relationship between arousal dampening drugs and AS,
individuals reporting both chronic back pain and high AS report greater use of
analgesic medications (Asmundson & Norton, 1995), and heightened AS has
been found to be associated with elevated use of anxiety medications in general
(Telch, Lucas, & Nelson, 1989). Bruce et al. (1995) examined successful benzodiazepine (Alprazolam) medication discontinuation in individuals receiving
treatment as usual or the same procedure together with CBT treatment.
While CBT significantly decreased anxiety and depression compared to control
at 6-month follow-up, across both groups successful drug discontinuation was
predicted by AS reduction from baseline to post-treatment. While McNallys
prediction has been generally supported regarding arousal dampening effects
(but see Forsyth, Parker, & Finlay, 2003), the prediction that individuals with
high AS should avoid arousal related drugs have not been confirmed to date.
No differences have been found in preferences for illicit stimulants (e.g., cocaine
or amphetamines) between high and low AS individuals (Norton et al., 1997;
DeHaas, Calamari, Bair, & Martin, 2001; Forsyth et al., 2003) or for other
stimulants such as caffeine (Stewart, Karp, Pihl, & Peterson, 1997). These
findings suggest that while AS may act as a risk factor for drugs with arousal
dampening effects, it does not act as a prophylactic against arousal producing
self-medication.
Research investigating the role of AS in marijuana use has provided mixed
results. Whereas marijuana use has been reported to correlate with high AS in
adolescents (Comeau, Stewart, & Loba, 2001), the opposite was found among
adults in which low AS correlated with marijuana use (Norton et al., 1997;
Stewart et al., 1997). In a recent investigation into adult tobacco users, marijuana users high in AS were at increased risk for more severe anxiety-related
symptoms (Zvolensky, Bonn-Miller et al., 2006), controlling for the effects of
cigarettes per day, alcohol use, and negative affectivity. In addition, AS has
been found to predict the severity of marijuana withdrawal symptoms among
young adult marijuana smokers, controlling for frequency of past 30-day
marijuana use, number of cigarettes smoked per day, alcohol consumption,
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This is consistent with Hayes and colleagues proposal to reconceptualize psychopathology, including substance use, as a behavior that serves an experientially avoidant function.
Experiential avoidance (defined as attempts to alter the form or frequency of
internal experience such as thoughts, emotions, and bodily sensations; Hayes,
Wilson, Gifford, Follette, & Strosahl, 1996) may be a particularly useful construct to examine in attempting to understand the pathway through which
heightened AS leads to both the pathogenesis of anxiety disorders and illicit
drug use. Experiential avoidance has been found to be associated with AS (e.g.,
Zvolensky & Forsyth, 2002), as well as a variety of anxiety disorder diagnoses
and anxiety disorder-related symptoms (for reviews, see Hayes, Luoma, Bond,
Masuda, & Lillis, 2006; Salters-Pedneault, Tull, & Roemer, 2004), as well as
substance use behaviors (Hayes et al., 1996; Stewart, Zvolensky, & Eifert,
2002).
Impulsivity (delay discounting). Impulsivity, defined as delay discounting, may
also provide a useful framework for considering the concurrent development of
anxiety disorders and illicit drug use. Traditionally, delay discounting has served
as a behavioral operationalization for understanding the construct of impulsivity,
which was developed following concern regarding the prevailing trait conceptualizations of the construct. Simply put, a delay discounting perspective considers
impulsive behavior to be the choice of a smaller, immediate reinforcer instead of a
larger, delayed reinforcer (Ainslie, 1975; Rachlin & Green, 1972). Taking this
approach, studies have shown that compared to non-users, illicit drug users are
more likely to select smaller amounts of immediate money instead of larger
amounts that are delayed (e.g., $5 today over $20 in 30 days; Coffey, Gudleski,
Saladin, & Brady, 2003; Kirby, Petry, & Bickel, 1999). In this way, this procedure
provides an analogue for real world behavior of illicit drug users where more high
impact yet delayed long-term goals (e.g., career development, relationship building) are sacrificed in favor of immediate gain in the form of drug use.
Complimenting this approach to reinforcers, delay discounting also may be
applied in its reciprocal form to aversive stimuli. In this case impulsivity
involves the selection of a larger, delayed aversive stimulus over a smaller, yet
immediate aversive stimulus. Said differently, this describes the tendency to put
off experiencing an aversive event, even though this delay will result in an
exacerbation of the negative consequences. A theoretical account of the relevance of this reciprocal approach to delayed discounting for SAD was provided
by McNeil, Lejuez, and Sorrell (2001), describing the tendency of individuals
with SAD to avoid potentially uncomfortable social interactions despite acute
awareness that this will result in considerably larger long-term consequences.
This approach is easily applied to other anxiety disorders as well. For example
in the case of PD with agoraphobia, an individual may choose to only leave
home with a safe person due to fear that of what will happen if alone in public
during a panic attack, thereby resulting in the more severe yet delayed consequences associated with a loss of independence in the service of avoiding
smaller yet immediate discomfort associated with leaving home alone.
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solving (e.g., Hien et al., 2004; Najavits et al., 1996; Zlotnick, Najavits, Rohsenow, & Johnson, 2003).
Concurrent Treatment of PTSD and Cocaine Dependence. Another treatment
specifically designed for individuals with comorbid PTSD and substance use
disorders is Back, Dansky, Carroll, Foa, and Bradys (2001) Concurrent Treatment of PTSD and Cocaine Dependence (CTPCD). This treatment consists of
16 individual 90-minute sessions. The treatment was designed by integrating
previously validated cognitive behavioral treatments for substance dependence
(Carroll, 1998) and PTSD (Foa, Rothbaum, Riggs, & Murdock, 1991; Foa &
Rothbaum, 1998). CTPCD involves psychoeducation on the link between
PTSD and cocaine dependence, coping skills training, relapse prevention skills,
and cognitive restructuring. Further, patients undergo in-vivo and imaginal
exposure in order to address their PTSD symptoms. In an initial examination of
CTPCD, Brady, Dansky, Back, Foa, and Carroll (2001) found that individuals
who completed treatment evidenced significant reductions in depressive symptoms, PTSD symptoms, and cocaine use severity.
Anxiety Sensitivity Treatment for Heroin Users. Targeting AS, as opposed to
any specific disorder, we (Tull, Schulzinger, Schmidt, Zvolensky, & Lejuez, 2007)
recently developed an acceptance-based behavioral treatment (the Anxiety Sensitivity Treatment for Heroin Users; AST-H) meant to be used in conjunction with
standard substance abuse treatment. Our treatment was designed to have specific
relevance for heightened heroin users with heightened AS. Previous research
(Lejuez et al., 2006) has demonstrated that heightened AS may increase risk for
substance use treatment drop-out among heroin users. In particular, a tendency to
fear of and unwillingness to have anxiety-related sensations may prompt individuals to attempt to avoid these sensations through the use of heroin. Therefore, we
developed a six session adjunctive treatment where individuals engage in interceptive exposure exercises in order to facilitate acceptance of, and tolerance for,
aversive internal sensations, with the goal of preventing the use of heroin for selfmedication of these sensations. In an initial examination of this treatments
effectiveness, the AST-H was found to result in reductions in AS, heroin cravings,
avoidance behavior, and emotion dysregulation (Tull et al., 2007). Improvements
were maintained when measured over one month post-treatment. Current efforts
are underway to replicate this finding within a randomized controlled trial.
Conclusion
Recent years have seen a rise in studies examining the co-occurrence of illicit
drug use and anxiety disorder diagnoses, and these studies provide convincing
evidence that illicit drug use is prevalent among individuals with anxiety disorder diagnoses. Further, the impact of this co-occurrence on psychological
functioning and physical health is clear. Yet, although studies have begun to
address the mechanisms underlying this co-occurrence, all anxiety disorders
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and forms of illicit drug use have not been examined equally. Therefore, future
research is needed to better understand the functional relationship between all
anxiety disorders and forms of illicit drug use, with the goal of informing the
development of novel and targeted interventions for this comorbidity, as well as
prevention efforts.
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Introduction
There is consistent evidence for the role of exercise in increasing longevity (Lee &
Paffenbarger, 2000; Lee, Hsieh, & Paffenbarger, 1995) and reducing risk for
coronary disease (Berlin & Colditz, 1990; Kohl, 2001), stroke (Wannamethee &
Shaper, 1992), diabetes (Chipkin, Klugh, & Chasan-Taber, 2001), obesity (Ross &
Janssen, 2001) and various cancers (Lee et al., 1995; Lee, Paffenbarger, & Hsieh,
1991; Lee, Paffenbarger, & Hsieh, 1992; Lee, Sesso, & Paffenbarger, 1999).
Evidence from a variety of sources also suggests that physical activity benefits
mental health (see for review Biddle, 2000; Stathopoulou, Powers, Berry, Smits, &
Otto, 2006). Several large cross-sectional population studies have demonstrated
that physical activity is associated with fewer symptoms of anxiety and depression
(Stephens, 1988), lower levels of stress, anger, and cynical distrust (Hassmen,
Koivula, & Uutela, 2000) as well as better social functioning and vitality among
persons with anxiety and substance use disorders (Schmitz, Kruse, & Kugler,
2004). Prospective studies have further shown that physical activity is associated
with a decreased risk of developing depression (Camacho, Roberts, Lazarus,
Kaplan, & Cohen, 1991; Paffenbarger, Lee, & Leung, 1994) even after controlling
for age, social economic status and educational level (Farmer, Locke, Mosciki,
Larson, & Radloff, 1998). Lastly, there is a growing body of research demonstrating the efficacy of exercise interventions for mental health (Stathopoulou et al.,
2006).
If effective for the prevention and treatment of anxiety disorders, physical
activity interventions would have a significant public health impact. In this
chapter, we review the literature on the relationship between physical activity
and anxiety. Specifically, we discuss findings from epidemiological, basic and
clinical studies, and consider potential mechanisms by which physical activity
Jasper A. J. Smits
Southern Methodist University, Department of Psychology, 6424 Hilltop Lane, Dallas, TX.
Tel: 214-768-4125, Fax: 214-768-0821
jsmits@smu.edu
81
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J. A. Smits et al.
83
HR Max (%)
RPE
Very Light
<20
<50
9
Light
2039
5063
11
Moderate
4059
6476
13
Hard
6084
7793
15
Very Hard
85
94
17
Maximal
100
100
20
Note: VO2R is oxygen reuptake reserve (i.e., the difference between resting
VO2 and maximal VO2); HRR is heart rate reserve (i.e., difference between
resting heart rate and maximum heart rate, where maximum heart rate is
220-age); HR Max is maximum heart rate; RPE is rating of perceived
exertion using a scale from 6 to 20 (Borg, 1998). Table is adapted from
ACSM guidelines for exercise testing and prescription (2006)
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J. A. Smits et al.
anchored to VO2R (i.e., the difference between resting VO2 and maximal VO2)
values. As can be seen in Table 1, intensity of exercise prescriptions can also be
guided by a persons heart rate reserve, maximal heart rate, or subjective ratings
of perceived exertion (i.e., RPE; Borg, 1998).
85
physical activity (78 minutes) compared to a control group receiving no intervention (12 minutes) after 2 months, although this effect was attenuated by
6 months. In the Project Active study, Dunn and colleagues (1999) showed that
interventions based on the Stages of Change model yield comparable benefits to
physical activity when utilized as a lifestyle or structured intervention, further
supporting the incorporation of the model in intervention strategies.
Indeed, research examining the TTM model has led to the development of
multi-component approaches to adoption of and adherence to exercise. When
assessing the feasibility of a treatment, it is important to consider
behavioral factors that may limit the likelihood of treatment compliance.
Multi-component interventions have been shown to be more effective than
single component interventions because no one strategy is effective for all
individuals (Ockene, Hayman, Pasternak, Schron, & Dunbar-Jacob, 2002;
Roter et al., 1998). Multi-component strategies include behaviors such as
developing a specific action plan for activity and targeting barriers to completion of the activity to increase the likelihood of exercise behaviors. This is
particularly true with psychiatric populations, where psychological aspects of
the disease process may increase barriers to exercise or create difficulty in
moving on to the next stage of behavioral change.
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J. A. Smits et al.
self-report and interviewer measures, while physical activity level and emotional
well-being were assessed by self-report. Of those suffering from anxiety
disorders (n = 573), 63% indicated that they were inactive. These inactive
individuals reported significantly lower quality of life across a number of health
and mental health domains relative to anxiety disorder sufferers who reported
regular exercise. Further, the associations remained significant after controlling
for theoretically-relevant variables, but they did not depend on age or gender.
In addition to evidence for the association between physical activity and general
emotional well-being, there is also survey data indicating that physical inactivity is
related to clinical levels of anxiety. Using data from the National Comorbidity
Survey (NCS), which comprised a probability sample of approximately 6,000
individuals between ages 15 and 54, Goodwin (2003) estimated the 12-month
prevalence of DSM diagnoses among persons who indicated that they exercised
regularly (60.3%) and compared the rate to those exercised occasionally, rarely
or never. Findings revealed a dose-response relationship between physical activity
and the likelihood of having an anxiety disorder. Specifically, physical activity was
associated with a significantly decreased likelihood of agoraphobia, panic attacks,
generalized anxiety disorder (GAD), specific phobia, and social phobia, even after
controlling for comorbid physical illness and demographic variables. Interestingly,
the relationship between physical activity and GAD was no longer significant after
additionally adjusting for comorbid mental disorders, suggesting that physical
inactivity may not be directly linked with GAD.
87
reduced VO2max. Specifically, the mean relative VO2max values for panic
disorder patients was 31.0 ml/kg/min (SD = 9.1) versus 37.6 ml/kg/min
(SD = 6.3) for non-psychiatric controls. In a follow-up study, the authors
(Meyer et al., 1998) showed that a 10-session exercise training program was
associated with significant improvements in VO2max values.
To clarify the link between panic disorder and fitness, Schmidt and colleagues
(Schmidt et al., 2000) designed a study to determine whether the relatively poor
cardiorespiratory fitness estimates among individuals with panic disorder may
be biased by elevated levels of anxiety symptoms. To this end, they randomly
assigned 27 panic disorder and 27 matched healthy control participants to a
submaximal bicycle ergometer test with or without heart rate feedback. This
study yielded several important findings. First, panic disorder participants
showed reduced cardiorespiratory fitness relative to non-psychiatric participants even after controlling for anxiety responses during the testing protocol
(26.4 ml/kg/min (SD = 11.4) versus 34.11 ml/kg/min (SD = 9.8), respectively).
Second, although anxiety sensitivity (i.e., fear of anxiety-related sensations), a
cognitive disposition that has been implicated in the onset and maintenance of
panic disorder (McNally, 2002), was not directly associated with poorer fitness,
it appeared to moderate the effects of diagnostic status and heart rate feedback
on cardiorespiratory fitness. Specifically, cardiorespiratory fitness was particularly poor among panic disorder suffers with elevated levels of anxiety sensitivity. Similarly, heart rate feedback during testing was only associated with poorer
fitness among individuals who reported elevated levels of anxiety sensitivity.
Collectively, these findings suggest that cardiovascular conditioning is impaired
among individuals with panic disorder, and emphasize the importance of considering anxiety sensitivity in investigations of the relationship between physical
activity and anxiety. Indeed, support for the linkage between anxiety sensitivity
and physical activity is growing. Recently, McWilliams and Asmundson (2001)
observed an inverse relationship between exercise frequency and anxiety sensitivity
in a non-clinical sample. Likewise, Smits and Zvolensky (2006) reported that
anxiety sensitivity mediated the relationship between physical inactivity and measures of panic severity in a community sample of individuals with panic disorder.
Further research regarding the linkage between exercise and anxiety sensitivity will
be discussed in the next section on the effects of exercise interventions on anxiety.
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J. A. Smits et al.
89
(e.g., 1230 minutes) intense exercise session (e.g., 70% of max HR; 6070%
VO2max, >6mm of blood lactate). Together, these findings suggest that single
exercise sessions result in anxiolysis in non-clinical participants.
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J. A. Smits et al.
maintenance of the disorder (McNally, 2002; Smits, Powers, Cho, & Telch,
2004). Cognitive-behavioral treatments for panic disorder target anxiety sensitivity by prescribing exposure to these feared sensations (i.e., interoceptive
exposure) in conjunction with cognitive interventions to help patients eliminate
catastrophic interpretations of these symptoms (Margraf, Barlow, Clark, &
Telch, 1993). Accordingly, in addition to the general benefits of exercise on
anxiety reduction, as documented for nonclinical samples, exercise also has the
potential to provide patients with exposure to feared sensations of bodily
arousal. Indeed, aerobic exercise induces many of the somatic sensations
(e.g., heart racing, rapid breathing, and sweating) that have shown to elicit
increased anxiety reactions in panic disorder patients (Rief & Hermanutz,
1996). The notion that exercise can serve as an interoceptive exposure procedure is also consistent with early reports that exercise can be anxiogenic for
these patients. For example, Cameron and Hudson (1986) observed significant
increases in subjective anxiety during submaximal exercise testing in 31% of
patients with panic disorder, but only in 7% of patient and non-patient controls. Similarly, two more recent studies reported that panic disorder patients
are more likely to prematurely terminate submaximal exercise testing compared
to non-clinical controls (Schmidt et al., 2000; Stein, Tancer, & Uhde, 1992).
Consistent with previous evidence that repeated exposure to biological provocation procedures is associated with clinical benefits for panic disorder
sufferers (van den Hout, van der Molen, Griez, Lousberg, & Nansen, 1987),
Broman-Fulks, Berman, Rabian and Webster (2004) developed a brief
exercise intervention to target anxiety sensitivity. The intervention consisted
of six 20-minute high-intensity (6090% maximal heart rate) sessions on a
treadmill. This intervention was compared to a similar protocol low-intensity
(below 60% of maximal heart rate) level aerobic exercise program. Neither
group received a specific treatment rationale or cognitive interventions. Results
revealed that the high intensity intervention was associated with significantly
greater reductions in anxiety sensitivity compared to the low intensity intervention (pre- to posttreatment raw score mean reductions of 9.14 and 2.88, respectively). Preliminary results from our own laboratories suggest that preceding
the interventions with a rationale emphasizing the importance of exposure to
reducing anxiety sensitivity coupled with coaching participants during and
following exercise sessions (i.e., what are you learning from this?)
may enhance the effect of this exercise intervention on anxiety sensitivity
(Smits et al., 2007).
In addition to the direct application of exercise as an interoceptive exposure
procedure to reduce anxiety sensitivity, exercise may also have general anxiolytic properties for patients with panic disorder. Using a counterbalanced
design, OConnor (2005) asked 10 women with panic disorder to complete a
maximal treadmill exercise test, 25 minutes of submaximal treadmill walking
(i.e., 65% of VO2 max), and 25 minutes of seated rest during three consecutive
sessions. Self-report of state anxiety was assessed 5 and 15 minutes before and
after each session. Consistent with hypothesis, patients reported significant
91
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J. A. Smits et al.
93
receptors, and specifically the 5-HT2C receptors. In a first study to test this
hypothesis, they compared marathon runners to sedentary controls on their
responses to meta-chlorophenylpiperazine (m-CPP), a 5-HT agonist that produces anxiogenic symptoms via 5-HT2C receptors (Broocks et al., 1999).
Marathon runners showed a diminished cortisol response to m-CPP, providing
evidence consistent with the idea that chronic exercise results in a reduced
hormonal reaction to m-CPP mediated by postsynaptic 5-HT2C receptors. In
a second study, the authors (Broocks et al., 2001) found that untrained
participants show a similar blunted cortisol response to m-CPP following a
10-week aerobic exercise program of moderate intensity. The authors
concluded that these data collectively suggest that the anxiolytic effects of
exercise may be mediated by the downregulation of 5-HT2C receptors.
The efficacy of benzodiazepines for reducing anxiety forms the basis of
research examining the potential of exercise on -aminobutyric acid (GABA)
function. Studies suggest that measuring the amount of time a rat spends in an
open field (open field locomotion) with or without treadmill exercise is a useful
animal model for studying the anxiolytic effects of exercise (Dishman,
Armstrong, Delp, Graham, & Dunn, 1988; Morgan, Olson, & Pedersen, 1982;
Royce, 1977). Injections of GABA into the nucleus accumbens septi (NAS)
reduces open field locomotion and injections of a GABA antagonist into
the NAS increases locomotion in rats (Jones & Mogenson, 1980a; Jones &
Mogenson, 1980b; Jones, Mogenson, & Wu, 1981). Since exercise also increases
open field locomotion in rats (Tharp & Carson, 1975); (Weber & Lee, 1968),
Dishman and colleagues (1996) have posited that exercise may reduce anxiety
by the downregulation of GABAa receptor density in the corpus striatum.
Consistent with this hypothesis, they found that voluntary exercise in rats
increased open field locomotion with a corresponding GABAa downregulation
(Dishman et al., 1996). Human studies are needed to test the hypothesis that
exercise anxiolysis in humans can be accounted for by GABAa downregulation
or other changes in central neurotransmitter function.
Sleep Restoration
Improved sleep as a proposed mechanism of change first emerged with the
delayed onset hypothesis, or the observation that antidepressant drugs rapidly
change plasma levels and sleep parameters (4872 hours), and that corresponding mood and anxiety changes in the weeks following (Chen, 1979; Ehlers,
Havstad, & Kupfer, 1996; Hyttel, 1994; Kupfer et al., 1994; Shipley et al.,
1984). There is also evidence that pharmacologic treatment of sleep symptoms
improves depression outcomes (Fava et al., 2006). Moreover, several studies
have now shown that exercise training programs are associated with significant
improvements in self-reported sleep quality (King, Oman, Brassington, Bliwise,
& Haskell, 1997; Singh, Clements, & Fiatarone, 1997). Interestingly, some
94
J. A. Smits et al.
findings converge to suggest that changes in slow wave sleep (SWS), which
occurs during restorative stages 3 and 4 of the sleep cycle, may be particularly
relevant to the anxiolysis following exercise. Specifically, reduced SWS is ubiquitous among anxiety disorder sufferers (Arriaga & Paiva, 1990; Arriaga et al.,
1996; Bourdet & Goldenberg, 1994; Fuller, Waters, Binks, & Anderson, 1997)
and exercise appears to enhance SWS (Horne, 1981; Shapiro, Griesel, Bartel, &
Jooste, 1975). There is some controversy with respect to the mechanism underlying the effects of exercise on SWS. Some studies suggest that it may be the
elevation in body temperature created by exercise that may be responsible for
sleep effects (Atkinson & Davenne, 2006; Horne & Moore, 1985; Horne &
Shackell, 1987; Horne & Staff, 1983). However, other studies show that low
intensity activity without a corresponding increase in body temperature can
also increase SWS (Naylor et al., 2000). Also, well-controlled studies show that
the anxiolytic effects of acute exercise are not solely due to body temperature
(Youngstedt, Dishman, Cureton, & Peacock, 1993).
Exposure
Recently, Stathopoulou and colleagues (2006) proposed that, among other
effects, exercise may exert positive effects on mental health by teaching persistence in the presence of negative somatic or emotional states. Indeed, the
modification of some of the self-perpetuating patterns in affective disorder
95
96
J. A. Smits et al.
2006b). Other elements of exercise dose that warrant further study are intensity
and duration.
In addition to exercise dose, it is important to determine the relative importance of exercise type. There is currently a paucity of available data on the
effects of anaerobic exercise (resistance training) for anxiety. Findings
from the depression literature indicate that resistance training may be equally
effective compared to aerobic activity in reducing symptoms of depression
(e.g., Doyne et al., 1987; Martinsen et al., 1989). Support for the use of
anaerobic exercise for depression was further strengthened by a recent study
completed by Singh and colleagues (Singh et al., 2005). They demonstrated that
high intensity progressive resistance training (PRT) (80% maximum load) was
more effective in treating depression than lower intensity PRT (20% maximum
load). Perhaps more important was the finding that the effects of PRT on
depression reduction were accounted for by expectancy in the low intensity
condition but not in the high intensity condition, suggesting that anaerobic
exercise, when prescribed at the higher doses, offers more than a placebo effect.
An important implication of these findings is that resistance training may be an
alternative for patients for whom aerobic activity may be inappropriate or for
those who do not have the initial motivation for aerobic activity.
When examining the utility of new interventions, it is important consider
issues related to effectiveness in addition to efficacy. It remains to be seen how
exercise is best integrated within provider networks. Within specialty care,
exercise interventions may emerge as another adjunctive clinical tool that has
the advantage of providing a broad spectrum of health benefits in addition to its
benefits on mental health (Stathopoulou et al., 2006). In primary care, exercise
may emerge as a more fundamental intervention that can be prescribed by the
primary care physician or provider team. Specifically, exercise has a potential
for targeting many mental and physical health problems simultaneously. In this
application, exercise is likely to bring with it all the challenges of any health
promotion intervention. Adherence to exercise recommendations has been low
in the United States (Schoenborn, Adams, Barnes, Vickerie, & Schiller, 2004);
although there is some evidence suggesting that exercise for mental health
benefits may fare better than when prescribed for improving physical health.
The use of exercise interventions for anxiety disorders has one clear advantage
over exercise for general health promotion. Unlike exercise interventions that
are prescribed for the prevention of health problems, exercise interventions for
treating anxiety disorders are linked with immediate benefits (i.e., acute bouts
of exercise are associated with significant changes in anxiety). As reported by
Christensen-Szalanski and Northcraft (1985), adherence to recommended
health behavior changes is greater when there is direct symptom reduction
that is linked with the behavior change. There also appears to be wide
acceptance of nontraditional treatment strategies for mental health among
individuals suffering from mood and anxiety disorders (Kessler et al., 2001).
Indeed, exercise interventions have the potential of avoiding the social stigma
associated with other mental health interventions (Sirey et al., 2001). Although
97
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Introduction
The major focus of this chapter is to identify future research directions for
advancing knowledge about two phenomena, anxiety and insomnia, which
are highly prevalent, co-existent problems in humans. Despite this universal
observation across different cultures, the medical field has a poor understanding of the pathophysiology and causal relationships between anxiety
and insomnia. The physiological and neurobiological relationships between
anxiety and insomnia remain one of medicines mysteries. Given the prominence and relevance of these co-occurring complaints among individuals
seeking medical care, the lack of research is somewhat surprising and may
be a by-product of conceptualizing anxiety and insomnia as simply nonspecific manifestations of most systemic diseases. Such attributions impede
the development of new treatments that can improve appreciably the health
and well-being of not only patients with primary insomnia and anxiety disorders but also individuals with cancer, metabolic, and other multi-system
medical diseases.
The goal of this chapter is to encourage clinicians and investigators to think
about anxiety-insomnia from different theoretical, even highly speculative
perspectives, with the hope that new areas of research will be undertaken by
the research community. We understand that some ideas regarding future
research directions are not necessarily logical next step studies, but rather,
areas of high-risk investigation that in their own right (and in the opinion of the
authors) may lead to an improved, understanding of the anxiety-insomnia
coupling.
Thomas W. Uhde
Department of Psychiatry and Behavioral Sciences, Medical University of South
Carolina (MUSC), 67 President Street, 5 South, Charleston, SC
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Definitions
Anxiety and insomnia are multidimensional phenomena that largely rely on
impairment criteria to achieve status as a disorder. There are two primary classification systems used by clinicians for the diagnosis of anxiety and sleep disorders:
Diagnostic and Statistical Manual (DSM-IV) and Tenth Revision of the International Classification of Diseases (ICD-10). While the Diagnostic and Statistical
Manual subdivides the anxiety disorders into a number of subtypes, the essential
feature of the anxiety disorders is impairment in work or social function or
ongoing distress as a result of the condition. For the purposes of this chapter,
unless otherwise indicated by reference to a specific anxiety disorder (e.g. panic
disorder), we are referring to the overall category of the anxiety disorders.
For the purposes of this chapter (and consistent with the conceptualization of
most sleep experts), insomnia refers to the subjective experience of having restless
and un-refreshing sleep, including difficulty falling asleep, multiple nocturnal
awakenings, or early morning waking. Later in this chapter, we make specific
distinctions between the subjective experience of insomnia and absolute sleep
restriction (i.e. insufficient amount of objective EEG sleep). The rationale for
underscoring this point is that there may be a large gap between subjective
experiences of sleep duration versus objective criteria of the hours of sleep per
night or sleep efficiency (i.e. the percent of time in bed when the person is actually
sleeping). In fact, a characteristic of many individuals suffering from insomnia
may be the lack of objective evidence of profound restricted sleep by either
polysomnography or multiple sleep latency testing (MSLT), despite the perception of having had little or no sleep. Thus, for the purposes of this chapter,
insomnia refers to a subjective experience of poor quality of sleep, which may or
may not be associated with an actual decrease in the normal amounts of sleep.
Theoretical Models
The high prevalence of co-morbid insomnia in primary anxiety disorders and
co-morbid anxiety symptoms in primary insomnia suggest an important underlying relationship between these clinical entities. However, using cross-sectional
methods, it is also known that anxiety symptoms, including the cognitive
process of worry, and insomnia are not 100% co-existent in all phases of illness
in either patients with primary insomnia or any primary anxiety disorder. These
observations can be explained on the basis of three theoretical constructs: a)
anxiety (or a diagnostic subtype) and primary insomnia represent a single,
spectrum disorder with a common diathesis (and predictable evolution of
symptoms) (see Fig. 1); b) anxiety and insomnia are separate and distinct
pathological conditions, each of which cause, permit, or promote the downstream development of secondary complications (Fig. 2) and c) anxiety and
insomnia are each caused by another critical, independent factor (Fig. 3). Each
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Fig. 1 In the single spectrum disorder model, anxiety (or a diagnostic subtype) and insomnia
represent the same disorder with a common diathesis and predictable evolution of symptoms.
In this model, the common underlying pathological process (i.e., neurobiological abnormality) leads to different symptoms or components (e.g. anxiety or insomnia) of the illness
Fig. 2 In the different disorders with secondary complications model, anxiety and insomnia are
separate and distinct pathological conditions with different underlying neurobiological
abnormalities. Early stages of the disorder may reflect this distinction, while later stages
show increasingly similar symptoms (e.g. anxiety and insomnia) due to the downstream
development of secondary complications
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of these theoretical models might explain high co-morbid rates of insomnia and
anxiety observed in patients seeking treatment for an anxiety disorder or
primary insomnia.
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Fewer studies have specifically assessed the age of onset for insomnia. In
one retrospective analysis of adolescents from the ages 13 to 15 years,
Johnson et al. (2006) reported a median age of onset for insomnia at age 11
(IQR = 5 years). Although this study found a relatively young age of onset
for children identified specifically with insomnia, most other studies with
children assess individuals with unspecified sleep problems that includes
insomnia, but could also include numerous other difficulties surrounding
sleep (Paavonen, Solantaus, Almqvist, & Aronen, 2003; Gregory &
OConnor, 2002; Johnson, Chilcoat, & Breslau, 2000), making it difficult
to draw clear conclusions about age of onset for insomnia.
B. Gender: A second factor that could distinguish anxiety and insomnia as a
single spectrum disorder versus two separate disorders is gender distribution.
With respect to both insomnia and anxiety, data suggest a similar gender
distribution for these two disorders. Anxiety, for example, is nearly twice as
prevalent in women as in men (Kessler et al., 1994, 2005). Although not as
consistent as the anxiety data, most studies report higher prevalence rates for
females than males, with female gender as a strong risk factor for insomnia
(Ford & Kamerow, 1989; Mellinger, Balter, & Uhlenhuth, 1985; Bixler,
Vgontzas, Lin, Vela-Bueno, & Kales, 2002; Zhang & Wing, 2006).
C. Symptoms and Sleep EEG: Insomnia, as a subjective sleep complaint, is
reported by many patients with anxiety disorders. The report of insomnia
is so prevalent among patients with anxiety disorders that it is widely
assumed among clinicians, and even by most anxiety disorder specialists,
that the treatment of core anxiety symptoms in anxiety disorder patients will
be associated with parallel improvement in sleep quality (see discussion).
Some anxiety disorders, however, appear to be more commonly associated
with insomnia and two specific anxiety disorders, panic disorder and generalized anxiety disorder, deserve special mention insofar as they appear to
share important but different symptom characteristics compared with
patients with primary insomnia.
Patients with generalized anxiety disorder often have subjective complaints that are nearly identical to those reported by patients with primary
insomnia. These include worrying about obtaining good quality or sufficient
amounts of sleep and problems falling or maintaining sleep. Patients with
primary insomnia, essentially by operational criteria, report almost identical
sleep complaints, but, for reasons that remain unclear, experience their
complaints within the context of a sleep problem, rather than within the
context of a mental health problem. Patients with GAD and primary insomnia typically report symptoms of physiological hyperarousal and increased
vigilance (feeling keyed up) with intermittent fatigue and disturbances in
concentration and memory. There are also nearly identical polysomnographic findings; sleep architecture and REM measures are normal whereas
both syndromes have EEG evidence of increased sleep latency and disturbances in maintaining sleep (for reviews, see Papadimitriou & Linikowski,
2005; Uhde, 2000).
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1997). Breslau, Roth, Rosenthal, and Andreski (1996) also found that a
history of insomnia increased the risk for developing anxiety compared to
individuals with no history of insomnia (OR=1.97, 95% CI 1.083.60).
2. Anxiety, with secondary insomnia.
Other evidence supports the course of illness progression from primary
anxiety to secondary insomnia. Ohayon and Roth (2003) retrospectively
assessed the temporal relationship between insomnia and anxiety in a
large, multinational European, general population study. In this study,
current severe insomnia was the strongest predictor of a past psychiatric
history (OR=5.8, 95% CI 2.414.0). Further evidence demonstrating an
illness progression from anxiety to insomnia included the finding that the
onset of insomnia preceded the development of anxiety in only 18% of the
cases, while the onset of anxiety preceded the insomnia in more than 43%
of the cases. In another retrospective analysis of a community-based
sample of adolescents from the ages 13 to 15 years, Johnson et al. (2006)
sought to assess the directionality of association between insomnia
and psychiatric disorders including anxiety and depression. This study
reported a high prevalence rate of insomnia in individuals with a
history of anxiety that varied between 24% and 43% depending on the
specific anxiety disorder. Additionally in 73% of the individuals that
were co-morbid for anxiety and insomnia, the anxiety disorder preceded
the onset of the insomnia. Risk associated with either anxiety or insomnia
by the prior onset of the other disorder was also assessed to evaluate
directionality. This analysis revealed that a prior anxiety disorder increased
the risk of subsequent insomnia more than 3 fold, but that prior insomnia
was unrelated to the later development of an anxiety disorder.
E. Neuroanatomy & Pharmacology: Any attempt to examine the relationship
between anxiety and insomnia should consider the neuroanatomical substrates and related neurotransmitter-neuromodulatory receptor systems that
mediate wake versus sleep states, keeping in mind that alarm mechanisms
are likely to influence both wakefulness and sleep. This is based on observations that states of fear (Uhde 2000) can take place during sleep and wakefulness. Neither insomnia nor anxiety, therefore, necessarily reflect
disturbances in those neurobiological systems that mediate either wakefulness or sleep per se. In fact, neuroreceptor-neurotransmitters that mediate
alarm functions might represent a third factor that contributes to the high
co-morbidity of chronic insomnia in many anxiety disorders (see Fig. 3).
Keeping these theoretical constructs in mind, we briefly review the neuroanatomy of wakefulness-promotion and sleep-promotion in relation to those
neurotransmitter and neuropharmacological systems most commonly implicated in anxiety and insomnia.
1. Wakefulness-Promotion versus Sleep-Promotion
Wakefulness is mediated in part by midbrain and pontine-acetyl cholinergic, pontine locus ceruleus-noradrenergic, reticular formation system
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al., 1998), and open field (Parks, Robinson, Sibille, Shenk, & Toth, 1998)
tests. In humans, fenfluramine, a 5-HT releasing agent, induces both
anxiety and increases in blood cortisol. Of interest, over-activity of the
hypothalamic-pituitary-adrenal (HPA) axis is associated with some types
of severe insomnia (for review, see Roth, Roehrs, & Pies, 2007).
Drug Action: Similar to benzodiazepines, selective serotonin reuptake inhibitors (SSRI) are widely used by clinicians to treat most of the
anxiety disorders. And, trazodone, a tetracylic SSRI with 5-HT2
antagonist effects, may be the most frequently prescribed medication
for the treatment of insomnia by psychiatrists and primary care physicians. There are limited data regarding the secondary improvement
in insomnia following the targeted treatment of anxiety (or vice versa).
It is known that older patients with anxiety disorders (60 years of age
with mainly GAD) show decreased change scores on the Pittsburgh
Sleep Quality Index (PSQI), suggesting that quality of sleep improves
after the targeted treatment of anxiety in elderly patients (Blank et al.,
2006). Not all anxiety disorders (e.g. PTSD), however, show convergent and parallel improvements in anxiety symptoms and insomnia (or
sleep efficiency on polysomnography) when treated with SSRIs;
moreover, responses to some SSRIs may be either ineffective or
actually induce insomnia in PTSD, people with primary insomnia or
healthy subjects (Davis, Frazier, Williford, & Newell, 2006; Winokur
et al., 2001). Thus, while the SSRIs play a crucial role in the treatment
of many anxiety disorders, including those wherein sleep problems are
a core feature, the effects of these same agents on the treatment of
insomnia appear to be less predictable.
F. Other Third Factors: An important question that remains to be answered is
whether sleep deprivation is a contributing factor to insomnia and/or anxiety.
Contrary to popular belief, there is a lack of good evidence for significant sleep
loss in insomnia. Despite the fact that insufficient sleep is a hallmark feature of
insomnia, there is little data demonstrating actual sleep loss or sleep restriction
in individuals reporting insomnia. Sleep polysomnography (PSG) documents
this lack of relationship between subjective reports of insomnia and objective
measures of poor sleep including reduced sleep time. In general, individuals
with insomnia underestimate sleep time compared to actual sleep time recorded
by PSG. For example, Rosa and Bonnet (2000) reported no relationship
between the subjective experience of insomnia and poor EEG sleep, defined
by increased sleep latency or decreased efficiency. Specifically, chronic insomniacs reported significantly worse laboratory sleep compared to controls, while
objective EEG-assessed sleep revealed little difference between the groups.
Means, Edinger, Glenn, and Fins (2003) who also assessed individuals with
insomnia and compared them to normal sleepers corroborate the findings of
Rosa and Bonnet (2000) and go further to describe that insomniacs show a
wide range of sleep misperception, from considerable underestimation to both
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accurate and overestimation of sleep time. In all, these studies suggest that
insomnia is a complex condition associated with factors that extend beyond
reduced sleep time.
Recent findings from our anxiety, stress and trauma laboratory also
suggest a difference between subjective reports of sleep duration (i.e., sleep
quantity) and subjective experience of sleep quality. We administered the
Pittsburgh Sleep Quality Index (PSQI) to a small group of individuals with
motor vehicle accident-related PTSD. The PSQI is a widely used, valid and
reliable instrument designed to measure sleep disturbance through seven
components including sleep quality, sleep latency, sleep duration, habitual
sleep efficiency, sleep disturbances, use of sleeping medications, and daytime
dysfunction (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). To
achieve a pure score for sleep quality (i.e., score that excludes sleep quantity)
we eliminated the two components of the sleep efficiency domain (i.e., sleep
duration and habitual sleep efficiency) from the overall PSQI score (Cole et
al., 2006). We then correlated this modified score (i.e., sleep quality) with
subjective reports of average sleep duration (i.e., amount of sleep in minutes)
and found no relationship between these two variables (r = 0.20;
F1,26=1.04, p=0.32). Our findings in this small group of anxious individuals
demonstrate an apparent distinction between sleep quantity and quality and
suggest that individuals suffering from anxiety who report poor sleep may
not have a reduction in sleep duration (i.e., restriction/deprivation).
Although limited data exists concerning the effects of sleep deprivation on
insomnia and anxiety, the available evidence suggests that sleep deprivation or
restriction could have opposing effects on insomnia or anxiety, findings that
support a clear distinction between these 2 disorders. On one hand, sleep
deprivation/restriction has shown positive results in people with insomnia,
while no consistent benefits have been shown for sleep deprivation in individuals diagnosed with anxiety. Specifically, sleep deprivation is associated with
an increase in anxiety symptoms in healthy individuals and has been shown to
worsen anxiety in patients with some but not all anxiety disorders. Roy-Byrne,
Uhde, and Post (1986) assessed depression and anxiety levels after one night of
total sleep deprivation in patients with panic disorder who were not currently
depressed. Individual responses of panic patients to sleep deprivation varied,
with a subset of panic patients (7/12 [58%]) demonstrating a worsening of
anxiety and 4 of the 12 panic patients (33%) experiencing a spontaneous panic
attack the day following the sleep deprivation procedure. Labbate et al. (1997)
also assessed the effects of sleep deprivation on anxiety and reported a
worsening of anxiety symptoms after sleep deprivation in a small sample of
panic (n=5) patients. In this study, 3 of the 5 panic patients experienced at
least one panic attack the morning after sleep deprivation, while none of the
control subjects experienced sleep deprivation-induced panic. With respect to
other anxiety subtypes, one night of sleep deprivation revealed inconsistent,
and for some negative, effects in patients with primary OCD (Joffe & Swinson,
119
1988; Labbate et al., 1997), social phobia (SP) and generalized anxiety disorder (GAD; Labbate et al., 1998).
Several studies describe the positive effects of sleep deprivation/
restriction on insomnia and suggest its potential utility in treating this disorder. In one study (Stepanski, Zorick, Roehrs, & Roth, 2000), sleepiness
and total sleep time for primary insomniacs was significantly increased,
compared to baseline, during the recovery night following one night of
total sleep deprivation. In addition, post-deprivation sleep measures in the
insomniacs were comparable to the age- and sex-matched normal sleeper
controls.
Discussion
Certainly, the collective data reviewed in the aforementioned sections argue
against the idea that anxiety and insomnia are entirely separate disorders with
distinctly different neurochemical disturbances. However, it is impossible without prospective studies, conducted in at-risk populations, to ascertain whether
these neurobiological findings represent different phases of a common diathesis
(Fig. 1), different disorders with coupled downstream abnormalities (Fig. 2), or
the consequence(s) of unknown other endogenous and/or external/exogenous factors (Fig. 3).
Given the prevalence of insomnia reported by patients with anxiety disorders
(Brown & Uhde, 2003; Craske & Tsao, 2005; Hoehn-Saric, 1981; Mellman &
Uhde, 1989, 1990; Saletu et al., 1997; Uhde, 2000), the portfolio of polysomnography and related sleep research studies in patients with anxiety disorders is
fairly modest in number. The greatest amount of polysomnography and related
sleep research has been conducted in panic disorder (PD), post-traumatic stress
disorder (PTSD), generalized anxiety disorder (GAD) and, to a lesser extent,
obsessive-compulsive disorder (OCD) (Dow, Kelsoe, & Gillin, 1996; Engdahl,
Eberly, Hurwitz, Mahowald, & Blake, 2000; Hurwitz, Mahowald, Kuskowski,
& Engdahl, 1988; Papadimitriou & Linkowski, 2005; Mellman, 1997; Ross
et al., 1994; Sheikh, Woodward, & Leskin, 2003; Uhde et al., 1984; Uhde,
2000). While sleep disturbances are a core and distinguishing feature of
PTSD, the anxiety disorders of GAD and PD, especially those patients with
sleep-nocturnal panic attacks (Craske & Tsao, 2005; Cortese & Uhde, 2006;
Mellman & Uhde, 1989), appear to share particularly poignant characteristics
with primary insomnia patients in terms of symptomatology, co-morbidity,
pharmacologic treatment response, and, sleep EEG measures. Because symptoms of psychic distress, worry, difficulty concentrating, feelings of jitteriness, agitation, and muscle tension are almost universally reported in part or
whole by patients with generalized anxiety disorder and primary insomnia, it is
not surprising that GAD was found to be the most prevalent co-morbid anxiety
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T. W. Uhde, B. M. Cortese
disorder assessed in a large general population study of individuals with insomnia complaints (Ohayon, Caulet, & Lemoine, 1998).
Taken together, these observations suggest that any attempt to further
dissect the theoretical models in a prospective manner should give priority to
the systematic investigation of patients with primary insomnia versus generalized anxiety disorder. The convergence of symptoms and their robust treatment
response to benzodiazepines are particularly compelling from a clinical perspective. If GAD and primary insomnia represent different phases of the same
disorder (Fig. 1) or different conditions whose neurobiology significantly converge over time (Fig. 2), one would predict that at later stages of illness both
GAD and primary insomnia would respond favorably to not only the same
pharmacologic treatments but also the same non-pharmacological interventions. Thus, one might predict that cognitive behavioral treatments specifically
designed to target the cognitive distortions of worry would be useful in both
syndromes. In an important preliminary investigation, Belanger, Morin,
Langlois and Ladouceur (2004) administered group CBT to GAD patients
based on targeting GAD-related worries (Dugas & Ladouceur, 2000), wherein
sleep complaints were not specifically addressed as part of the treatment. In this
study, 86.5% of the GAD patients reported that they had never experienced
insomnia without worry and the majority reported difficulties maintaining
sleep; indeed, 25% reported suffering from all phases of insomnia (i.e. early,
middle, and late). Additionally, group CBT was associated with a significant
improvement on the Insomnia Severity Index (Morin, 1993).
One cannot help but speculate that cultural or socioeconomic factors might
largely influence whether one self-identifies anxiety-insomnia as a medical
(i.e. sleep) versus mental health problem (i.e. anxiety), which in the case of
GAD and primary insomnia might lead to the conclusion that major difference
in primary insomnia versus GAD patients are mainly related to help-seeking
strategies.
Future Research
To validate any of the theoretical models, future research must investigate
patients with primary insomnia and anxiety disorders using both cross-sectional
and retrospective (Uhde, Boulenger, Roy-Byrne, Vittone, & Post, 1985) lifecharting as well as prospective methods. Prospective studies in patients whose
initial presentation is anxiety versus insomnia or, in well-defined at-risk populations, would be particularly desirable. Assessment tools must be developed,
validated and employed in a systematic fashion. The conduct of such studies
will be particularly challenging due to pragmatic considerations, which will
necessitate that such investigations be conducted across different institutional
sites and specialty clinics (i.e. sleep medicine clinics versus anxiety disorder
clinics). Ideally, it is desirable to conduct such studies within department(s) or
121
institution(s), which have research expertise in both sleep and anxiety disorder
research in order to minimize internal and external sources of variation. To
investigate the convergent, co-morbid relationship between anxiety and insomnia, priority might be given to the study of patients who a) meet DSM-IV criteria
for GAD plus seek treatment at anxiety disorder clinics versus b) patients meeting ICD-10 criteria for insomnia plus seek treatment from sleep clinics. Other
than these entry criteria, we recommend that there be few, if any, exclusion
criteria in designing such comparator studies. Specifically, we would not include
or exclude on the basis of sleep misperception or, perhaps, even the degree or
duration of subjective insomnia. Such differences or similarities across groups
seeking treatment for anxiety versus insomnia might themselves be markers that
distinguish group differences.
A particular problem for clinicians is the lack of information on the impact
of long-term pharmacological treatments or the comparative efficacy of drug
versus cognitive behavioral interventions. Such studies are time-intensive but
necessary to advance knowledge about the validity of any of the proposed three
theoretical models but also to develop evidence-based treatment packages for
the long-term treatment of anxiety-insomnia syndromes. Even more problematic is the lack of information on the course of anxiety and insomnia after
treatment discontinuation.
It is beyond the scope of this chapter to review and recommend the behavioral, physiological, and neuroimaging studies, which might be conducted to
best characterize the relationship between insomnia and anxiety. Clearly, neuroimaging strategies would be useful, although current MRI, MRS and fMRI
imaging strategies have resolution limitations that make it difficult to define with
precision the neuroanatomical substrates and functional circuits underlying
anxiety, insomnia, and mixed anxiety-insomnia syndromes. Nonetheless, the
emerging field of sleep neuroimaging (Nofzinger, 2004) may ultimately provide
tools for understanding fundamental constructs such as time perception or
sleep consciousness (Uhde et al., 2006). Such hypothesized third factors
(Fig. 3) might be amenable to investigation with imaging strategies, which are
not conducive to examination with traditional polysomnography or even
spectral analysis methods (Nofzinger et al., 1999, 2002, 2004). An examination
of the comparator effects of sleep deprivation under laboratory-controlled
conditions would be of interest to better differentiate the behavioral, cognitive,
MSLT and neuroendocrine effects of sleep restriction. Likewise, caffeine is an
ideal chemical model of anxiety (Lin, Uhde, Slate, & McCann, 1997; Uhde,
1995) and has been recently proposed as a tool to study primary insomnia
(Drake, Jefferson, Roehrs, & Roth, 2006). Studying the behavioral (including
sleep perception and polysomnographic measures), neuroendocrine, and physiological effects of caffeine in primary insomnia and GAD would provide useful
information. Disturbances in hypothalamic-pituitary-adrenal axis function
remain a focus of much anxiety (Uhde & Singareddy, 2002) and insomnia
research (Drake, Roehrs, & Roth, 2003; Vgontzas & Chrousos, 2002); yet, the
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T. W. Uhde, B. M. Cortese
specific origin, maintenance, and neuroanatomical impact of putative glucocorticoid disturbances in the anxiety disorders and insomnia remain unknown.
The most exciting area of future research is the theoretical possibility that
designer drugs might be developed with non-sedating anxiolysis or, even,
cognitive enhancing, pro-vigilance, anxiolytic properties. As reviewed elsewhere (Dawson, Collinson, & Atack, 2005; Mohler et al., 2002, 2005), the
development of a compound that binds to 2 GABAA and/or 3 GABAA
sites, which are located primarily in the fear-related substrates (i.e. amygdala)
and cortex, but without binding to the sedation-associated 1 GABAA binding
site, would theoretically have non-sedating anxiolytic properties. Such a drug
would be particularly useful for patients who wish to maintain alertness or who
experience increased anxiety as a result of increasing relaxation or sedation
(e.g. patients with nocturnal panic attacks). Even more speculative, but equally
provocative, is the idea that drugs with hypocretin agonist actions might also be
useful in the treatment of nocturnal panic attacks or patients whose insomnia is
related to a fear of sleeping (Uhde, 2000; Singareddy et al., 2006).
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Part II
Introduction
There has been a considerable body of research exploring associations between
physical illness and depressive disorders, but similar research examining a
possible association of physical illness with anxiety disorders has lagged behind.
More recently, research into the association of anxiety disorders with physical
illness has also been expanding, prompted in part by large epidemiologic survey
data revealing a high prevalence of anxiety disorders in community samples
(Kessler et al., 2005). Some studies have reported an association with anxiety
disorders as strong as or stronger than that with mood disorders (McWilliams,
Cox, & Enns, 2003; McWilliams, Goodwin, & Cox, 2004; Von Korff et al.,
2005). Some studies examining associations between anxiety disorders and
specific illnesses, including thyroid disease, cancer, diabetes, cardiac disease,
gastrointestinal disease, respiratory disease, and chronic pain, have found levels
of anxiety disorders among patients seeking treatment for medical conditions to
be higher than expected compared to the general population.
Attempts to explore and clarify associations between anxiety disorders and
physical disorders have focused on two main sources of data: clinical samples
and community samples. Within these two broad categories, sample size and
methodology of studies vary considerably. Many studies offer intriguing findings, but are challenging to interpret due to inconsistencies in nosological
terminology, psychometric measurements, and methodology. This overview
chapter is designed to be selective rather than exhaustive, and attempts to
Tanya Sala
Department of Psychiatry, University of Manitoba. PsycHealth Centre, PZ430-771
Bannatyne Avenue, Winnipeg, MB, Canada, R3E 3N4, Tel: 204-787-7078, Fax: 204-787-4879
tsala@hsc.mb.ca
Acknowledgements Dr. Sareen is supported by the Canadian Institutes of Health Research
New Investigator Award. Dr. Cox is supported by the Canada Research Chair Award. The
authors thank Natalie Mota for her assistance in manuscript preparation.
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T. Sala et al.
focus on large epidemiologic and clinical studies where available in the existing
literature. However, the relative lack of such studies mandates some consideration of research that falls outside these parameters. The majority of currently
available studies in this area are cross-sectional in nature. To avoid unnecessary
repetition, unless otherwise specified, all studies referred to are cross-sectional.
The chapter is organized into sections for each anxiety disorder, with subsections
by system of disease where warranted by available literature.
For the purposes of this literature review, searches of PubMed and PsycInfo
were performed using the general term anxiety disorder as well as each specific
anxiety disorder (e.g. panic disorder), in combination with the general terms
medical condition, physical illness, and medical illness as well as terms for
individual systems of disease (e.g. cardiovascular). Searches included studies
published from 1985 to 2007. For a discussion of associations between pain and
anxiety disorders, please refer to the chapter by Asmundson et al.
133
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T. Sala et al.
associated with poor quality of life and disability in this study. Important
clinical implications of these associations exist, including the possibility that
the co-occurrence of physical disorders and anxiety disorders may confer a
more disabling condition.
Method of assessment of anxiety and physical illness varies considerably
between studies. Some have assessed anxiety as a unified entity, rather than
distinguishing amongst anxiety disorders (Anderson et al., 2002; Engum, 2007;
Engum, Bjoro, Mykletun, & Dahl, 2002; Hermanns, Kulzer, Krichbaum,
Kubiak, & Haak, 2005; Kruse, Schmitz, & Thefeld, 2003; Shaban, Fosbury,
Kerr, & Cavan, 2006), adding to the challenge of interpretation and clinical
application.
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Cardiovascular Disease
A link between PTSD or trauma and cardiovascular disease has been suggested
by a number of studies. A recent prospective study of community-dwelling US
military veterans found a significant association between PTSD symptoms at
baseline and subsequent development of coronary heart disease, even after
controlling for depressive symptoms (Kubzansky et al., 2007). A study of
Korean War and World War II veterans reported increased rates of physician-diagnosed cardiovascular disease among veterans with PTSD (Schnurr,
Spiro, & Paris, 2000). Studies demonstrating increases in basal cardiovascular
activity in PTSD sufferers offer a potential biological pathway (Buckley &
Kaloupek, 2001).
One important possible consequence of PTSD secondary to a medical condition or medical treatment is the potential for lower levels of adherence to
medical treatment. Shemesh et al. (2001, 2004, 2006) examined the hypothesis
that symptoms of MI-related PTSD were linked to nonadherence to medical
follow-up. The authors hypothesized that patients who experience myocardial
infarction as a traumatic event may not take medications as prescribed, with
nonadherence representing part of the avoidance dimension of PTSD. In these
studies, PTSD symptoms were significantly associated with nonadherence to
medical treatment. In support of these findings, others have reported that
alleviation of PTSD symptoms in a series of burn patients could improve
adherence to treatment (Countermanche & Robinow, 1989).
Neurological Disease
A number of studies have sought to determine whether PTSD diagnosis is
associated with psychogenic nonepileptic seizure (PNES), also referred to as
pseudoseizure and psychogenic seizure. Fiszman, Alves-Leon, Nunes,
DAndrea, and Figueira (2004) recently conducted a review of studies on the
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prevalence of traumatic events and/or PTSD in patients with PNES. Among the
17 studies included in this review, ten analyzed the PTSD diagnosis in PNES
patients. Although the prevalence rates reported in these ten studies varied
considerably, rates of PTSD were consistently higher than those found in the
general population. However, when compared with control groups who had
epilepsy, only two studies found a significant difference in rates of PTSD.
Limitations acknowledged by the authors include the fact that all 17 studies
were hospital-based, and many had small sample sizes. The authors speculate
that PNES, which has been traditionally thought of as a dissociative phenomenon, might be understood as a severe form of PTSD that includes prominent
dissociative features. There is currently too little information to warrant conclusions on this premise.
Endocrine/Metabolic/Autoimmune Disease
Among the significant associations with PTSD in the study by Sareen et al.
(2005), metabolic/autoimmune conditions showed the most robust association
(AOR 3.32, CI 1.96-5.62). A number of studies have supported an alteration
in thyroid function in individuals with PTSD, both in chronic combat-related
PTSD (Mason et al., 2004; Wang & Mason, 1999; Wang et al., 1995) and in
survivors of childhood sexual abuse (Friedman, Wang, Jalowiec, McHugo, &
McDonagh-Coyle, 2005). In both studies by Wang et al., alterations in
thyroid function were specifically associated with increased hyperarousal
symptoms. Through promotion of ongoing noradrenergic transmission,
elevations in triiodothyronine (T3) have been proposed by some authors as
a possible underlying biological mechanism perpetuating arousal features in
PTSD (Prange, 1999), although this hypothesis remains speculative at this
stage.
Using data from a large national sample of Vietnam veterans, Boscarino
(2004) tested the hypothesis that chronic sufferers of PTSD may be at increased
risk for certain autoimmune diseases, including rheumatoid arthritis, thyroid
disease, insulin-dependent diabetes, and psoriasis. After adjusting for a variety
of factors, including age, alcohol and drug abuse, and history of cigarette
smoking, the authors noted significant associations between chronic PTSD
and all the above-mentioned illnesses. In a large study of US male veterans
with diabetes, Trief, Ouimette, Wade, Shanahan, and Weinstock (2006) noted
significantly higher cholesterol, LDL, weight, and BMI in subjects with PTSD
and depression, compared to depression alone, PTSD alone, or neither.
Goodwin and Davidson (2005), using the NCS dataset, examined the association between self-reported diabetes and PTSD in a community sample of
adults. In this study, self-reported diabetes was found to be significantly associated with an increased likelihood of PTSD, but not with an increased likelihood of any other mental disorder. This study not only provides evidence for
137
Cancer
The majority of studies assessing incidence or prevalence of PTSD in individuals with cancer have involved cross-sectional assessment of individuals with
breast cancer following completion of primary treatment, and have reported
rates ranging from 0 to 32% (e.g. Andrykowski, Cordova, Studts, & Miller,
1998). Several studies (Andrykowski, Cordova, McGrath, Sloan, & Kenady,
2000; Mehnert & Koch, 2007) also included a longitudinal component in the
form of either a 12 or 6-month follow-up assessment for PTSD. Analysis of data
from a large US community sample (Honda & Goodwin, 2004) found no
significant association between cancer and PTSD.
A variety of factors have been reported to be predictive of PTSD in individuals with cancer, including increased emotional distress following diagnosis,
female gender, a history of negative life stressors, prior psychological disturbance, lower socioeconomic status, poor social support, and reduced physical
functioning (e.g. Jacobsen et al., 2002). Some have reported an association
between more severe PTSD symptoms and a more advanced stage of disease
(Jacobsen et al., 1998), while other studies have found no association between
medical variables of the illness and risk of PTSD (Alter et al., 1996; Green et al.,
1998). With respect to the predictive value of any specific medical variable,
studies have been mixed.
In summary, challenges exist in the interpretation of existing PTSD literature, one of which is the predominance of cross-sectional methodology in
evaluating associations of PTSD with physical illnesses. Research examining
PTSD related to discrete trauma may not generalize to the experience of a
significant physical illness. Clarifying the precise event or events that represent
trauma can be difficult but clinically relevant, as some evidence exists that
prolonged or multiple traumatic events may result in greater severity or chronicity of PTSD symptoms. The relative contributions of the diagnosis itself,
treatment, side effects, prognosis, disrupted physical, social and occupational
functioning, and risk of exacerbation or recurrence cannot be examined within
a cross-sectional design.
Diagnostic validity using current DSM-IV criteria also presents special
challenges in this population. Divergent definitions of the stressor may increase
variability in the diagnosis of PTSD in the context of physical illness. The utility
of specific symptoms within DSM-IV criteria for PTSD needs to be assessed in
this population. For example, sense of a foreshortened future may be a
realistic concern in individuals with more serious physical illnesses such as
cancer. Arousal symptoms may overlap considerably with side effects of
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T. Sala et al.
Cardiovascular Disease
Given the high level of symptom overlap, it is not surprising that an association
between panic disorder and cardiac disease has been relatively well studied. Of
the 13 symptoms of a panic attack listed in DSM-IV, many could also represent
cardiovascular disease. Many patients with panic disorder present first to the
emergency room requesting medical assessment (Huffman & Pollack, 2003).
Data from the NIMH ECA study suggested that individuals who present with
numerous medically unexplained symptoms have 200 times increased odds of
having panic disorder, compared with 17 for major depression (Simon & Von
Korff, 1991). A strong relationship has been reported between panic attacks and
hypertension diagnosed by physical exam in a primary care sample (Davies et al.,
1999). Similarly, myocardial infarction has been associated in at least two studies
with increased likelihood of new-onset panic attacks. Physiological mechanisms
such as decreased heart rate variability, increased platelet activity, and increased
sympathetic tone have been implicated in the relationship between anxiety and
cardiac disease (Kawachi, Sparrow, Vokonas, & Weiss, 1995).
In a retrospective study of a large random community sample, Weissman,
Markowitz, Ouellette, Greenwald, and Kahn (1990) examined the association
between PD and cardiovascular/cerebrovascular disorders. After adjusting for
a number of demographic factors, participants with PD were at higher risk of
reporting high blood pressure, heart attack, and stroke than a group of respondents with no psychiatric disorder, but when compared with other psychiatric
disorders, only stroke remained significant. One limitation of this study is that
existence of cardiovascular or cerebrovascular disease was based on self-report.
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Respiratory Disease
Chronic obstructive pulmonary disease (COPD) and asthma are featured most
prominently in the literature, although a smaller number of studies examine an
association between panic disorder and allergic reactions in both children and
adults (Goodwin, 2002; Kovalenko et al., 2001). As with cardiovascular disease,
the high level of symptom overlap presents unique challenges in understanding
repeatedly observed associations. Given the early age of onset of asthma, many
have speculated that it could be a contributor to the development of panic
disorder, although there is evidence supporting a bidirectional influence of the
disorders (Hasler et al., 2005), as well as studies questioning whether both may
be due to a third variable (Goodwin, Fergusson, & Horwood, 2004).
Lifetime rates of respiratory disease have been reported to be as high as 47%
in individuals with panic disorder (Zandbergen et al., 1991). Rates of panic
disorder in individuals with respiratory illness have also been found to be
increased above those reported in general population studies, not only within
clinical samples of adults, but also in community samples and within child and
adolescent populations (Goodwin & Eaton, 2003; Goodwin, Jacobi, et al.,
2003; Goodwin, Olfson, et al., 2003; Goodwin, Pine, & Hoven, 2003). In a
community sample of more than 4000 individuals with current severe asthma,
10% also had panic disorder (Goodwin, Jacobi, et al., 2003).
Using the NCS dataset, Sareen et al. (2005) did not find a relationship
between panic attacks and respiratory disease, as previous studies have reported
(Goodwin & Eaton, 2003; Goodwin, Jacobi, et al., 2003; Goodwin et al., 2003;
Goodwin, Pine, et al., 2003; Ortega, McQuaid, Canino, Goodwin, & Fritz,
2004). A possible explanation suggested by the authors is that the discrepancy
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may be related to severity. The NCS did not distinguish severity of physical
disorders, but in a German community sample, severe asthma diagnosed by a
physician was associated with panic attacks while non-severe asthma was not
(Goodwin, Jacobi, et al., 2003).
Special considerations arise in the treatment of comorbid asthma and panic
disorder. Treatments for asthma, in particular short-acting b2 agonists, may
exacerbate anxiety symptoms as a side effect of their use, presenting a dilemma
both for the individual and health care provider. If symptoms are attributed to
asthma and a short-acting b2 agonist is used, symptoms may worsen if related to
panic rather than respiratory causes. Some evidence exists that patients with
comorbid panic disorder and asthma may make greater use of short-acting b2
agonists than asthma-only patients, independent of pulmonary function,
asthma medication class, and sociodemographic status (Feldman, Lehrer,
Borson, Hallstrand, & Siddique, 2005).
Several studies have reported an increased risk of panic disorder in individuals with COPD (e.g. Karajgi, Rifkin, Doddi, & Kolli, 1990). A recent review
by Brenes (2003) noted consistently increased rates of panic disorder and GAD
across studies, but commented on the lack of evidence to guide treatment
decisions in this population.
Neurological Disease
Studies examining associations with neurological illness have focused mainly on
epilepsy or vestibular dysfunction. The majority of those involving epilepsy
have concentrated on the diagnostic challenges in differentiating partial seizure
epilepsy involving pre-ictal or ictal fear from panic attacks or panic disorder,
and available literature is limited mainly to case reports (e.g. Bernik, Corregiari,
& Braun, 2002; Thompson, Duncan, & Smith, 2000). Some authors have
speculated on the existence of a subgroup of panic attacks, in which panic
constitutes symptoms of simple partial seizures with primarily psychic content
(Alvarez-Silva, Alvarez-Rodriguez, Perez-Echeverria, & Alvarez-Silva, 2006).
Patients with partial seizures may have symptoms similar to panic attacks
prodromal tension, fear, and autonomic disturbances, including changes in
blood pressure, heart rate, and skin color. This category of overlap once
again highlights the importance of treatment providers maintaining an index
of suspicion to rule out physical illness as an etiologic factor in the presentation
of anxiety symptoms. Possible indications for neurological investigations
include atypical symptoms or age at onset, non-response to standard treatments, abnormalities in routine physical exam or laboratory investigations, or
family history.
With respect to vestibular dysfunction, a two-year prospective study examining the role of cognitions in the development of panic disorder after the
experience of vestibular neuritis (Godemann, Schabowska, Naetebusch,
141
Heinz, & Strohle, 2006) reported that although fear arising on the first day
of an acute vestibular episode did not predict the development of panic,
fear of vertigo one week after the dysfunction was a significant predictor.
After six weeks, persistent fear of vertigo remained a significant predictor.
Results of a small clinical study suggested that subclinical vestibular dysfunction might contribute to symptoms of panic disorder, (Jacob, Furman,
Durrant, & Turner, 1996). Although the majority of studies assessing
vestibular function in individuals with panic disorder report a high prevalence of abnormal results of vestibular testing, no consistent pattern of
vestibular dysfunction has been observed across studies. Similarly, although
results of studies examining psychiatric symptoms in patients with vestibular dysfunction in general show increased levels of anxiety symptoms,
especially panic, no consistent pattern of association has yet been
described.
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non-IBS subjects. Although IBS was more prevalent in females, comorbidity did not differ between males and females.
Endocrine/Metabolic Disease
Within this category, thyroid disease and diabetes have received the most
attention from researchers. A recent review of studies examining associations
between thyroid dysfunction and anxiety disorders found significantly elevated
rates for panic disorder in patients with a history of thyroid disease, and
concluded that inquiring about thyroid symptoms and screening for thyroid
disease is warranted in patients with panic disorder (Simon et al., 2002). However, of the 12 studies included in this review, only six were controlled, and the
findings of studies varied considerably.
Results from larger studies have been mixed. Analyzing a community
sample, Sareen et al. (2005) did not find an association between panic attacks
and self-reported diagnosis of metabolic/endocrine disease. Analysis of a
different community sample also did not find a significant association
between panic disorder/agoraphobia and self-reported thyroid disease
(Patten, Williams, Esposito, & Beck, 2006). However, analysis of a large
clinical sample showed an association between panic disorder and thyroid
disease (Rogers et al., 1994).
Cancer
A review of studies between 1980 and 1994 examining psychological disturbances in cancer patients (vant Spijker, Trijsburg, & Duivenvoorden, 1997)
found no significant differences from the general population with respect to
anxiety and psychological distress. In fact, in comparison with other medical
patients, cancer patients showed significantly less anxiety in this review. In
contrast, Honda and Goodwin (2004) used NCS data to examine the association between cancer and mental disorders, adjusting for sociodemographic
characteristics. Among other reported findings, cancer was associated with
increased risk of agoraphobia, although this finding barely reached statistical
significance. There was no significant association in this study with panic
disorder. The findings of Honda and Goodwin have been criticized on a number
of grounds (Coyne & Palmer, 2005), including the low prevalence of cancer
diagnosis in the NCS (n=45, 0.76%), making it possible for small sampling
biases to have large effects. It has also been suggested that diagnoses made in the
NCS may have been less valid when a significant medical comorbidity was
present, as distinguishing between psychiatric symptoms and physical symptoms could pose an even greater challenge for lay interviewers than clinicians.
143
Gastrointestinal Disease
Goodwin and Stein (2002) examined a possible link between GAD and peptic ulcer
disease (PUD) among adults in a community sample. After controlling for differences in sociodemographic characteristics, psychiatric comorbidity, and physical
comorbidity, the authors found a significantly increased risk of self-reported PUD
in subjects with GAD. A dose-response relationship was also found between
number of GAD symptoms and higher likelihood of PUD. A review of a number
of smaller studies (Lydiard, 2001) reported a consistent link between irritable
bowel syndrome and GAD. In the NCS sample, Sareen et al. (2005) found GAD
to be associated exclusively with gastrointestinal disease after adjusting for sociodemographic factors, other anxiety disorders, and depression. See the section on
Panic Disorder and gastrointestinal disease for discussion of a relevant study by
Hochstrasser and Angst (1996).
Endocrine/Metabolic/Autoimmune Disease
Studies of this body system have primarily examined associations with either
thyroid disease or diabetes mellitus. In a small study of a clinical sample, Carta
et al. (2005) found that subjects with Hashimoto disease showed higher frequencies of GAD compared to subjects with euthyroid goiter and controls. See
the section on Panic Disorder and endocrine/metabolic disease for discussion of
a relevant review by Simon et al. (2002).
Studies in clinical samples have also supported an association between GAD
and diabetes (Kovacs, Goldston, Obrosky, & Bonar, 1997). However, both studies
of diabetes and studies of thyroid disease typically involve smaller numbers of
individuals and are subject to the sampling bias that accompanies studies of
treatment-seeking populations. In a recent review of anxiety in adults with diabetes
(Grigsby, Anderson, Freedland, Clouse, & Lustman, 2002), the authors concluded
that 14% of diabetic subjects in the included studies also had GAD, well in excess
of the prevalence reported in community surveys (Kessler, Chui, Demler,
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T. Sala et al.
Merikangas, & Walters 2005). However, of the 18 studies included in this review,
only 5 included a non-diabetic control group, and most of the subjects were drawn
from clinical populations. In contrast, an analysis of general population data
(Sareen et al., 2005) found no significant association between metabolic/endocrine
or autoimmune diseases and GAD.
145
Endocrine/Metabolic Disease
Results of smaller studies examining an association between social anxiety
disorder and thyroid disease have been mixed, with some authors reporting
significant associations (e.g. Carta et al., 2005), and others finding no increased
prevalence compared to the general population (Simon et al., 2002). Studies
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T. Sala et al.
using larger community samples have generally supported a significant association. Analysis of NCS data by Sareen et al. (2005) revealed a strong association
between social phobia and metabolic/autoimmune disorders. Using data from a
Canadian general population sample, Patten et al. (2006) reported that after
adjusting for sex, age, and other chronic conditions, social phobia remained
associated with thyroid disease.
Autoimmune Disease
Lindal, Thorlacius, Steinsson, and Stefansson (1995), in an analysis of all
known individuals with lupus in Iceland, reported that social phobia was
more common in persons with lupus than in the general population. Reasons
for this association are unclear, although the authors speculated that the
occurrence of disfiguring facial rashes in certain lupus sufferers could be related
to increased social anxiety.
Gastrointestinal Disease
See the section on Panic Disorder and gastrointestinal disease for discussion of
a relevant study by Hochstrasser and Angst (1996).
Endocrine/Metabolic Disease
As part of an examination of the epidemiology of blood-injection-injury phobia
in the Baltimore ECA Follow-up Study, Bienvenu and Eaton (1998) found no
147
Cancer
See the section on Panic Disorder and cancer for discussion of relevant studies
by vant Spijker et al. (1997) and Honda and Goodwin (2004).
Concluding Comments
Conclusions
Examination of the relationship between anxiety disorders and physical illness
is a limited but expanding area of the scientific literature. The prevalence of
both anxiety disorders and many physical illnesses in the population argues
convincingly for the clinical relevance of this area of research. In addition to
informing screening and detection of both mental and physical disorders, early
evidence suggesting an impact on risk of death and disability underscores the
importance of extending our understanding of these relationships. The impact
of this comorbidity on treatment for either condition remains largely unexplored. Results of an analysis of primary care patients with panic disorder
(Roy-Byrne et al., 2005) suggest that patients with a higher burden of physical
illness responded equally well to CBT and pharmacotherapy targeted at panic
symptoms, but more research in this area is needed to provide support for these
findings and to explore treatment implications for other anxiety disorders.
Although an impressive number of studies support associations between
anxiety disorders and physical illness, the variety among reported findings is
equally striking. This variety represents the current state of the literature:
sufficient evidence exists to argue convincingly that associations between anxiety disorders and physical illness exist, but the precise nature of the relationships remains elusive, and a number of important methodological concerns
limit conclusions. Which anxiety disorders are associated with which physical
illnesses, and the exact nature of these associations, is a task for future research
efforts.
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(Angold, Costello, & Worthman, 1998), eating disorders (Killen, et al., 1992),
and substance use problems (Patton et al., 2004).
With this backdrop, researchers have begun to consider the potential role
that puberty and its associated parameters (e.g., timing) may play in the
development and maintenance of anxiety problems among adolescents. Indeed,
a number of empirical articles have been published on this topic in the past
decade; nonetheless, the literature is still in its relative infancy. Accordingly, the
overarching objective of the current chapter is to stimulate additional research
in this important domain; our specific goals are to 1) discuss methodological
and conceptual issues pertinent to the study of puberty, 2) present an overview
of the empirical literature focused on the association between puberty and
anxiety, and 3) provide some conceptually-driven suggestions for future work
in the area.
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Dick, Rose, Viken, & Kaprio, 2000). Although the timing of puberty has
changed in the past two decades (earlier onset), given the current state of our
knowledge, altering the timing of puberty is not currently conceptualized as a
reasonable target of intervention. Therefore, pubertal timing is considered
non-malleable and classified as a fixed marker. Importantly, pubertal timing
is non-specific in nature as it has been linked to an array of clinical sequelae,
including problematic health behaviors (e.g., excessive dieting and
exercise [McCabe & Ricciardelli, 2004]; alcohol, cigarette, and marijuana use
[Lanza & Collins, 2002; Wichstrom, 2001; Weisner & Ittel, 2002]) as well as
elevated risk of clinical symptomatology and diagnoses (e.g., depressive-type
problems [Graber, Seeley, Brooks-Gunn, & Lewinsohn, 2004; Kaltiala-Heino,
Kosunen, & Rimpela, 2003); eating-related pathology [Kaltiala-Heino,
Rimpela, Rissanen, & Rantanen, 2001]).
As highlighted by the current volume, the important link between health
behaviors and anxiety is just beginning to be fully appreciated. As these two
outcomes, anxiety and unhealthy behaviors, both increase at puberty, it will
become increasingly important to untangle both pubertal status and pubertal
timing effects associated with health behaviors in addition to unraveling the
potential interaction between onset of anxiety and initiation of unhealthy
behaviors in the peripubertal period.
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E. W. Leen-Feldner et al.
among 123 psychologically healthy adolescents aged 1217 years, Leen-Feldner and colleagues (2006) found that more mature youth who also were high
in anxiety sensitivity [AS], a cognitive vulnerability factor reflecting a tendency to fear the consequences of anxiety (Reiss & McNally, 1985), reported
the most fearful reactivity in response to a panic-relevant voluntary hyperventilation challenge. That is, advancing pubertal status was associated with
panic-relevant reactivity only among those youth who were vulnerable to
such reactivity by virtue of elevated cognitive vulnerability (i.e., AS). These
effects were significant above and beyond age, gender, and pre-experimental
anxiety. These data highlight the utility of investigating potential moderators
of the pubertal status-anxiety association. Indeed, a number of conceptually
relevant diatheses may be important in terms of enhancing anxiety vulnerability during pubertal development, including behavioral inhibition (Hirshfeld et al., 1992), negative affectivity (Craske, 2003), anxiety sensitivity
(Schmidt, Zvolensky, & Maner, 2006), and traumatic event exposure
(Caffo, Forresi, & Lievers, 2005). With the exception of AS, no empirical
work has addressed these questions, and thus they represent important future
directions (please see the Suggestions for Future Research section for additional recommendations).
Pubertal Hormones and Anxiety. Perhaps due to the complexities of hormone
research described earlier, the literature focused on the link between anxiety and
pubertal hormones is quite limited, precluding integrative conclusions. Prior to
reviewing the available literature, it is worth noting that several studies
conducted with adolescents have investigated the general association between
anxiety and specific hormones that are present during puberty (e.g., cortisol;
Gerra et al., 2000). For instance, in a study of 131 adolescents, Terleph, Klein,
and Roberson-Nay (2006) reported a positive association between mean
cortisol levels before and during a biological challenge procedure and panic
attacks elicited by the challenge, suggesting elevated cortisol may represent a
panic-relevant vulnerability variable. Although these findings are theoretically
interesting in their own right, without an index of pubertal status, it is difficult
to extrapolate their relevance in terms of the puberty-anxiety association
because observed associations could be due to other variables that
are confounded with hormone levels, such as the social consequences of
hormonally-driven secondary sex characteristic development (Slap, Khalid,
Paikoff, & Brooks-Gunn, 1994). Therefore, studies reviewed below included
an index of pubertal status.
In a seminal study, Olweus, Mattsson, Schalling, and Low (1980) reported
no association between blood serum testosterone and both trait and state
anxiety elicited by the blood draw among 58 Swedish males aged 15 to
17 years. In a more fine-grained analysis of the role of testosterone, Granger
and colleagues (2003) found, in a mixed gender study of over 200 youth aged
1117 years, a negative association between testosterone and concurrent
anxious/depressed symptomatology. In addition, anxious/depressed symptoms
were related to diurnal variation such that those males who exhibited less of a
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E. W. Leen-Feldner et al.
165
association such that, compared to on-time and late developers, early maturing
females who also were associated with mixed (as opposed to same-sex) peer
groups in the 7th through 9th grades were more likely to evidence psychological
distress in the 10th grade. This study highlights the complex inter-relations that
characterize the association between pubertal timing and anxiety, and furthermore suggests that negative effects of off-time maturation may not be transient,
but rather persist over time.
Overall, pubertal timing appears to be an important fixed marker in the
development and maintenance of anxiety-type symptoms, particularly among
females. Interestingly, not only does the timing of puberty alter psychiatric risk
but psychological factors may alter the timing of puberty (reviewed in more
detail below). Thus, in theory, pubertal timing is malleable. However, from an
intervention standpoint, understanding how pubertal timing affects outcomes
may be a more feasible goal than attempting to alter the timing of puberty itself.
Therefore, at this stage of research development, we consider pubertal timing to
be non-malleable (i.e., fixed marker). In addition, as noted earlier, the association between pubertal timing and psychiatric outcomes is non-specific in
nature. For both these reasons (non-malleability; non-specificity) identification
of mediators and moderators of the pubertal timing-anxiety association
is critical. In particular, it will be important for researchers to consider
gender-specific characteristics that may mediate or moderate the timing-anxiety
association, as the link between timing and anxiety appears to differ across
males and females. For instance, sexual assault exposure (Hayward & Sanborn,
2002) and body image and weight concerns (Richards, Boxer, Petersen, &
Albrecht, 1990) may be particularly important among females, whereas
risk-taking activities (e.g., substance use; Andersson & Magnusson, 1990)
may be important to consider among males.
Temporal Dimensions of the Pubertal Timing-Anxiety Association. As
mentioned above, a complicating facet of the putative link between pubertal
timing and anxiety pertains to the chicken-and-the-egg issue. Specifically, two
pathways are viable. First, the timing of maturation may potentiate anxiety for
some youth (e.g., early maturing females develop anxiety-related problems;
Graber et al., 2004). However, it has also been posited that the direction of
the association may be from contextual stress in the early environment to
pubertal timing. Both neurobiological (e.g., changes to the HPA-axis secondary
to childhood stress; Meschke, Johnson, Barber, & Eccles, 2003) and
sociobiological (Belsky, Steinberg, & Draper, 1991) mechanisms have been
theorized. For instance, Belsky and colleagues highlight the utility, from an
evolutionary perspective, of commencing reproductive activities as soon as
possible if an organism is reared in a stressful environment where the viability
of progeny is questionable. Therefore, children reared in a stressful environment are predicted to experience the hormonal and physical changes of puberty
earlier than youth from stable home environments. There is a relatively large
body of work examining the role of early stress in relation to pubertal timing.
For instance, among females, dysfunctional family background (e.g., parental
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divorce; alcoholism; Hulanika, 1999) and childhood sexual abuse (HermanGiddens, Sandler, & Friedman, 1988) have been found to predict earlier
menarche. Similarly, familial conflict in the childhood environment has been
shown to predict early spermarche (Kim & Smith, 1998). Conflicting findings
also have been observed, however, with some studies suggesting childhood
stress predicts later maturation (e.g., Malo & Tremblay, 1997) and others
reporting no association at all (see Kim, Smith, & Palermiti, 1997, for a review).
With regard to anxiety symptoms specifically, the literature is similarly
mixed, with some studies reporting that anxious symptomatology in
childhood is associated with earlier menarche (Kim & Smith, 1998) and
spermarche (Kim & Smith, 1999), others suggesting it is linked with later
spermarche (Malo & Tremblay, 1997), and still others indicating it is unrelated
to maturational timing (Graber, Brooks-Gunn, & Warren, 1995). In addition,
at least one study calls attention to the importance of the type of anxiety being
assessed. Specifically, Meschke and colleagues (2003) found, among males,
economic and school anxieties predicted earlier and later puberty, respectively.
These studies represent a useful first step toward specifying the role of early-life
anxiety in affecting pubertal onset. However, the mixed findings, due at least in
part to methodological issues (e.g., reliance on retrospective recall) make it
difficult to draw definitive conclusions about issues of temporal order.
Nevertheless, these data suggest that interventions designed to reduce anxiety
early in life might also secondarily alter the timing of puberty. This is a critical
area for future work.
Summary of the Empirical Literature Focused on the Puberty-Anxiety
Association. Although the available research is promising, there is a great deal
of work to be done to fully understand the association between puberty and
anxiety. Much of the early work was characterized by significant methodological limitations, including small sample size, assessment of only one aspect
of puberty, one-time hormone assessments, analyses with males and females
combined, and utilization of non-specific measures of anxiety. Indeed, in
drawing conclusions from the extant work, greater weight should be placed
on those studies (e.g., Ge et al., 1996, 2001; Graber et al., 1997, 2004; Hayward
et al., 1992, 1997) where some of these limitations are addressed. Accordingly,
three tentative conclusions can be drawn at this stage of research development.
First, anxiety symptomatology appears to increase as youth traverse puberty;
the more methodologically rigorous studies suggest a positive association
between pubertal status and anxiety that cannot be explained by chronological
age (e.g., Patton et al., 1996). From a conceptual perspective, however, it makes
sense to continue exploring mechanisms that may explain this association, as
puberty itself is not considered to be pathological in its own right (Graber,
2003); examination of individual-difference variables that might be expected to
influence the association is an exemplar of an important next step in this
literature. Second, the hormone literature is too under-developed to draw any
firm conclusions at this point; additional work is needed to cull out the
main, additive, and interactive effects of pubertal hormones on anxiety
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169
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E. W. Leen-Feldner et al.
Panic-Related Problems
Mediators
(e.g., fear-relevant
learning; gonadal
steroids)
171
Time
Moderator
(e. g., youth HIGH in
anxiety sensitivity)
Puberty
Moderator
(e. g., youth LOW in
anxiety sensitivity)
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E. W. Leen-Feldner et al.
Conclusions
The period of adolescence is characterized by both puberty and an increase in
anxiety-related psychopathology, prompting researchers to examine the
relation between the two. The available literature suggests there is a meaningful
association between puberty and anxiety; for some youth (particularly females),
173
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uterus, ovary, and pituitary play a large role in menstrual cycle functioning with
the hypothalamus playing a central control function. Research in the menstrual
literature has typically delineated 3 distinctive phases: follicular (days 113),
ovulation (days 1314), and luteal (days 1528). Days 17 represent menses and
days 2128 are generally considered the premenstrual or late luteal phase of the
cycle.
183
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Table 1 Sample of measures used in assessing symptoms across the menstrual cycle
Retrospective
Measure
Purpose (PMS/PMDD)
or Prospective
Premenstrual Tension Rating Scale, self
and observer forms (Steiner et al., 1980)
Daily Rating Form (Endicott et al., 1986)
Premenstrual Symptom Diary
(Thys-Jacobs et al., 1995)
Calendar of Premenstrual Experiences
(Mortola et al., 1990)
Menstrual Distress Questionnaire (Moos,
1968)
Menstrual Distress
Questionnaire Today version (Blake et al.,
1998)
Premenstrual Assessment Form (Halbreich
et al., 1982)
Daily Record of Severity of Problems
(Endicott et al., 2006)
Daily Symptom Rating Scale (Taylor, 1979)
Both
Diagnostic PMS
Diagnostic PMS;
Treatment response
Diagnostic PMDD
P
P
185
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S. T. Sigmon, J. G. Schartel
depression or anxiety. Hartlage and Gehlert (2001) suggest the problem is that
symptoms of PMDD overlap significantly with other affective disorders and
argue for phase specificity in diagnosing PMDD (i.e., symptoms occur solely
during the premenstrum). They propose that PME can be distinguished from
PMDD if clinicians consider one symptom at a time. This leaves unresolved the
possibility of some symptoms of an anxiety disorder occurring across the entire
cycle while others do not. How many of the symptoms of PMDD must be
distinct from the symptoms of the ongoing anxiety disorder remains unclear.
The criteria of five symptoms has also been challenged as being arbitrary and
too restrictive to accurately assess the impact of symptoms on womens
functioning (Smith et al., 2003; Freeman, 2003). Yonkers (1997) suggests that
premenstrual complaints can vary in severity, degree of comorbidity with other
psychological disorders and level of impairment. For example, a woman may
only demonstrate two out of five symptoms, but they may be severe enough to
cause significant interference with her day to day functioning.
Researchers have also questioned the validity of defining and measuring the
absence of a symptom. The requirement of symptom absence is unique to
PMS/PMDD, and there are currently no good assessment measures that
reliably measure this criterion. Furthermore, most criteria require symptoms
be absent for the duration of the follicular phase. This requirement has been
challenged as being unrealistic due to the natural fluctuations in mood and
occurrence of life events over the course of the cycle (Freeman, 2003; Smith
et al., 2003). For example, Bailey and Cohen (1999) assessed the number of
women seeking treatment for premenstrual symptoms who experienced symptoms across the menstrual cycle. Over 60% of their sample met criteria for either
a mood or anxiety disorder or both, indicating they experienced symptoms
diagnostic of PMS across all phases of the cycle. Instead, researchers like
Freeman (2003) suggest we would be better served to look at changes in
symptom severity or overall frequency (i.e., degree of change). Although
suggestions have been made (e.g., Smith et al., 2003), no conclusion has yet
been reached regarding what would represent a clinically significant change
from one menstrual cycle phase to the next phase.
There is a significant amount of variability both between and within individual womens symptoms from cycle to cycle. Bloch, Schmidt, and Rubinow
(1997) looked at the stability of premenstrual symptoms in 16 women with PMS
(defined as 30% increase in symptom frequency during the luteal phase) for 3 or
more cycles. Results indicated that symptom presentation from cycle to cycle
varied considerably, with anxiety (83%), irritability (85%), and mood lability
(77%) exhibiting the most stability across the 3 cycles. Freeman (2003) also
notes that the timing of symptom appearance/remission varies between women.
Some women experience PME for only a few days of the premenstrual phase at
either the beginning or end and some symptoms are experienced on nonconsecutive days. Thus, the literature suggests that in well-defined PMS samples,
symptoms persist across time and can cause significant impairment in womens
187
lives even if two consecutive symptomatic cycles are not established during the
diagnostic period.
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189
could not distinguish between women with PMS alone or women with PMS who
also met criteria for an anxiety disorder.
Cross-cultural research in Western societies seems to parallel the results
obtained in the United States. A study on women in the United States, United
Kingdom, and France (N = 1045) revealed considerable impairment at home,
in social relationships, and work. Across countries, more than 60% of women
reported increases in anxiety, fears and tension premenstrually, and less than
25% had sought treatment for their symptoms (Hylan et al., 1999).
Premenstrual Dysphoric Disorder. Researchers have estimated that the impact
and burden associated with PMDD to be similar to that of other affective
disorders (e.g., Halbreich et al., 2003). Wittchen, Becker, Lieb, and Krause
(2002) contend that PMDD can persist for the duration of a womans reproductive years. In their research, depression was the first ranked symptom (91%) and
anxiety was noted by 67% of the sample, with 47% of women with PMDD
meeting criteria for a comorbid anxiety disorder. Several studies have found
that comorbid anxiety disorders may be found in as many as 59% of women
diagnosed with PMDD (Fava et al., 1992; Pearlstein, Frank, Rivera-Tovar,
Thoft, et al., 1990). Research has also indicated that women with PMDD report
more stressors and experience more distress premenstrually than intermenstrually
compared to controls (e.g., Fontana & Badawy, 1997) and also report more state
anxiety than controls (e.g., Christensen & Oei, 1989).
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S. T. Sigmon, J. G. Schartel
191
experience of premenstrual symptoms is complicated, regardless of the methodology used. Research on PME of panic symptoms assumes that women are able to
accurately distinguish the causes of their symptoms, and symptom misattribution
has been cited as a contributor to inconsistent findings as well as a significant
component of panic disorder (Stein, Schmidt, Rubinow, & Uhde, 1989).
Retrospective assessments suggest that a large proportion of women experience an increase in panic symptoms premenstrually. For example, Breier and
colleagues (1986) found that more than half of women reported PME of their
symptoms. Women in other studies have reported increases in severity of
symptoms (Cameron et al., 1988), overall anxiety, frequency of panic attacks
and phobic avoidance (Cook et al., 1990).
Prospective studies have yielded mixed results with respect to PME of panic
disorder. Cameron et al. (1988) found that women reported all symptoms as more
severe retrospectively, but only muscle tension was statistically significant
prospectively. Similarly, other researchers have failed to find premenstrual
increases in overall levels of anxiety (e.g., Stein et al., 1989; Cook et al., 1990)
or frequency of panic attacks (Cook et al., 1990). Women have also rated
symptoms as more severe during the premenstrual phase. For example, Cook
and colleagues (1990) found that approximately half of their sample prospectively
rated one out of two menstrual cycles with a greater than 30% increase in panic
symptom severity. In contrast, Kaspi, Otto, Pollack, Eppinger and Rosenbaum,
(1994) found that panic attack frequency increased premenstrually whereas panic
severity, avoidance, and anticipatory anxiety did not. Half of the participants in
this study experienced twice as many panic attacks during the premenstrual phase
compared to only 5 women who retrospectively reported symptom worsening.
Unsubstantiated retrospective reports of premenstrual worsening only occurred
in four out of twelve participants.
Several reasons for these inconsistencies have been suggested. The experience
of negative life events, fatigue, or other stressors may affect womens experience
of anxiety from one cycle to the next and assuming consistency across
consecutive cycles may be inappropriate (Cook et al., 1990). The influence of
beliefs about menstruation, social expectations or social roles may also play a
part in womens symptom expression (Sigmon, Dorhofer, et al., 2000). Memory
biases (Cameron et al., 1988) and symptom misattribution during different
phases have also been suggested. Natural fluctuations in anxiety might be
mistakenly attributed to the menstrual cycle because it is a salient anchor
point for women (Stein et al., 1989).
Obsessive-Compulsive Disorder. Retrospective studies have suggested a
significant portion of women with OCD experience premenstrual worsening
of their symptoms (Labad et al. 2005; Williams & Koran, 1997). Interestingly,
many of the women reporting premenstrual worsening also reported significant
premenstrual mood symptoms indicative of PMS or PMDD (Williams &
Koran, 1997). No studies utilizing daily prospective symptom monitoring
have been conducted; however Vulink, Denys, Bus, and Westenberg (2006)
assessed women at three time points concordant with menstrual, premenstrual,
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S. T. Sigmon, J. G. Schartel
and intermenstrual phases of their cycles. Results indicated that half of the
women reported PME of OCD symptoms.
Generalized Anxiety Disorder. Only one study has investigated menstrual cycle
relationships with GAD (McLeod, Hoehn-Saric, Foster, & Hipsley, 1993) and
PTSD (Perkonigg, Yonkers, Pfister, Lieb, & Wittchen, 2004). McLeod and
colleagues (1993) recruited women with GAD with and without comorbid PMS.
Results indicated that women who had both GAD and PMS reported significant
PME of anxiety symptoms during the luteal phase. Unfortunately, assessment
points were not consistent between groups, making comparisons difficult.
PTSD. Perkonigg and colleagues (2004) followed women with PTSD over a
span of 42 months, assessing for predictors of PMDD at three time points. The
best predictor of PMDD diagnosis was subthreshold PMDD symptoms at the
initial interview. However, the experience of traumatic events and anxiety
disorder presence both significantly predicted subsequently meeting diagnostic
criteria for PMDD. PMDD symptoms were only assessed retrospectively and
interviews were conducted without respect to menstrual cycle phase; however
their results do suggest that trauma and anxiety may impact womens experience of symptoms across the menstrual cycle.
Although results across different disorders, populations, and methods of
reporting have been inconsistent, there is nonetheless some evidence to suggest
that for some women, menstrual cycle phase may have a significant impact on
their experience, or at least the reporting of symptoms. Symptom patterns may
also vary from cycle to cycle and may be related to life events, stress, fatigue,
interpersonal or relationship problems. Many authors have suggested that this
heterogeneity both between and among women may interfere with accurate
diagnosis and interpretation of effect sizes in treatment studies (Vulink et al.,
2006). Given recent advances in statistical methods for prospective data and in
general understanding of anxiety disorders, more research investigating
menstrual cycle effects on womens experience of anxiety is warranted.
193
to humans. To study any aspect of the menstrual cycle without the contexts of
stress and lifestyle will result in incomplete assumptions (e.g., Koeske, 1983).
Thus, feminist views about the menstrual cycle mirror similar concerns that
have been raised in other approaches.
Biological Explanations. Reproductive hormones play a significant role in
mood symptom fluctuation across the menstrual cycle; however, the exact
mechanisms involved are not well understood (e.g., Hendrick, Altshuler, &
Burt, 1996). Progesterone metabolites and estrogen levels typically decrease
during the premenstrual phase and remain low through the early follicular
phase. These hormones modulate neurotransmitter levels (e.g., serotonin,
GABA, dopamine, norepinephrine) that are hypothesized to play an important
role in the development and maintenance of psychological disorders, in
particular anxiety and depression (e.g., Dubrovsky, 2006; Le Melledo &
Baker, 2002). This area of research is relatively new and is hampered by the
use of small samples, retrospective methodology, and lack of precision in
determining menstrual cycle phase.
Biological explanations of PMS typically begin with a discussion of hormonal
control of the menstrual cycle. The development of premenstrual symptoms is
purported to be linked to the rapid decrease in progesterone during the late luteal
phase (e.g., Poromaa, Smith, & Gulinello, 2003). However women with and
without PMS often do not show differences in absolute levels of progesterone
across the menstrual cycle (e.g., Rubinow et al., 1988; Hammarback, Damber, &
Backstrom, 1989). Thus, researchers have proposed that there may be differences in sensitivity to the changing hormone levels (e.g., Poromaa et al., 2003;
Halbreich, 2003). In addition, because progesterone metabolites enhance GABA
(i.e., gamma-aminobutyric acid) activity (e.g., Olsen & Sapp, 1995) and GABA
has been implicated in anxiety symptoms (e.g., Ninan et al. 1982), researchers
have proposed models of complex hormonal interactions that may link
premenstrual symptoms and anxiety disorders (e.g., Facchinetti, Tarabusi, &
Nappi, 1998). However, more research is needed to determine the mechanisms
affecting sensitivity to these interactions (Roy-Byrne, Cowley, Greenblatt,
Shader, & Hommer, 1990).
Research has also demonstrated several biological links between menstrual
disorders and anxiety disorders. Women diagnosed with PMS and LLPDD
(i.e., Late Luteal Phase Dysphoric Disorder) report increased in panic
symptoms, negative interpretations of sensations, and state anxiety in response
to a lactate challenge (e.g., Facchinetti et al., 1998; Kent et al., 2001). Further,
approximately 6070% of women with panic disorder and with LLPDD experience panic attack in response to lactate infusion and inhaled carbon dioxide.
Panicogenic responding to challenge tasks was previously thought to be specific
to panic disorder, and the similar rates of responding may suggest a shared
biological vulnerability and account for the high levels of anxiety reported by
LLPDD patients (for a review see Vickers & McNally, 2004). Other evidence to
support a link between PMS and anxiety disorders comes from the responsiveness to alprazolam in women with PMS (e.g., Facchinetti et al., 1998). Although
194
S. T. Sigmon, J. G. Schartel
these findings are preliminary, they do suggest intriguing links between anxiety
symptoms and PMS. Biological links between PMDD and anxiety have also
been explored. For example, symptoms disappear or decrease in women diagnosed with PMDD when they do not ovulate, when ovaries are removed, or
when they take medications that inhibits ovulation (e.g., Steiner, 2000).
Biopsychosocial Models. More complex models of menstrual distress incorporating social and psychological processes are surfacing as it has become clear
that biological explanations alone cannot suffice (e.g., Anson, 1999). A womans
experience of premenstrual symptoms is influenced by socialization practices and
environmental contextual factors (e.g., Anson, 1999). Menstrual attitudes and
beliefs that develop from interactions with peers, family, and the media (e.g.,
Aubuchon & Calhoun, 1985; Woods, Mitchell, & Lentz, 1995) may play a
significant role in the reporting and experience of premenstrual symptoms.
Reports of premenstrual complaints vary depending on retrospective reports
(e.g., Marvan & Cortes-Imiestra, 2001; Rapkin, Chang, & Reading, 1988),
number and severity of daily and life stressors (e.g., Fontana & Palfai, 1994),
use of maladaptive coping strategies (Sigmon, Whitcomb-Smith, Rohan, &
Kendrew, 2004), complex role conflicts (e.g., Ross & Steiner, 2003), and history
of sexual abuse (e.g., Ross & Steiner, 2003). These represent but a few of the
factors proposed to play a contributory role in the experience and reporting of
premenstrual difficulties.
Researchers have also examined the role that the perception of stress and
interference with functioning might play in the reporting of increases in anxiety
during the premenstrual phase. Davydov and colleagues (2004) assessed anxiety
symptoms during the luteal and follicular phases in nurses, who reported higher
levels of anxiety on working days during the luteal phase than during days off
during the luteal phase or during the follicular phase. Studies examining
menstrual interference in college samples (e.g., Brooks-Gunn & Ruble, 1986)
have found that perceived interference, menstrual pain, and premenstrual pain
were the best predictors of emotional distress. The menstrual cycle itself has
been conceptualized as a stressor (e.g., Logue & Moos, 1986). Elliott and
Harkins (1992) found that for normal women menstrual and premenstrual
pain and perception of interference were the strongest predictors of emotional
distress. According to the authors, results provided support that how
individuals appraise or perceive interference from a particular condition or
stressor (e.g., menstrual cycle) may represent an important component in stress
and coping processes.
195
196
S. T. Sigmon, J. G. Schartel
a wait-list control condition (Blake et al., 1998). However, CBT may be more
effective for managing depressive symptoms than anxiety symptoms, as some
studies have found no reduction in anxiety scores following treatment (Blake
et al., 1998). CBT has demonstrated equal efficacy to medication (i.e., fluoxetine)
in treating PMDD with better maintenance after one year (Hunter et al., 2002 ).
A combination of medication and psychotherapy did not demonstrate any
additional benefits to each alone. It is interesting to note, that women treated
with fluoxetine reported greater improvement in anxiety than those who received
CBT. The authors attributed this to either the known anxiolytic effects of the
medication or the tendency for CBT to focus on depressive symptoms and not
anxiety.
Selective serotonin reuptake inhibitor (SSRI) anti-depressants have been
found to be effective for alleviating symptoms of PMS and PMDD (see
Kornstein & Smith, 2004). Only two controlled trials have demonstrated
efficacy for intermittent dosing of anxiolytic medication for treating PMS
(e.g., Freeman, Rickels, Sondheimer, & Polansky, 1995). However, treatment
with SSRIs can result in decreases in both anxiety and depression symptoms,
with the option to add anxiolytics if residual anxiety symptoms remain
(Rapkin, 2003). Several reviews of the existing literature on antidepressant
treatment of PMS and PMDD are available (e.g., Kornstein & Smith, 2004;
Dimmock, Wyatt, Jones, & OBrien, 2000). Clearly, more research is needed
on what components of psychological and biological treatments are effective
for anxiety symptoms across the menstrual cycle.
197
198
S. T. Sigmon, J. G. Schartel
number of normal women and those suffering from menstrual or clinical anxiety
disorders may experience increased anxiety symptoms during the premenstrual
phase. Prospective assessment of at least 2 months is necessary to determine if
the anxiety symptoms only increase during the premenstrual phase. Such a
determination is crucial given that different treatment options may be
warranted. If anxiety symptoms persist across all phases of the menstrual
cycle, then treatment may be focused more on anxiety than phase-specific
effects. Thus, assessment and treatment decisions are crucial given the possible
complex relationships between anxiety and the premenstrual phase.
Future Research
Although anxiety is often associated with premenstrual complaints and
premenstrual exacerbation of anxiety disorders has been documented, more
research needs to be conducted that distinguishes between the symptoms of
anxiety disorders and premenstrual disorders. The complex interactions of
steroidal hormones with neurotransmitters associated with the development
and maintenance of anxiety and its disorders deserves more attention. Following
the tenets of the biopsychosocial approach to understanding premenstrual
difficulties may prove useful in research that attempts to disentangle some of
the complexities of these relationships. In addition, prevention research in
adolescence that targets emotional vulnerability factors, such as anxiety sensitivity may be helpful.
There continues to be a great need for more basic research on furthering our
understanding of the physiological and psychological bases of how menstrual
199
cycle phases and anxiety interact. More information is also needed to increase
our understanding of how beliefs, expectations, cultural knowledge, and
personal experiences influence the experience, reporting, and attribution of
symptoms as well as the perception of control over them. A taxometric
approach may also be helpful in investigating emotional vulnerability factors
in the prediction of premenstrual anxiety. Finally, measurement issues need to
be addressed. The use of prospective monitoring over longer periods of time
coupled with agreement over definitions of premenstrual concepts needs to
standardized. In general, the relationship between menstrual cycle effects and
anxiety symptomatology needs further refinement.
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Introduction
There is growing evidence that chronic pain, typically that which is associated
with the musculoskeletal system (e.g., arthritis, low back pain, fibromyalgia),
frequently co-occurs with the anxiety disorders. This co-occurrence is often
overlooked in practice because it is neither standard protocol nor obvious that
clinicians consider pain experiences in the context of screening or assessment of
anxiety disorders. Yet, people with both an anxiety disorder and chronic
musculoskeletal pain typically present with greater distress and functional
impairment compared to those with only one of these conditions. As a result,
both assessment and treatment can be complicated. The goals of this chapter
are several. First, we review the core characteristics of acute and chronic pain,
and present data regarding the extent of its co-occurrence with the anxiety
disorders. Second, we summarize models that have been offered to explain the
co-occurrence of these conditions. Third, we review evidence supporting the
postulates of these models. Fourth, we discuss practical issues that are intended
to improve assessment, treatment, and outcomes for people who present with
an anxiety disorder accompanied by clinically significant pain. Much of the
discussion focuses on the relationship between chronic musculoskeletal pain
and posttraumatic stress disorder (PTSD), as it is the anxiety disorder that has
received the most empirical attention in this context. We conclude with a brief
outline of issues that warrant future research attention.
Gordon J. G. Asmundson
Anxiety and Illness Behaviours Laboratory, University of Regina, Regina, Saskatchewan,
S4S 0A2, Tel: (306) 347-2415, Fax: (306) 585-4854
gordon.asmundson@uregina.ca
207
208
G. J. G. Asmundson et al.
Understanding Pain
Pain was once conceptualized strictly as a sensory experience resulting from
stimulation of specific noxious receptors, such as might occur at the time of
physical injury or from progressive disease. We now understand that pain is
more than sensation. Contemporary models of pain recognize that it is a
complex perceptual experience that is determined by sensory as well as psychological (i.e., thinking, emotions, behaviors) and social influences (Asmundson
& Wright, 2004). Generally speaking, we experience pain in order to adapt to
and survive in our environment; that is, pain alerts us that potential or actual
tissue damage may be pending, and it motivates us to take action to limit
damage and recover from it (Wall, 1978). Compelling evidence for the adaptive
significance of pain comes from observations of people who have a rare autosomal recessive genetic disease called congenital analgesia. These individuals do
not experience pain and, as a consequence, often die in childhood from the
effects of undetected (i.e., painless) life threatening injuries or disease (for
review, see Nagasako, Oaklander, & Dworkin, 2003).
For most people, physical injury or disease is accompanied by pain. This
pain typically abates with recovery. However, for some people pain becomes
chronic (i.e., persists for three months or more; International Association for
the Study of Pain, 1986), losing its adaptive qualities and, instead, causes
considerable emotional distress and impairment of social and occupational
abilities. Many people with chronic pain make frequent physician visits, sometimes undergo inappropriate medical evaluations, and miss work and other
important activities because of their symptoms and associated suffering
(e.g., Gureje, Von Korff, Simon, & Gater, 1998). As a result, chronic pain has
become one of the most common chronic health conditions in North America.
Estimates from the US indicate that approximately 7% of the general population has experienced chronic pain in the past 12 months (McWilliams, Cox, &
Enns, 2003) at a cost of about $100 billion annually (Weisberg & Vaillancourt,
1999). While chronic pain is often associated with these negative outcomes, it is
important to note that some people with chronic pain cope effectively with the
pain, and adapt to it in a manner that does not impose limitations on their wellbeing.
In recent years it has become increasingly evident that a substantive number
of people who have an anxiety disorder also have chronic pain symptoms.
Likewise, people with chronic pain frequently report significant expressions
of fear and anxiety, often at levels and with impacts that warrant diagnosis of an
anxiety disorder. Fear and anxiety specific to pain, while prevalent in some
people with chronic pain, are not the focus of this chapter; these constructs are
discussed in detail elsewhere (e.g., Asmundson, Vlaeyen, & Crombez, 2004).
Below we review the available data on the epidemiology of co-occurring clinically significant pain and anxiety disorders in both community and treatmentseeking samples. It is noteworthy that chronic musculoskeletal pain has
209
received the vast majority of theoretical and empirical attention with regard to
co-occurrence with the anxiety disorders; thus, unless otherwise indicated, it
will be the focus of much of the discussion that follows.
Epidemiology
Prevalence of Anxiety Disorders in Pain Samples
Investigators have consistently observed that rates of some anxiety disorders are
elevated in people with chronic musculoskeletal pain. Table 1 and Table 2 show
the 12-month prevalence of various anxiety disorders in people reporting
primarily chronic musculoskeletal or migraine headache pain in community
and treatment seeking samples, respectively. In community samples, the most
prevalent past 12-month anxiety disorders were specific phobia (formerly
simple phobia; ranging from 12.5% to 15.7%), social anxiety disorder (SAD;
ranging from 8.3% to 11.8%), and PTSD (ranging from 7.3% to 10.7%). This
pattern of findings is consistent with, but higher than, the general US population 12-month prevalence rates (i.e., specific phobia, 8.7%; SAD, 6.8%; PTSD,
3.5%; Kessler, Chiu, Demler, & Walters, 2005). In a large (N=85,088) survey
of community dwelling adults from 17 countries, Demyttenaere et al. (2007)
most recently reported pooled results indicating that those with back or neck
pain, compared to those without, were approximately two times more likely to
have had past 12-month panic disorder (PD)/agoraphobia and SAD, and
almost three times more likely to have had generalized anxiety disorder
(GAD) or PTSD. Raphael, Janal, Nayak, Schwartz, and Gallagher (2006)
have likewise reported that community-dwelling women with fibromyalgia
were five times more likely than others to have had a lifetime diagnosis of
obsessive-compulsive disorder (OCD), four times more likely to have had
PTSD, and more than four times as likely to have had GAD.
In treatment seeking samples the most prevalent past 12-month anxiety
disorders were phobic disorders (including SAD; ranging from 9% to 13%),
followed generally by GAD (ranging from 0% to 13.4%) and PD (ranging from
1% to 7.2 %). Twelve-month prevalence of any anxiety disorder was 26.5% to
35.1% in community samples with chronic pain, and 8 to 28.8% in treatment
seeking samples with chronic pain, both elevated relative to the general population (18.1%; Kessler, Chiu, et al., 2005). Lifetime prevalence of various anxiety
disorders reported by patients with chronic musculoskeletal pain, as illustrated
in Table 2, have been elevated relative to the general population (Kessler,
Berglund, Demler, Jin, & Walters, 2005) in some (Atkinson, Slater, Patterson,
Grant, & Garfin, 1991), but not all (Kinney, Gatchel, Polatin, Fogarty, &
Mayer, 1993; Polatin, Kinney, Gatchel, Lilio, & Mayer, 1993), studies.
It is noteworthy that the 12-month and lifetime prevalence rates for PTSD in
the treatment seeking chronic pain samples described in Table 2 were neither
Nationally
representative
sample of the
U. S.
population (n
= 3032)
Nationally
representative
sample of the
U. S.
population (n
= 5692)
McWilliams et
al. (2004)
DSM-III-R
National
Comorbidity
Survey
Replication
(NCS-R)
DSM-IV
Midlife
DSM-III-R
Development in
the United States
Survey (MIDUS)
National
Comorbidity
Survey Part II
(NCS)
Arthritis (n = 588)
Panic attacks
GAD
Migraine (n = 340)
Panic attacks
GAD
Back pain (n = 614)
Panic attacks
GAD
13.0
6.2
17.4
9.1
11.2
5.6
5.3
2.5
5.5
2.5
5.8
2.7
Nationally
representative
sample of the
U. S.
population (n
= 5877)
McWilliams et
al. (2003)
Table 1 Prevalence of anxiety disorders among persons with pain (community samples)
Study
Participants
Data set
Diagnostic criteria % Meeting criteria for an anxiety disorder
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G. J. G. Asmundson et al.
DSM-III
Fishbain et al.
(1986)
Atkinson et al.
(1991)
DSM-III
Large (1986)
DSM-III-R
DSM-III
DSM-III
DSM-III
Any anxiety
disorder
Generalized
disorder
PD
OCD
Any anxiety
disorder
PD
Phobic disorders
OCD
PTSD
GAD
PD
OCD
Any anxiety disorder
PD
Phobic disorders
OCD
PTSD
GAD
3.0
17.0
3.0
2.0
4.0
Generalized disorder
8.2
13.4
29.0
22.7
37.9
3.0
13.0
3.0
2.0
4.0
7.2
8.2
25.0
13.4
28.8
8.0
4.0
2.0
2.0
19.4
16.2
7.0
DSM-III-R
Diagnostic
Criteria
Any anxiety
disorder
PD
Phobic disorders
OCD
PTSD
GAD
3.0
11.0
2.0
1.0
2.0
19.0
17.0
PD
3.0
Phobic disorders
9.0
OCD
2.0
PTSD
1.0
GAD
2.0
Asmundson et al.
Chronic musculoskeletal pain patients
DSM-IV
Any anxiety disorder
17.0
(1996)
(n = 200)
PD
2.1
SP
11.0
SiP
2.7
OCD
0.0
PTSD
2.1
GAD
0.0
Note: PD = Panic Disorder; OCD = Obsessive-Compulsive Disorder; PTSD = Posttraumatic Stress Disorder; GAD = Generalized Anxiety
Disorder; SP = Social Phobia (also called social anxiety disorder); SiP = Simple Phobia; Not all studies evaluated all anxiety disorders.
Participants
Study
Table 2 (continued)
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G. J. G. Asmundson et al.
213
214
G. J. G. Asmundson et al.
ranging from 50% to 80% (for recent reviews, see Asmundson et al., 2002; Otis
et al., 2003). Recent findings from a sample of female veterans using the
Veterans Administration (VA) Health Care System confirm that these finding
generalize across gender (Asmundson, Wright, & Stein, 2004). Road traffic
collisions, work-related injury, and service in combat and emergency theatres
are the most common events precipitating the development of PTSD accompanied by chronic pain (Asmundson, Norton, Allerdings, Norton, & Larsen,
1998; Beckham et al., 1997; Blanchard & Hickling, 2004).
Sareen, Cox, Clara, and Asmundson (2005) recently used data from the US
National Comorbidity Survey Part II to evaluate associations between the
anxiety disorders and diagnoses of general medical conditions, including
those for which pain is often a significant component. After controlling for
socio-demographic variables and other common mental disorders, robust associations were found amongst PTSD, panic attacks, and agoraphobia and the
physical disorders. Most strikingly, individuals with PTSD were more than
twice as likely as others to have a past-year neurological disorder (e.g., multiple
sclerosis), roughly twice as likely to have a past-year gastrointestinal disorder
(e.g., ulcer, hernia), more than three times as likely to have a past-year metabolic or immune disorder (e.g., diabetes, lupus), two and one half times as likely
to have a past-year bone or joint conditions (e.g., arthritis, rheumatisms, other
bone/joint disease), and almost twice as likely as others to have one or more
past-year physical disorders.
Overall, it appears that conditions characterized by some degree of persistent
pain are prevalent in people with anxiety disorders, particularly PTSD and
panic-related conditions. This avenue of inquiry is in its infancy; thus, further
investigation geared toward replication of findings in community and treatment-seeking samples, using comprehensive pain assessment batteries, is
warranted.
Course
Few studies have systematically investigated the extent to which anxiety disorders exist prior to the onset of pain, or vice versa. There is some evidence to
suggest that anxiety disorders precede the onset of pain. In a sample of injured
workers with chronic musculoskeletal pain, Asmundson, Jacobson, Allerdings,
and Norton (1996) found that in all but one case, the anxiety disorder preceded
the pain complaint. Kinney et al. (1993) found that among 90 chronic low back
pain patients, 23% had a preexisting anxiety disorder. In the only prospective
study to date, we recently demonstrated that PTSD symptoms measured prior
to surgery made a unique contribution to the prediction of post-surgical pain
disability in chronic pain patients undergoing general surgery (Martin, Dzyuba,
Halket, Asmundson, Katz, 2007); thus, PTSD symptoms may be important in
the development and/or maintenance of pain disability. There is also evidence
215
that the probability of onset of an anxiety disorder before versus after pain
onset is comparable. In a study of 97 chronic back pain patients, 30 of whom
had a comorbid anxiety disorder, 46.7% reported onset of anxiety before pain,
and 53.3% reported onset after pain (Atkinson et al., 1991). Additional
research, particularly that which uses prospective methods, is needed to delineate the temporal sequence of co-occurring anxiety disorders and chronic pain.
Theoretical Overview
The substantial degree of co-occurrence of the anxiety disorders and clinically
significant pain experiences suggests that these conditions are related in some
way. Yet, establishing co-occurrence provides neither an understanding of the
nature of the associations between the conditions nor an understanding of
the mechanisms by which they are linked. There are several possible scenarios
that might explain the relationship. For any two variables (or, in this case,
conditions), possible relationship scenarios are as follows: (1) one causes the
other (i.e., the anxiety disorder causes pain or vice versa), (2) they influence one
another in some mutually maintaining way (e.g., pain exacerbates symptoms of
the anxiety disorder and vice versa), or (3) some third factor (e.g., a common
predisposition, a shared environmental event) increases vulnerability to both.
The second and third possibilities are not mutually exclusive.
There are, to the best of our knowledge, no theoretical positions that explicate the first of the possibilities noted above; nor are there data to support the
position that one condition causes the other. Several models, rooted in the
second and third possibilities, have been recently posited to explain the relationship between the anxiety disorders and chronic pain. For the most part, they
have been developed in the context of efforts to understand mechanisms underlying co-occurring PTSD and chronic musculoskeletal pain, and are based
on tenets of empirically supported cognitive-behavioral models of each of
these conditions (e.g., Ehlers & Clark, 2000; Foa & Rothbaum, 1998; Norton
& Asmundson, 2003; Vlaeyen & Linton, 2000). Below we review these models
and speculate on their value in explaining the association between the other
anxiety disorders and chronic musculoskeletal pain.
216
G. J. G. Asmundson et al.
example, that pain sensations experienced by a person with chronic musculoskeletal pain will be persistent and arousal-provoking reminders of the trauma
that precipitated the pain. Physiological arousal in response to recollection of
the trauma will, in turn, promote avoidance of pain-related activities and (over
time) physical deconditioning, which makes the experience of pain more likely.
The person thereby becomes trapped in a vicious cycle whereby the symptoms
of PTSD and chronic musculoskeletal pain interact to produce self-perpetuating distress and functional disability.
Psychological
Vulnerability
(e.g., high injury
sensitivity, high
anxiety sensitivity)
Autonomic Nervous
System and Muscular
Responsivity
Life Event
(e.g. traumatic
incident, injury)
Emotional
Response
(e.g. fear, anxiety,
worry, agitation)
Avoidance
of situations or activities
perceived as negative
Hypervigilance and
Cognitive Biases
Disabling
Condition
(specific or
co-occurring)
217
Summary
It is plausible that postulates of the mutual maintenance and shared vulnerability models will prove useful in delineating why some, if not all, of the anxiety
disorders are often accompanied by conditions characterized by chronic pain
(and vice versa). Efforts to understand the mechanisms of co-occurrence are
only just beginning; however, as summarized below, there is a growing body of
support for these postulates emerging from investigations of co-occurring
PTSD and chronic musculoskeletal pain.
218
G. J. G. Asmundson et al.
Symptom Overlap
There is considerable symptom overlap between PTSD and chronic musculoskeletal pain. Both are characterized by somatic hypervigilance and (possibly)
biases in attention toward threatening stimuli, heightened startle, emotional
numbing (e.g., absence of positive emotion), avoidance, and dysregulations
in stress response and pain modulation (for review, see Asmundson et al.,
2002). These findings indicate that PTSD and chronic musculoskeletal pain
share similar response patterns in the cognitive, behavioral, and physiological
domains. There is also evidence to suggest that particular PTSD symptom
clusters are more closely associated with certain aspects of the pain experience;
for example, re-experiencing symptoms are uniquely associated with pain
severity, self-report of physical symptoms, and limitations in functional ability
(Asmundson, Wright, et al., 2004; Beckham et al., 1997; Zoellner, Goodwin, &
Foa, 2000), whereas hyperarousal is associated with detection of pain
(Asmundson, Wright, McCreary, & Pedlar, 2003).
Anxiety Sensitivity
AS (i.e., fear of anxiety based on the belief that it may have harmful consequences) is one of several individual difference factors that increase sense of
danger and fearful responding. AS is elevated in patients with PTSD (Taylor
et al., 2001, 2003) and in some patients with chronic musculoskeletal pain (for
review, see Asmundson, Wright, & Hadjistavropoulos, 2000), is positively
correlated with the severity of PTSD symptoms (Fedoroff, Taylor, Asmundson,
& Koch, 2000), increases the risk of pain-related avoidance and disability
following physical injury (for review, see Keogh & Asmundson, 2004), and
is partly influenced by genetic factors (Stein, Jang, & Livesley, 1999). Consequently, it has been postulated that AS is responsible for the extreme emotional
219
responses to trauma and pain associated with injury, and that it denotes the
specific vulnerability that predisposes people to develop both PTSD and
chronic musculoskeletal pain (Asmundson et al., 2002; Asmundson & Taylor,
2006; Turk, 2002). It has yet to be established that elevated AS precedes the
development of PTSD and chronic musculoskeletal pain; thus, it remains a
possibility that AS becomes elevated as a consequence of PTSD and chronic
musculoskeletal pain and thereafter serves to maintain symptoms (see Sharp &
Harvey, 2001). Longitudinal studies are needed to assess these possibilities.
Additional study of other potential vulnerability factors (e.g., illness/injury
sensitivity, fear of pain) is also warranted.
220
G. J. G. Asmundson et al.
221
and neural tissue when prolonged (e.g., Kiecolt-Glaser, McGuire, Robles, &
Glaser, 2002; Melzack & Katz, 2004). In short, prolonged physiological arousal
and activation of neural and hormonal processes, whether initiated by pain or
anxiety, act as a stressor (i.e., they are perceived as threatening and uncontrollable) that can have detrimental effects on various body systems (McEwen,
1998). Illustrating these effects, and as noted in our discussion of epidemiology
of co-occurrence, Sareen et al. (2005) found strong associations between anxiety
disorders, particularly PTSD, and general medical conditions characterized
by pain.
We have been particularly interested in the role that autonomic nervous
system (ANS) dysregulation may play in anxiety disorders and in chronic
musculoskeletal pain. This interest is predicated on the notion that chronic
arousal is, in part, responsible for the symptoms of both conditions. One of the
most robust findings reported in the PTSD literature over the past two decades
is that sympathetic activity is increased and parasympathetic activity decreased,
both in general and in response to trauma-related stimuli. This pattern of
findings has been observed across a wide variety of measures of cardiovascular
reactivity in both traumatized adults (Keane et al., 1998) and children
(Scheeringa, Zeanah, Myers, & Putnam, 2004). Although ANS dysregulation
in chronic musculoskeletal pain has received little empirical scrutiny, available
findings suggest a pattern similar to that observed in PTSD. Rainville, Bao, and
Chretien (2005), for example, used hypnosis to alter mood, perceived pain
unpleasantness, and severity of pain induced in healthy participants, showing
that increases in negative mood and pain unpleasantness were positively associated with changes in heart rate variability. This suggests that pain-related
emotion impacts ANS responsivity. We recently completed an investigation of
patients with chronic musculoskeletal pain (n=33), acute musculoskeletal pain
(n=12), and healthy controls (n = 30) using tasks designed to evoke measurable, bi-directional ANS responses. Preliminary analyses indicate no betweengroup differences with regard to tasks that augment vagal tone; however, the
chronic pain patients exhibited increased sympathetic activity compared to
controls on tasks designed to induce rapid vagal withdrawal followed by
sympathetic discharge (i.e., dysregulated sympathetic discharge). Collectively,
these data indicate both PTSD and chronic musculoskeletal pain are characterized by labile sympathetic responsivity.
The literature regarding pain threshold (i.e., the point at which a stimulus is
detected as being painful) and pain tolerance (i.e., the length of time that a pain
stimulus can be endured) in each of PTSD and chronic musculoskeletal pain
may also provide some clues as to the mechanism of association; however, the
findings are mixed and complex. There is, for example, a body of evidence
indicating that hyperalgesia (i.e., reduced pain threshold and tolerance or, in
other words, exaggerated pain perception) is induced by elevations in state and
trait anxiety (e.g., Carter et al., 2002; James & Hardardottir, 2002). Since
elevations in state and trait anxiety are central features of PTSD and chronic
musculoskeletal pain, it is plausible that PTSD and chronic musculoskeletal
222
G. J. G. Asmundson et al.
pain may induce hyperalgesia. On the other hand, there is a body of literature
indicating that conditioned stress-induced hypoalgesia/analgesia (i.e., increased
pain threshold and tolerance or, in other words, attenuated pain perception)
plays an important and potentially causal role in both chronic musculoskeletal
pain (e.g., Flor, Birbaumer, Schulz, Grusser, & Mucha, 2002) and PTSD (e.g.,
Foa, Zinbarg, & Rothbaum, 1992). This literature suggests that dysregulation
of the endogenous opioid system perhaps functioning to deactivate fear
structures in the short term through heightened release of endogenous opioids
may play a role in blunting pain perception (e.g., higher pain threshold and
tolerance), reducing avoidance behavior, and increasing emotional numbing
associated with chronic musculoskeletal pain and PTSD. It is noteworthy that
pain tolerance, but not threshold, is affected by naloxone (a drug that blocks
opioid receptors) only when pain levels are high, suggesting only partial mediation by the endogenous opioid system.
These mixed findings are intriguing when placed in the context of evidence
showing that AS does not impact pain tolerance or threshold, but is associated
with pain intensity (for review, see Keogh & Asmundson, 2004). It is possible
that different mechanisms may be operating at different levels of the stimulusresponse range (i.e., from just noticeable sensation through intolerable pain) and
that their operations are partially regulated by individual difference factors that
influence processing of pain sensation as alarming. Given recent observations
that unpredictable and predictable pain are associated with hyperalgeisa and
hypoalgesia/analgesia, respectively (Ploghaus, Becerra, Borras, & Borsook,
2003), it is equally possible that different mechanisms are operative depending
on whether pain evokes anxiety (i.e., response to unpredictable, future threats)
or fear (i.e., response to an immediate threat).
Chronic dysregulation of the ANS and endogenous opioid system appears to
play important, possibly interactive roles in reducing the threshold for alarm in
PTSD and chronic musculoskeletal pain and, in part, may account for their
substantive co-occurrence. This remains to be evaluated in direct comparisons
between those with PTSD, chronic musculoskeletal pain, both PTSD and
chronic musculoskeletal pain, and healthy as well as clinical control participants. This, combined with evidence that the serotonergic system an aminergic neurotransmitter system responsible for maintaining homeostasis via
modulation of the release of 5-HT from serotonergic neuron terminals may
be dysregulated in both PTSD and chronic musculoskeletal pain (e.g., Davidson & Connor, 2001), provides clues as to the peripheral and central physiological mechanisms underlying the suggestion of a lower threshold for alarm.
Summary
There exists a small and growing body of empirical support for postulates of the
mutual maintenance and shared vulnerability models of co-occurring PTSD
223
Assessment
Comprehensive assessment of pain requires delineation of pain severity or
intensity, pain location and distribution, attitudes and beliefs about pain and
its effects, ways of coping with pain, pain-specific emotional distress (i.e., fear,
anxiety, mood changes), and pain-related functional abilities and limitations
(Asmundson, 2002; Tait, 1999). Below we highlight specific assessment methods that may be useful in the context of assessing pain in patients with anxiety
disorders. We assume that (a) a comprehensive assessment of the anxiety
disorders and related Axis I and Axis II psychopathology has been conducted,
(b) individual difference factors pertinent to the anxiety disorders and relevant
in the context of mutual maintenance and shared vulnerability, particularly AS,
have been assessed (see Taylor, 1999), and (c) appropriate steps will or have
been taken to identify and medically address organic pathology or other identifiable physical factors that might account for the patients presenting pain
symptoms.
Assessment methods include reviewing hospital medical records (in order
to chart the course of the patients problems), clinician-administered structured
clinical interviews, clinician observation techniques (e.g., pain behaviors, facial
action coding), prospective monitoring forms, and self-report questionnaires.
In the context of patients presenting for treatment of an anxiety disorder, and
for future research efforts, we recommend brief semi-structured interviewing
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225
pain-related anxiety, including cognitive anxiety (e.g., I find it hard to concentrate when I hurt), fearful appraisal of pain (e.g., Pain sensations are terrifying),
escape and avoidance behavior (e.g., I try to avoid activities that cause pain),
and physiological anxiety associated with pain (e.g., Pain seems to cause
my heart to pound or race). Individuals rate each item on a 6-point Likert
scale ranging from 0 (never) to 5 (always). The PASS and PASS-20 have been
found to have good psychometric properties. While both versions of the PASS
are widely used, several other measures of pain-related anxiety are available; for
a detailed discussion see Asmundson and Carleton (in press).
Chronic Pain Coping Inventory (CPCI; Jensen, Turner, Romano, & Strom,
1995). The 65-item CPCI, and its abbreviated 42-item short form (Romano,
Jensen, & Turner, 2003), measure cognitive and behavioral strategies that
people might use while experiencing or trying to prevent pain. Eight coping
strategies are assessed, including positive coping self-statements, guarding,
resting, asking others for assistance, seeking social support, relaxing, task
persistence, and exercising. Use of past-week coping strategies is measured on
an 8-point scale expressed in number of days. The CPCI provides a comprehensive and psychometrically valid assessment of pain-related coping strategies
(Hadjistavropoulos, MacLeod, & Asmundson, 1999).
Treatment
Cognitive-behavioural therapy (CBT) is a highly effective treatment for both
anxiety disorders (Butler, Chapman, Forman, & Beck, 2006) and chronic pain
(Morley, Eccleston, & Williams, 1999). Therefore, treatment of clinically significant pain in patients with an anxiety disorder may effectively incorporate
elements of CBT for both the anxiety disorder and chronic pain. While the
specific application of CBT for managing pain in patients with anxiety disorders is still in its infancy it is, nonetheless, very promising. Several features of
CBT for managing pain can be used in the context of CBT for the anxiety
disorders. These include psychoeducation, relaxation training, attention diversion strategies, cognitive restructuring, graded activity, and one or more of
several exposure techniques.
Psychoeducation. Patients experiencing pain often desire to be pain-free. This
goal is somewhat unrealistic. Accordingly, education can be used to help the
patient reformulate his or her view of pain as a signal of impending catastrophe
(e.g., permanent disability, disease, reinjury) to one of pain as a common
experience that can be self-managed. A basic understanding of the typical
course of pain (and, if appropriate, healing), combined with appreciation of
the premise that hurt does not always equal harm, can ameliorate reservations
about making pain worse and thereby encourage activity participation. A key
advantage of psychoeducation is that it is simple to administer and can be
delivered in groups.
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227
228
G. J. G. Asmundson et al.
229
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Asthma is a respiratory disease with symptoms including reversible airway obstruction, airway inflammation, and hyperactive airways that affects approximately 6%
to 9% of the U.S. population (Carr, 1998; Turkeltaub & Gergen, 1991). Asthma is
one of the most chronic respiratory disorders and the cost of caring for asthma is
estimated to be higher than that of AIDS/HIV and tuberculosis combined (World
Health Organization, 2000). Furthermore, the economic impact of asthma is
considerable, with total US expenditures for 1990 in excess of $6 billion (Weiss,
Gergen, & Hodgson, 1992). Individuals with asthma appear to be at an increased
risk for psychological difficulties, and report high prevalences of anxiety,
depressive, and substance disorders (Scott et al., 2007). Although asthma is a
treatable condition, morbidity and mortality due to asthma have increased
(Afari, Schmaling, Barnhart, & Buchwald, 2001; Sly, 1988; Weiss, Gergen,
Wagener, 1993). The availability of efficacious interventions for the management
of asthma suggests that some proportion of poor outcomes is preventable
(Greineder, Loane, & Parks, 1995). This conclusion has prompted health care
providers to give special attention to risk factors for poor asthma outcomes.
Psychological difficulties may increase the distress associated with asthma symptoms and may be linked with poor asthma management (Katon, Richardson,
Lozano, & McCauley, 2004; Lavoie et al., 2005). The current chapter reviews
literature examining the relation between asthma and anxiety symptoms and disorders. The chapter will begin with a brief description of asthma symptomatology,
assessment, treatment, and non-psychological risk factors. The general association
between asthma and anxiety disorders in children and adults will then be reviewed
followed by a more in depth examination of the relation between asthma and panic
disorder. Next, the chapter will review studies that examine the link between anxiety
and asthma severity, control, and quality of life. The relation between psychological
vulnerabilities to anxiety and asthma will then be discussed. The chapter will then
Lisa S. Elwood
National Crime Victims Research and Treatment Center, Medical University of South
Carolina, 165 Cannon Street, P.O. Box 250852, Charleston, SC 29425, Tel: 843-792-2366,
Fax: 843-792-3388
elwood@musc.edu
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L. S. Elwood, B. O. Olatunji
consider the specificity of the relation between asthma and anxiety. Finally,
cognitive behavioral models of the asthma and anxiety relation will be provided
and the efficacy of cognitive behavioral treatments for individuals with asthma will
be reviewed.
Asthma
During an acute asthma attack, a stimulus initiates an airway response that
includes inflammation, bronchospasm, and increased mucus production (Sims,
2006). Additional asthma symptoms include coughing, wheezing, shortness of
breath, and tightness in the chest. An individuals asthma symptoms can be
classified as mild intermittent, mild persistent, moderate persistent, or severe
persistent (Banasiak, 2007). Although the diagnosis and classification of
asthma varies, three factors are typically taken into consideration when classifying the severity of asthma: frequency of daytime symptoms, frequency of
nighttime symptoms, and lung functioning. Lung functioning is assessed using
peak flow rates and forced expiratory volume in 1 second (FEV1). The FEV1
is the amount of air the individual is able to forcibly exhale in 1 second. FEV1 is
measured using spirometry, with a lower number indicating increased severity
(Sims, 2006). Peak expiratory flow (PEF) rates compare the individuals pulmonary functioning to what is normal for his or her height, age, weight, and sex.
Normal peak flow rates range from 80% to 100%, while severe asthma attacks
yield peak flow rates of less than 60% (Sims, 2006). An individual with mild
intermittent asthma endorses daytime symptoms less than twice a week, nighttime symptoms less than twice a month, FEV1 or PEF greater than 80% of the
predicted amount, and PEF variability of less than 20%. Mild persistent asthma
includes daytime symptoms greater than two times a week, nighttime symptoms
greater than two times a month, and FEV1 or PEF rates greater than 80% with
2030% variability. Criteria for moderate persistent asthma include daily daytime symptoms, nighttime symptoms more than once a week, and FEV1 or PEF
greater than 6080% predicted with PEF variability of greater than 30%.
Finally, severe persistent asthma describes persistent daily symptoms, frequent
nighttime symptoms, and FEV1 or PEF less than 60% of the predicted value
with PEF variability greater than 30% (Banasiak, 2007). Asthma is often treated
using bronchodilators, corticosteroids, and leukotriene antagonists (Sims, 2006).
Research has revealed that there is a considerable amount of variability in
the course of asthma. It has been suggested that asthma should be conceptualized as a syndrome, with many etiologies that may result in different presentations and outcomes (Reed, 2006). Different asthma etiologies may include
intermittent wheezing with respiratory infection in infants, Immunoglobulin
E (IgE; related to allergic responses) mediated asthma, intrinsic asthma, and
asthma associated with other chronic lung diseases (Reed, 2006). While frequent wheezing in infancy is associated with an increased likelihood of chronic
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L. S. Elwood, B. O. Olatunji
Atopy has consistently been supported as a risk factor for asthma (Shapiro,
2006). Atopy describes an allergic response which frequently affects parts of the
body that are not in contact with the allergen. Atopic responses include eczema,
allergic rhinitis, and allergic conjunctivitis. Both the presence of atopy in the
child and parental atopy or asthma appear to serve as risk factors for the
development or maintenance of asthma symptoms in children (Shapiro,
2006). Studies have consistently shown a high comorbidity between asthma
and rhinitis (i.e., irritation and inflammation of the nose) and have posited that
rhinitis serves as a risk factor for asthma (Bousquet, van Cauwenberge, &
Khaltaev, 2001). It has been proposed that rhinitis and asthma may be two
expressions of a common mucosal susceptibility and may affect and amplify
each other (Jani & Hamilos, 2005). For individuals with both rhinitis and
asthma, there is some evidence that treatment of rhinitis may improve coexisting asthma symptoms (Bousquet et al., 2001). Other medical conditions
that have been associated with asthma include heartburn and acid regurgitation
(Hancox et al., 2006).
Studies suggest that smoking or being exposed to second hand smoke serves
as a strong risk factor for the development of asthma (McCoy et al., 2006;
Shapiro, 2006). In fact, a recent study found that the risk of developing asthma
was significantly higher among current smokers with an adjusted odds ratio
(OR) of 1.33 (95% CI 1.001.77) and among ex-smokers with an adjusted
OR 1.49 (CI 1.121.97) compared with never-smokers (Piipari, Jaakkola,
Jaakkola, & Jaakkola, 2004). Similarly, a prospective cohort study among
2,609 children with no lifetime history of asthma or wheezing found that regular
smoking was associated with increased risk of new-onset asthma and the
increased risk from regular smoking was greater in nonallergic than in allergic
children (Gilliand et al., 2006). A third study which assessed individuals over a
eight year period reported that smokers reported a higher frequency of new
onset asthma than non-smokers, OR 2.14 (95% CI 1.303.00; Frank, Hazell,
Morris, Linehan, & Frank, 2007). A study examining poor asthma control,
based on patient diaries over a 4 week period, in individuals being treated for
asthma revealed that smoking, along with lung function and ethnicity, was
associated with the presence of asthma episodes (McCoy et al., 2006). Smoking
has been shown to be a unique and independent predictor of the development of
asthma. The smoking-asthma relation may be largely attributable to airway
narrowing and hyperresponsiveness secondary to emphysema and chronic
bronchitis.
241
factors on asthma has received relatively less attention (Katon et al., 2004). The
available literature does suggest that approximately 40% of individuals with
asthma present with clinically elevated levels of psychological distress (Mullins,
Chaney, Pace, & Hartman, 1997) with 21% to 25% reporting depressive symptoms (Badoux & Levy, 1994; Chaney et al., 1999). Furthermore, it has been
shown that asthma is longitudinally associated with a significant increase
in suicidal ideation and suicide attempt, independent of major depression
(Goodwin & Eaton, 2005). These findings highlight the importance of psychological distress in the conceptualization of the etiology, maintenance, and treatment of asthma.
Recent research has shown that a wide range of mental health problems
are common among patients with asthma (Goodwin, Messineo, Bregante,
Hoven, & Kairam, 2005). However, data from epidemiologic samples suggest
that anxiety disorders, relative to other mental health problems, are especially
prevalent among patients with asthma (e.g., Ortega, McQuaid, Canino,
Ramirez, Fritz, & Klein, 2003).
Sample
Study
Butz and
Alexander
(1993)
Goodwin
et al. (2003)
Goodwin,
Fergusson,
&
Horwood
(2004)
Classified as presence of
absence of asthma
during age 1618 and
1821. Presence was
determined by reported
diagnosis and
symptoms during the
Asthma Measurement
Anxiety Measurement
None
Asthma to no
asthma
None
Comparison
group
Table 1 Findings of studies examining the relation between asthma and anxiety in children and adolescents
Main Findings
242
L. S. Elwood, B. O. Olatunji
Sample
Study
Gupta et al.
(2001)
Table 1 (Continued)
Asthma Measurement
Main Findings
parental conflict) OR
= 1.2 (CI .52.9);
suggested a third
common factor
Compared to
cardiology
patients
Comparison
group
Anxiety Measurement
Sample
Community sample,
sample based on
island-wide probability
household sample of
children
Community sample,
sample based on
island-wide probability
household sample of
children
Study
Ortega et al.
(2003)
Ortega et al.
(2004)
Table 1 (Continued)
Parental reports of an
asthma diagnosis and
parental reports of the
child ever having an
asthma attack
Asthma Measurement
Anxiety Measurement
Children with
and without
reported
histories of
asthma
Asthma to no
asthma
Comparison
group
Main Findings
244
L. S. Elwood, B. O. Olatunji
Sample
Outpatients from
pediatric allergology
and pneumology
department compared
to healthy community
participants recruited
from schools
Study
Rietveld
(2000)
Rietveld et al.
(2000)
Vila et al.
(2000)
Table 1 (Continued)
Moderate to severe
persistent asthma
Severity of asthma
classified from one to
five; class 1 (if needed
bronchodilator) to
class 5 (oral
corticosteroids)
Severity of asthma was
classified based on
prescribed medicine:
severe, moderatesevere, moderate,
moderate-mild, mild
Asthma Measurement
STAI
STAI
Anxiety Measurement
Asthmatic
children to
controls
Compared
asthmatics
to healthy
controls
With asthma to
healthy
controls
Comparison
group
Main Findings
Wamboldt
et al. (1998)
Severity was determined
by a pediatric
pulmonologist and
allergist/immunologist
by reviewing medical
records. Asthma rated
as mild, moderate, or
severe. Parent report of
number of days missed
from school, number of
hospitalizations,
number of days
hospitalized, and
number of emergency
visits for asthma.
Asthma Measurement
RCMAS; CBCL (parent
report)
Anxiety Measurement
None
Comparison
group
Neither child-reported
anxiety nor parentreported internalizing
symptoms were
significantly elevated
Main Findings
Note. ADHD = Attention Deficit Hyperactivity Disorder, CBCL= Child Behavior Checklist, CIDI = Composite International Diagnostic Interview, DISC = Diagnostic Interview Schedule for Children; GAD = Generalized Anxiety Disorder PTSD = Posttraumatic Stress Disorder, RCMAS
= Revised Childrens Manifest Anxiety Scale, STAI = State-Trait Anxiety Interview, Sig. = p < 0.05.
Sample
Study
Table 1 (Continued)
246
L. S. Elwood, B. O. Olatunji
247
McQuaid, Canino, Goodwin, & Fritz, 2004) samples. The association between
asthma and anxiety in children has been reported by studies using a variety of
methodologies, including cross-sectional (Butz & Alexander, 1993; Gupta et al.,
2001; Vila et al., 2000), epidemiological (Goodwin et al., 2003; Ortega et al., 2003;
Ortega et al., 2004), and longitudinal (Goodwin et al., 2004). However, it should
be noted that some studies have failed to find a relation between asthma and
anxiety in children (e.g., Wamboldt, Fritz, Mansell, McQuaid, & Klein, 1998).
While one study reported that children suffering from asthma report higher levels
of general anxious symptoms than healthy controls (Gupta et al., 2001), two
studies failed to find significant differences between children with asthma and
healthy controls on trait anxiety (Rietveld, 2000; Rietveld, Everaerd, & van Beest,
2000). A detailed review of the literature suggests that the discrepancy between
studies may partially be accounted for by methodological differences. When
relations between asthma and specific anxiety disorders are examined, asthma
has been linked specifically to panic disorder (Goodwin, Pine, et al., 2003),
separation anxiety disorder (Ortega et al., 2003; Ortega et al., 2004; Vila et al.,
2000), and generalized anxiety disorder (Vila et al., 2000) in children.
The inconsistent findings regarding the relationship between asthma and
anxiety in children highlights the importance of considering sampling
approaches as well as the source of data. For example, Wamboldt and colleagues (1998) found that child and parent ratings of the childs psychological
symptoms displayed inconsistent patterns. While the childs reported level of
anxiety failed to be significantly related to asthma severity, asthma severity was
significantly related to parents ratings of the childs internalizing symptoms. In
addition, parental ratings of the childs internalizing symptoms were significantly related to the parents personal level of physical symptoms, suggesting
that parental reports of child symptoms may be biased by their own distress
(Wamboldt et al., 1998).
Recruited participants
using medication
regularly scheduled to
receive prednisone at an
asthma clinic,
Evidence of asthma,
recruited from an
asthma clinic
Afari et al.
(2001)
Brown et al.
(2000)
Di Marco
et al. (2006)
Davis et al.
(2002)
Sample
Study
diagnosis of COPD;
FEV1 values; Italian
versions of the
modified Medical
Resource Council
dyspnea scale and the
St. Georges
Respiratory
Questionnaire
objective evidence of
asthma based on the
Canadian Consensus
Guidelines
Completed a
methacholine
inhalation challenge
test to confirm
airway reactivity;
FEV1/ FVC
FEV1
Asthma Measurement
None
COPD
patients
compared
to healthy
controls
None
SCID-IV
Compared to
prevalence
rates
Comparison
group
DIS-III-R
Anxiety Measurement
Table 2 Findings of studies examining the relation between asthma and anxiety in adults
Findings
248
L. S. Elwood, B. O. Olatunji
Sample
Adult participants of an
epidemiological study
Study
Erhabor &
Mosaku
(2004)
Goodwin &
Eaton
(2003)
Goodwin,
Jacobi,
et al. (2003)
Table 2 (Continued)
Self-report of current
and past asthma
diagnosis, method of
assessment by
physician, type of
asthma, treatment
Self-report of asthma
and treatment of
asthma
Diagnosis of asthma,
Asthma Measurement
German National
Health Interview
and Examination
Survey-Mental
Health Supplement
General Health
Questionnaire,
STAI 1 and 2
Anxiety Measurement
Community
individuals
without
asthma
Individuals
with
asthma
compared
to those
without
Orthopedic
and healthy
controls
Comparison
group
Findings
Sample
Study
Goodwin &
Pine (2002)
Table 2 (Continued)
Self-report. Assessed
both respiratory
disease (asthma,
chronic bronchitis,
and emphysema) and
lung disease (other
lung disease).
Asthma Measurement
followed by Munich
CIDI
Anxiety Measurement
Community
individuals
without
respiratory
& lung
disease
Comparison
group
Findings
250
L. S. Elwood, B. O. Olatunji
Sample
Adult participants of an
epidemiological study,
data collected over 20 yrs
Study
Goodwin,
Olfson, et al.
(2003)
Halser et al.
(2005)
Table 2 (Continued)
Self-report of asthma
symptoms and selfreport of physician
diagnosis
Asthma diagnoses
obtained from billing
encounter data
Asthma Measurement
SCL-90-R, Structured
Psychopathological
Interview and
Rating of the Social
Consequences for
Epidemiology;
assessed for the
presence of panic
disorder, any panic,
and childhood
anxiety
PRIME-MD; Patient
Health
Questionnaire;
panic attack and
panic disorder were
collapsed into one
group
Anxiety Measurement
Compared
patients
with and
without
diagnoses
of asthma
Comparison
group
Findings
Heaney
et al. (2005)
Jonas et al.
(1999)
Sample
Study
Table 2 (Continued)
HADS; psychiatric
interview offered to
participants
Examined difficult to
control asthma;
Asthma defined on
the basis of symptom
with documented
reversible airflow
obstruction (FEV1 of
> 12%), skin prick
testing to 12 inhalant
allergens, chest x-ray,
and spirometric
testing; Asthma
related quality of life
assessed using the
Juniper scale
Self-report of doctor
diagnosed asthma
General Well Being
Schedule, relaxed
Anxiety Measurement
Asthma Measurement
None
Compared
treatment
(for
asthma)
responders
to
treatment
non
responders
Comparison
group
Findings
252
L. S. Elwood, B. O. Olatunji
Lavoie et al.
(2005)
Study
Spirometry was
measured as 65%
FEV1, 65%, or no
best trial.
Respiratory
symptoms were
coded as present or
absent: 1) a cough in
morning or winter or,
2) in the summer,
3) any phlegm from
chest in the morning
in the winter, or 4)
the summer, 5) a
period of increased
cough and phlegm
lasting for 3 weeks
during the past 3
years,
6) shortness of
breath, and 7)
wheezy or whistling
sounds in chest
Primary diagnosis of
asthma; Asthma
Control
Questionnaire and
Asthma Quality of
Adults 25 to 74 at baseline
and received a medical
examination.
Asthma Measurement
Sample
Table 2 (Continued)
PRIME-MD
versus anxious
scale.
Anxiety Measurement
Compared
asthma
patients
with and
without
Comparison
group
Findings
Sample
Outpatients presenting to
an anxiety disorders
specialty clinic, met
criteria for a principal
diagnosis of PD with or
without agoraphobia
Study
Meuret et al.
(2005)
Table 2 (Continued)
Anxiety Measurement
ADIS-IV-L
Asthma Measurement
Life Questionnaire
asthma diagnoses
confirmed by chart
evidence of a 20%
fall in FEV1 after
metacholine
challenge and/or
bronchodilator
reversibility in FEV1
of 20% predicted;
severity rated based
on clinical
symptoms,
medication usage,
and pulmonary
functioning
Self report
anxiety
disorders
Comparison
group
Findings
254
L. S. Elwood, B. O. Olatunji
Sample
Outpatients from an
asthma unit (age range
1380, mean 50.2)
Study
Nascimento
et al. (2002)
Perna et al.
(1997)
Table 2 (Continued)
asthma defined by
recurrent episodes of
dyspnea with diffuse
wheezing and either a
20% improvement in
FEV1 following a
nebulized b2 agonist
bronchodilator or a
20% decrease in
FEV1 after the
metacoline
bronchoprovocation
test
Age and onset of use of
beta-agonists by
inhalation obtained
from medical files.
severity of asthma
scored as mild,
moderate, or severe
based on criteria
defined by National
Asthma Education
Program.
Asthma Measurement
MINI
Anxiety Measurement
None
None
Comparison
group
Findings
Sample
Study
Pollack et al.
(1996)
Shavitt et al.
(1992)
Table 2 (Continued)
Used a computerized
grading system
developed by the
hospital
Asthma Measurement
Screening
questionnaire
asking about the
presence of panic/
anxiety symptoms
in association with
troubled breathing
or subjective
anxiety, previous
experience of panic,
agoraphobic fears,
and a question
about whether or
not they considered
themselves to be
anxious; SCID
SCID
Anxiety Measurement
None
None
Comparison
group
Findings
256
L. S. Elwood, B. O. Olatunji
Sample
Relatives of individuals
receiving treatment at an
anxiety clinic
Study
Sreedhar
(1989)
Table 2 (Continued)
Lifetime prevalence of
respiratory disorder
was assessed using a
questionnaire that
distinguishes
between asthma,
bronchitis,
emphysema, and
other respiratory
disorders; each was
rated as past and
present
Diagnosis at clinic
Asthma Measurement
MINI
Manifest Anxiety
Scale
Anxiety Measurement
General
hospital
outpatients,
neurotic
psychiatry
patients,
and
controls
(no
physical or
mental
disorder)
Relatives of
individuals
diagnosed
with panic
disorder
were
compared
to relatives
of
individuals
diagnosed
with other
anxiety
disorders
Comparison
group
Family members of
individuals with PD were
sig more likely to report
lifetime prevalence of a
COPD and of asthma
specifically than family
members of individuals
diagnosed with other
anxiety disorders
Findings
van PeskiOosterbaan
et al. (1996)
Yellowlees
et al. (1987)
Physician diagnosis
based on chart
review; International
Union Against
Tuberculosis and
Lung Disease
Questionnaire; Borg
scale to assess
breathlessness;
spirometry; FEV1
Pulmonary function
tests- FEV1, PaO2,
PaCO2
Asthma Measurement
Participants
given
diagnosis
of asthma
compared
to those
not given
diagnosis
of asthma
None
Interview assessing
DSM-III criteria
Comparison
group
ADIS-R, STAI,
Agoraphobic
Cognitions Scale,
Body Sensations
Questionnaire,
Panic Attack
Questionnaire
Anxiety Measurement
Findings
Note: ASI = ADIS = Anxiety Disorders Interview Schedule, Anxiety Sensitivity Inventory, COPD = Chronic Obstructive Pulmonary Disorder, DISR = Diagnostic Interview Schedule- Revised, FEV1 = Forced Expiratory Volume in the first second of exhalation, FVC = Full Vital Capacity, GAD
= Generalized Anxiety Disorder, HADS = Hospital Anxiety and Depression Scale, MINI = Mini International Neuropsychiatric Interview, PAs =
Panic attacks, PD = Panic Disorder, PTSD = Posttraumatic Stress Disorder, SCID = Structured Clinical Interview for DSM-III-R, SCL-90-R =
Symptom Checklist 90-R, STAI = State Trait Anxiety Inventory. Sig. = p < 0.05.
Sample
Study
Table 2 (Continued)
258
L. S. Elwood, B. O. Olatunji
259
Kelly, & Gamble, 2005; Nascimento et al., 2002; Yellowlees et al., 1987),
posttraumatic stress disorder (Brown et al., 2000), specific phobia (Brown et al.,
2000; Goodwin, Olfson, et al., 2003), and anxiety not otherwise specified
(Goodwin, Jacobi et al., 2003). The association between anxiety and asthma in
adults has been supported in clinical (Afari et al., 2001; Brown et al., 2000; Davis,
Ross, & MacDonald, 2002; Di Marco et al., 2006; Erhabor & Mosaku, 2004;
Goodwin, Olfson, et al., 2003; Heaney et al., 2005; Lavoie et al., 2005; Nascimento
et al., 2002; Perna et al., 1997; Pollack et al., 1996; Shavitt et al., 1992; Sreedhar,
1989; Yellowlees et al., 1987) and non-clinical samples (Goodwin & Eaton, 2003;
Goodwin, Jacobi et al., 2003; Goodwin & Pine, 2002; Halser et al., 2005; Jonas et
al., 1999). The relation has been reported by cross-sectional (Afari et al., 2001;
Brown et al., 2000; Davis et al., 2002; Di Marco et al., 2006; Erhabor & Mosaku,
2004; Goodwin & Pine, 2002; Goodwin, Olfson, et al., 2003; Heaney et al., 2005;
Lavoie et al., 2005; Meuret, White, Ritz, Roth, Hofmann, & Brown, 2005;
Nascimento et al., 2002; Perna et al., 1997; Pollack et al., 1996; Shavitt et al.,
1992; Sreedhar, 1989; Yellowlees et al., 1987), epidemiological (Goodwin & Eaton,
2003; Goodwin, Jacobi, et al., 2003; Halser, et al., 2005), and longitudinal (Halser
et al., 2005; Jonas, Wagener, Lando, & Feldman, 1999) studies. Recently, the
World Mental Health Survey examined the relation between psychopathology
and asthma (Scott et al., 2007). Participants from 17 different countries provided
information about whether or not they had ever been diagnosed with asthma and
completed a structured interview to assess for the presence of selected psychological disorders (GAD, panic disorder, PTSD, social phobia, dysthymia, major
depressive disorder, and alcohol use and dependence) in the past year. The pooled
estimate of the OR for the anxiety disorders fell within the 1.31.8 (all anxiety
disorders exhibited an OR greater than 1) and the pooled estimate of the OR for
any anxiety disorder was 1.5 (95% CI 1.41.7, Scott et al., 2007). When the
individual surveys were examined, all but one survey fell within the 95%
confidence interval. Both depressive disorders and alcohol use disorders were
also significantly associated with asthma and similar strengths of association
were evidenced across the mental disorders (Scott et al., 2007).
Although it is clear that the experience of asthma and anxiety share many
overlapping features, research attempting to highlight the specific nature of this
overlap in adults has yielded inconsistent findings. For example, some studies
have found that individuals with asthma display higher levels of general anxious
symptoms than healthy controls (Di Marco et al., 2006; Sreedhar, 1989). However, another study found significant differences in state, but not trait, anxiety
(Erhabor & Mosaku, 2004). One study differentiating between airway obstruction specific anxiety and trait-like anxiety also failed to find a significant
relation between levels of airway obstruction anxiety and baseline measures
of anxiety (Spinhoven, van Peski-Oosterbaan, Van der Does, Willems, & Sterk,
1997). However, a recent longitudinal study found that the onset of anxiety
was significantly associated with the development of asthma nine years later,
OR = 3.53 (CI 1.0312.1; Neuman et al., 2006).
260
L. S. Elwood, B. O. Olatunji
261
suffer from additional consequences. For example, individuals with asthma and
panic have been found to endorse increased dyspnea at rest, irritable bowel
syndrome, and global distress (Dorhofer & Sigmon, 2002; Pollack et al., 1996).
Feldman and colleagues (2005) found that individuals with asthma (physician
diagnosed) and panic disorder (based on results of a structured interview)
reported more frequent visits to their primary care providers, lower overall
quality of life, greater restriction of activities, and greater emotional difficulties
than individuals with asthma alone. In addition, women with asthma and panic
exhibited significantly greater skin conductance responses and anxious mood
than individuals with asthma alone after being exposed to both neutral and
asthma related scenes (Dorhofer &, Sigmon 2002). Taken together, these findings suggest that individuals with comorbid asthma and panic disorder display
lower levels of functioning across various domains than individuals with
asthma alone.
Longitudinal examinations may provide valuable information about the
temporal nature of the comorbidity of asthma and panic. In a longitudinal
epidemiological study, Goodwin and Eaton (2003) found that the presence of
asthma was significantly associated with the presence of panic attacks one
year later. A recent 20 year longitudinal epidemiological study found a
bidirectional relationship between panic disorder and asthma (Halser et al.,
2005). Asthma served as a significant predictor of future panic disorder, OR
= 4.5 (CI 1.120.1), and panic disorder served as a significant predictor of
future asthma, OR = 6.3 (CI 2.814.0). When the criteria were expanded
to include any panic symptoms, panic symptoms predicted future asthma
but asthma failed to predict future panic symptoms. Interestingly, when
demographic variables were controlled for, asthma remained a predictor
of future panic disorder in women, OR = 2.9 (CI 1.18.6), and smokers,
OR = 3.5 (CI 1.013.4), but not for men, OR = 1.9 (CI .219.6), and
nonsmokers, OR = 2.1 (CI .58.5). Family history of allergy, OR = 1.8 (CI
1.12.9), smoking, OR = 1.6 (CI 1.02.5), and childhood anxiety, OR = 0.6
(CI .31.3), demonstrated the strongest relations with the development of
panic disorder and appear to be the strongest confounds of the panic-asthma
relation (Halser et al., 2005).
Although more recent research has begun to address processes that underlie
the comorbidity between asthma and panic disorder, the specificity of the
asthma-panic relation remains somewhat unclear. For example, one study
failed to find significant differences in the diagnosis of panic disorder between
the asthma and non-asthma groups among patients referred for a histamine
challenge test (van Peski-Oosterbaan, Spinhoven, van der Does, Willems, &
Sterk, 1996). In addition, no differences in asthma symptom severity were
found between those with and without panic disorder. The authors concluded
that panic disorder was unlikely to be specifically related to asthma, but rather
was likely to be generally related to illness and medical attention seeking
behaviors (van Peski-Oosterbaan et al., 1996).
262
L. S. Elwood, B. O. Olatunji
263
anxiety (Hommel et al., 2002, Hommel et al., 2003). Rather, the influence of
anxiety may result in behavioral changes such as increased treatment seeking,
increased avoidance of situations perceived as threatening, and decreased selfefficacy which may reduce the individuals quality of life.
264
L. S. Elwood, B. O. Olatunji
265
those without panic disorder (Carr et al., 1994). A similar study found that
women with asthma alone, panic alone, and asthma and panic endorsed higher
levels of AS than controls (Dorhofer & Sigmon, 2002). However, one study did
fail to find a significant relation between severity of asthma and level of AS
(Asmudson & Stein, 1994). The precise nature of the relation between AS and
asthma is unclear. However, a review of the available literature did lead to a
tentative conclusion that that there may not be a direct relation between asthma
and AS, but instead that the relation may be mediated by their common
association with panic disorder (Asmundson, Wright, & Hadjistavropoulos,
2000).
266
L. S. Elwood, B. O. Olatunji
anxiety than the general outpatients and controls, but were not significantly
different on anxiety than the psychiatric participants (Sreedhar, 1989). Similarly, Erhabor and Mosaku (2004) found that patients with asthma reported
higher levels of state anxiety and other psychiatric symptoms than orthopedic
participants and controls, but failed to find significant group differences for
trait anxiety. However, there is evidence that children with asthma endorse
higher levels of trait anxiety than children with diabetes (Vila et al., 1999).
Asthma patients have also been found to report higher levels of trait anxiety
than patients with peptic ulcers and controls (Shanmugam & Kaliappan, 1982).
Children with asthma and those with congenital heart disease have been found
to score significantly higher than the general population on multiple measures
of anxiety (Gupta et al., 2001). However, asthmatic children were found to
score higher than children with congenital heart disease only on medical fears
(Gupta et al., 2001). These findings generally suggest that individuals with
asthma endorse greater levels of anxiety than individuals with other medical
conditions.
267
268
L. S. Elwood, B. O. Olatunji
Asthma-related dysfunctional beliefs among those fearful of bodily sensations may then motivate vigilance for respiratory cues. For example, it has been
shown that asthma patients with panic disorder tend to perceive more symptoms of dyspnea during a histamine challenge than asthma patients without
panic disorder, although the two groups did not differ with regard to the effects
of histamine on pulmonary function (van Peski-Oosterbaan et al., 1996).
Excessive respiratory vigilance among asthmatics increases the likelihood of
noticing and misinterpreting respiratory and other bodily sensations. Indeed,
there is evidence that asthmatic who are also high in anxiety symptoms mislabel
nonrespiratory sensations (i.e., feelings of fatigue) as symptoms of asthma
(Dirks, Schraa, & Robinson, 1982). These beliefs increase the risk of developing
catastrophic cognitions when individuals are exposed to ambiguous (benign)
bodily symptoms. For example, someone who believes they are at high risk of
having an asthma attack might become anxious if he or she notices even a slight
feeling of tightness in the chest (this symptom means I am having an asthma
attack). Catastrophic cognitions about benign symptoms may increase feelings
of worry, anxiety, and panic in individuals with asthma. Feelings of uncertainty
about respiratory symptoms may also contribute to the development of clinical
anxiety among individuals with asthma. Indeed, it has been shown that uncertainty contributes unique variance to anxiety symptoms among patients with
asthma when controlling for demographic, disease, and psychological variables
(Hommel et al., 2003).
The cognitive-behavioral model also suggests that anxiety symptoms are
maintained by the very strategies individuals with asthma use to cope with
their symptoms, such as attempts to prevent or regulate the experience of bodily
sensations. For example, anxiety symptoms in patients with asthma are associated with excessive use of as-needed medications (Kinsman, Dahlem, Spector,
Staudenmayer, 1977) and more hospital readmissions (Dirks, et al., 1977) even
when controlling for asthma disease severity (Wamboldt et al., 1998). These
safety-seeking behaviors function to prohibit individuals with asthma from
acquiring information that would disconfirm their dysfunctional beliefs.
269
Dysfunctional Beliefs
Overestimating the likelihood/severity of having an
asthma attack
prevents acquisition of
disconfirmatory evidence
selective attention
to signs of asthma
Safety-Seeking Behaviors
Respiratory Vigilance
increase likelihood of noticing
benign respiratory sensations
Uncertainty/Anxiety/Panic
Perception of
Airway Symptoms
misinterpretation of
ambiguous symptoms
Catastrophic Cognitions
About Symptoms
Fig. 1 Cognitive-behavioral model of excessive anxiety in patients with asthma
270
L. S. Elwood, B. O. Olatunji
Conclusion
Summary of Extant Research
The presence of asthma may induce the clinical expression of anxiety and panic
in those that may already be genetically vulnerable. Indeed, many studies have
shown that asthma and anxiety, specifically panic disorder, are often comorbid
with the onset of anxiety-related conditions occurring after the onset of asthma.
However, there is evidence that the association between asthma and anxiety and
its disorders is not necessarily causal and the high rate of comorbidity may
reflect common factors/diathesis that are related to both conditions (Goodwin
et al., 2004). Indeed, there is little evidence suggesting individuals with comorbid asthma and anxiety display more impaired pulmonary functioning than
those with asthma alone. Furthermore, other chronic medical problems that
share symptoms with anxiety presentations (e.g., cardiac problems) display a
271
similar pattern of relations with anxiety and its disorders. Thus, the specificity
of the asthma-anxiety relation remains relatively unclear. However, what is
clear is that the comorbidity between asthma and anxiety may influence interpretations of and reactions to respiratory symptoms. The consequences of this
comorbidity appear to be largely observed in poorer asthma related quality of
life, worse asthma control, and increased treatment seeking. Attempts to
address these poor outcomes have appealed to the identification of common
factors/diatheses that are related to both asthma and anxiety conditions. The
tendency to fear physical symptoms due to their perceived harmful consequences (i.e., panic-fear, AS) may function as the underlying vulnerability for
the development of excessive anxiety among patients with asthma.
272
L. S. Elwood, B. O. Olatunji
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Introduction
A broken heart is a common metaphor used when a human being suffers an emotional
or physical loss, to the extent that it begins to cause them physical or physiological pain.
This condition is known as heartbreak.
Wikipedia
Despite the age-old and virtually universal idea that emotions stem from the
heart, science has only recently begun to understand why a stressed, sad, or
anxious heart is unhealthy. Speculation about the role of psychological factors
in the etiology of heart problems dates back to the early 19th century (irritable
heart) (Da Costa, 1871). Systematic study of the association between heart and
mind began in the late 1950s with the pioneering work of Meyer Friedman and
Ray Rosenman, two cardiologists who coined the term Type A behavior
pattern. Since that time, increasing clinical attention and empirical research
has been focused on both biomedical and psychosocial influences on coronary
heart disease (CHD).
CHD is the leading cause of death and disability in the United States
(American Heart Association, 2006) and in much of the Western world,
especially among industrialized nations (Zevallos, Chiriboga, & Herbert,
1992). CHD claims more lives each year than the next five causes of death
combined. Psychosocial factors that may be important to the presentation and
clinical course of CHD include: Psychological stress, job strain, vital exhaustion, social isolation and lack of social support, hostility and anger, depression,
and anxiety. Negative emotions exert a harmful influence on CHD outcomes
and quality of life. Relative to the sizeable, persuasive literature linking the
negative emotions of depression and hostility and CHD morbidity and
mortality, less is known about how anxiety may influence CHD. Failure to
Kamila S. White
University of Missouri-Saint Louis, Department of Psychology, One University Boulevard,
212 Stadler Hall, Saint Louis, MO 63121. Tel: 314.516.7122, Fax: 314.516.5392
whiteks@umsl.edu
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understand and address some of these more upstream psychological risk factors
including anxiety may be one explanation for why CHD morbidity and
mortality remain so high.
Chest pain is one of the most common, frightening medical complaints. And
anxiety is one of the first, most powerful psychological responses to a cardiac
event. Sudden, strong emotion is one of the two most common precipitating
events experienced prior to sudden cardiac death (SCD); exercise is the other
event (Lampert et al., 2005). Considerable epidemiological evidence implicates
the emotion of anxiety in the development of CHD and SCD. This chapter
reviews the empirical literature on the emotion of anxiety and its relation with
cardiovascular illness. First, epidemiological evidence that points to anxiety
(particularly phobic anxiety) as a risk factor for CHD morbidity and mortality
is reviewed. Several prospective studies are described, and a number of
methodological challenges to the interpretation of this research are noted.
Considering the apparent comorbidity of anxiety and depression, studies
encompassing the construct of negative affectivity which includes the
underlying structure of both anxiety and depression are also described. Next,
research on the comorbidity of anxiety disorders and CHD are highlighted.
Included is a discussion of patients with non-cardiac chest pain (NCCP),
a sizable segment of the population referred for cardiological workup and a
group worthy of psychological study. Second, pathophysiological mechanisms
or pathways by which negative emotions (i.e., anxiety, depression, and anger/
hostility) are thought to influence CHD development and progression are
discussed. Several possible mechanisms for the anxiety-CHD link include
connections with behavior, with the atherosclerotic process, and with cardiac
instability. Third, treatment studies designed to reduce negative emotion and its
impact on CHD endpoints are reviewed. Finally, the chapter ends with a
discussion of the limitations of past research and highlights of a number of
exciting future directions in understanding the anxiety-CHD association.
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roughly 40 million American adults in a given year (Kessler, Chiu, Demler, &
Walters, 2005). Relative to other negative emotions (i.e., depression, anger/
hostility), far less empirical research has been paid to the impact of anxiety and
its possible cardiotoxic influences in CHD development, progression, and
outcome. Most research to date on the anxiety-CHD link has examined the
role of a construct defined as phobic anxiety. Increasing evidence from several
prospective studies has implicated phobic anxiety as a risk factor for CHD, and
considerable retrospective and correlational research has consistently found a
link between anxiety and CHD. Indeed, the relationship between anxiety
disorders and other forms of subclinical anxiety symptoms and CHD have
not been studied systematically. Correlational and prospective studies with
both healthy and ill populations are reviewed here, and some important
methodological challenges to interpretation of this research are highlighted.
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not all of this risk was accounted for by CHD risk factors (i.e., hypertension,
diabetes, and elevated cholesterol) associated with phobic anxiety (Albert,
Chae, Rexrode, Manson, & Kawachi, 2005). Similar to results with male-only
samples, findings suggest that phobic anxiety is prospectively associated with
increased risk of fatal CHD among females (Albert et al., 2005).
In sum, these prospective epidemiological studies using initially healthy
samples provide compelling evidence that anxiety contributes to subsequent
CHD. Both the strength and consistency of the claim that anxiety contributes to
CHD risk and outcomes beyond the traditional CHD risk factors are evident
across the studies. Moreover, in each of these studies, varied but valuable efforts
were made to control for the effects of known risk factors, and at least one or
multiple hard endpoints (i.e., documented MI, cardiac mortality) were
investigated.
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1998; Martin, Cloninger, Guze, & Clayton, 1985) have not found a significant
prospective anxiety-CHD association. The extent to which publication bias has
influenced the availability of negative findings is also uncertain.
Summary
Drawing from these prospective studies, the available evidence appears to
conservatively point to support for an anxiety-CHD relationship. However,
the directionality of this relationship is less certain. Although data has
accumulated across different study samples (i.e., initially healthy, individuals
with CHD, individuals with anxiety conditions), the anxiety-CHD relationship
appears to be most compelling and consistent in the epidemiological prospective studies. And the claim that self-reported anxiety confers CHD risk appears
to be most persuasive in studies with initially healthy samples; this is particularly true in light of the fact that the studies highlighted herein often controlled
for possible confounds and used hard endpoints for disease (e.g., MI, cardiac
mortality). One interpretive caveat to these studies, however, is that the extent
to which comorbid health behaviors (e.g., exercise) and addictive behaviors
(e.g., smoking) were controlled for across studies was variable. Nevertheless,
these findings are noteworthy in light of the fact that most studies to date have
found these associations using less than optimal and possibly diluted measures
of anxiety. Findings with prognostic samples (i.e., known CHD, in- and
out-patients with psychiatric illness) are less persuasive. Indeed, it may be that
anxiety confers a stronger role in CHD development than in the disease
progression (Suls & Bunde, 2005), or it may be that difficulties with distinction
between anxiety and declaration of CHD have lead to weaker findings among
the groups studied.
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well-understood (Eifert, Zvolensky et al., 2000; Fleet et al., 1996; White &
Raffa, 2004). Theoretical conceptualizations of NCCP generally assert that
the etiology of the pain is multi-causal and interactive (Eifert, Zvolensky
et al., 2000; Mayou, 1998; White & Raffa, 2004). It has been hypothesized
that the functional syndrome of NCCP may partially result from psychological
vulnerabilities (i.e., greater awareness of internal bodily sensations, somatic
hypervigilance) that focus on circumstances associated with threat or danger
(e.g., heart disease, death) (White & Raffa, 2004).
Although most cases of NCCP are thought to be benign, unrecognized
CAD and microvascular angina (i.e., cardiac syndrome X, a condition characterized by apparent vasospasm of the arteries that nourish the heart but that
are not visible on cardiac catheterization) may explain an unknown portion of
NCCP cases in the general population (Allan & Scheidt, 1999). Recent
reviews have suggested that the clinical prognosis of patients with NCCP
may not be as benign as is commonly thought (Bugiardini & Bairey Merz,
2005). Moreover, identification of heart disease risk factors in this patient
group may help to determine optimal methods for identification and prevention of clinical events through risk factor management (White, Malone, &
Gervino, 2006). In light of the extensive research that has documented the
heritable (e.g., sex, age, race, family history) and modifiable risk factors
(e.g., tobacco use, obesity, hypertension, physical inactivity, diabetes mellitus)
associated with an increased risk for heart disease (American Heart
Association, 2006), a systematic examination of cardiac risk in patients with
NCCP may have important implications for identification, risk stratification,
or intervention. One study conducted by our research group found that
patients with NCCP endorsed on average 4 CHD risk factors (SD = 1.6)
(White, Malone et al., 2006). The most common risk factors endorsed
included a family history of CHD (46%), physical inactivity (42%), and
obesity (34%). This elevated risk was associated with elevated anxiety (both
in general and heart-focused anxiety), and hierarchical regressions showed
that risk factor incidence, general anxiety, and heart-focused anxiety all
predicted significant variance in chest pain interference (45%; large effect
size f 2 = .81). These findings indicated that not only are CHD risk factors
present and appear to exacerbate chest pain in patients with NCCP, but that
the subjective anxiety may be well-founded and perhaps prematurely related
to later CHD. Ongoing longitudinal research by our group and others may
help to disentangle this important question.
Considerable research has investigated the relationship between psychiatric
illness and NCCP. Bass and colleagues conducted a series of studies and
concluded that two-thirds of patients with normal or near-normal coronary
arteries have predominantly psychiatric, as opposed to cardiac disorders; anxiety neurosis was the most common diagnosis in this patient group (Bass &
Wade, 1984; Bass, Wade, Hand, & Jackson, 1983). Indeed, research by our
group has explored the prevalence of anxiety and mood disorders in patients
with NCCP and found that almost half of patients (47%) with NCCP also were
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persuasive and undeniably indicate that anxiety plays a part in CHD; however,
some qualifications need to be considered when interpreting this research.
A number of factors influence how robust these findings are including: 1) factors
associated with study outcome (i.e., type of research design, method of assessment), 2) factors associated with construct definition (i.e., fear, anxiety, the
panic spectrum, anxious arousal, worry) and construct validity (i.e., type of
anxiety or anxiety disorder assessed, construct overlap among negative
emotions), and 3) factors associated with assessment (i.e., diagnostic structured
clinical interviews, self-report symptom rating scales). Relevance to current
conceptualizations of anxiety and their psychometric acceptance, construct
definition overlap (i.e., the co-occurrence, intersection of anxiety and other
negative emotions), and the directionality of anxiety and CHD may be vital.
Conceptualizations of Anxiety
Anxiety occurs along a continuum from adaptive to maladaptive. Emotion
theorists have long distinguished between basic emotions, such as fear, and
more invasive cognitive-affective processes, such as anxiety and worry (Ekman,
1992; Izard, 1992). Unlike the basic emotion of fear, anxiety represents a
higher-order cognitive elaboration that is considered by many to be a related
but distinct construct (Barlow, 2002; Craske, 1999; White & Barlow, 2002).
Much of the research examining the anxiety-CHD connection predates
contemporary conceptualizations of anxiety, and studies to date have yet to
explore empirically supported models of anxiety and panic in CHD. Research
on the panic spectrum (e.g., fear, anxious arousal, anxiety sensitivity, PD)
including the recurrent, intense, and often private experience of panic attacks
which is a common comorbidity of anxiety and mood disorders may be
the most potent aspect of fear and anxiety (White & Barlow, 2002) to
influence CHD.
Interpreting the research on anxiety and CHD begs consideration of the
varied conceptualizations of anxiety (i.e., phobic anxiety, general anxiety,
worry, panic, fear) and the domains assessed in past research. Nearly all
studies to date have relied primarily on self-report measures of anxiety
symptoms rather than anxiety diagnoses. And little research has explored
the clinically significant end of the anxiety continuum with regard to the
presence of anxiety disorders, panic attacks, and the available research is
limited with regard to pure anxiety and CHD. In fact, of the studies
demonstrating an anxiety-CHD connection, most have used scales that may
serve to dilute the assessment of anxiety (e.g., Framingham Tension scale,
STAI, Crown-Crisp). With few exceptions, research conducted on anxiety in
heart disease has been conducted using scales that are not generally considered both gold-standard and empirically-based measures of anxiety (Antony,
Orsillo, & Romer, 2001). For instance, most research to date on the
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Directionality
Although critical reviews of the anxiety-CHD association have concluded that
anxiety, and perhaps PD in particular, is associated with increased incidence
of cardiovascular morbidity, the absolute direction of this causality remains
unclear (Chignon, 1993; Fleet et al., 2000). Moreover, individuals experiencing anxiety and anxiety disorders commonly use medication, and the extent
to which psychotropic medication use is causally associated with CHD risk is
not fully known (Thorogood, Cowen, Mann, Murphy, & Vessey, 1992). In
short, it may be too preliminary to conclude any definite causal directions in
the anxiety-CHD relationship. Research using truly prospective designs
measuring anxiety with gold-standard measures of anxiety and negative affect
that are conducted with initially healthy samples of both men and women are
needed to more completely document onset of anxiety, other negative
emotions, risk factor initiation, and CHD onset would resolve many of
these questions.
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Reduced Heart-Rate Variability (HRV). The healthy heart displays beatto-beat variations that result from fluctuations in autonomic nervous system
(ANS) activity at the sinus node. HRV decreases with stress (emotional or
physical) and increases with rest. Therefore, HRV is considered a noninvasive
marker of ANS function (Hayano, Sakakibara, & Yamada, 1991; Task Force
of the European Society of Cardiology and the North American Society of
Pacing and Electrophysiology, 1996) and it is a commonly used means of
studying sympathetic tone and inadequate parasympathetic tone. Greater autonomic dysfunction, as indicated by decreased HRV has been proposed as a
plausible mechanism linking anxiety to increased cardiac mortality in post-MI
patients. Increased sympathetic or decreased parasympathetic nervous system
activity predisposes patients with CHD to ventricular tachycardia, ventricular
fibrillation, and SCD (Podrid, Fuchs, & Candinas, 1990; Pruvot et al., 2000).
Specifically, low HRV is indicative of excessive sympathetic and inadequate
parasympathetic tone (Task Force of the European Society of Cardiology and
the North American Society of Pacing and Electrophysiology, 1996). Moreover, low HRV is a robust, independent predictor of post-MI mortality (Bigger
et al., 1992; Kleiger, Miller, Bigger, & Moss, 1987; Sudhair, Stevenson,
Marchant, & al., 1994), and it has been linked to increased risk of CHD (Dekker
et al., 2000), atherosclerosis (Task Force of the European Society of Cardiology
and the North American Society of Pacing and Electrophysiology, 1996), MI
(Bigger, Fleiss, Rolnitzky, & Steinman, 1993), cardiac events (Liao et al., 1997;
Tsuji et al., 1996), and mortality (Dekker et al., 2000).
Decreased HRV is associated with anxiety (Kawachi et al., 1995) and PD in
particular (Yeragani et al., 1998). Using power spectral analysis of heart rate,
Yeragani found that patients with PD had lower amplitudes of respiratory sinus
arrhythmia during paced breathing and elevated levels of mid-frequency power
during spontaneous breathing compared with normals (Yeragani et al., 1993).
In a later study, these researchers studied beat-to-beat QT interval variability
(QTV), identified as a predictor of SCD, and found that QTV is indeed elevated
in patients with anxiety and depression. Interestingly, individuals with PD
showed higher QTV at nighttime than controls (Yeragani, Pohl, Balon,
Jampala, & Jayaraman, 2002).
Findings from HRV studies suggest that the decreased vagal tone and
increased sympathetic tone may contribute to increased risk for cardiac mortality in patients with anxiety, with some exceptions. One contradictory study
conducted with 42 CAD patients with and without PD found that patients
suffering both PD and CAD showed lower sympathetic modulation (Lavoie et
al., 2004). These results suggest that alterations in HRV may not be the underlying mechanism for the increased morbidity and mortality among CAD
patients with PD. One particular challenge in interpreting this research is that
HRV has also been proposed as a marker of less favorable health in general
(Dekker et al., 2000). Moreover, similar to studies with anxiety, decreased HRV
has been linked with depression. Mean 24-hour HRV is lower in depressed than
in medically similar nondepressed patients with stable CHD (Carney et al.,
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1995; Krittayaphong et al., 1997; Stein et al., 2000) and decreased HRV is
generally accepted as one mechanism linking depression to increased cardiac
mortality in post-MI patients (Carney et al., 2001). Failure to consider overlap
and co-occurrence among the negative emotions may have influenced some of
the conclusions that can be drawn from the HRV research to date.
Susceptibility to Ventricular Arrhythmia. A related possible mechanism that
may explain the harmful effects of anxiety on CHD and CHD-related mortality
is through a susceptibility to ventricular arrhythmias. Ventricular arrhythmias
occur when a group of heart cells in the lower two chambers of the heart (i.e., the
ventricles) trigger contractions out of sync with the normal rhythm established
by the sinus node; in short, arrhythmias are abnormal rhythms of the heart that
cause the heart to pump blood less effectively. Blood is pumped through the
heart in a controlled sequence of muscular contractions; these contractions are
controlled by bundles of cells which control the electrical activity of the heart.
When this sequence is disturbed, heart arrhythmias occur. Arrhythmias are
abnormal rhythms of the heart, and many types of heart disease are associated
with ventricular arrhythmias. Some researchers have posited that anxiety may
be related to an increased risk of CHD and CHD-related mortality through the
altered electrical stability of the heart including ventricular arrhythmias.
Evidence of an association between psychological factors and ventricular
arrhythmias is mixed (Follick et al., 1990; Follick et al., 1988; Freeman,
Cohen-Cole, Fleece, Waldo, & Folks, 1984; Orth-Gomer, Edwards, Erhardt,
Sjogren, & Theorell, 1980). Support for anxiety in particular as an arrhythmic
mechanism is demonstrated by the known relationship between anxiety and
increased sympathetic and parasympathetic cardiac control (Kawachi et al.,
1995; Thayer, Friedman, & Borkovec, 1996; Watkins, Blumenthal, & Carney,
2002) and by findings that phobic anxiety increases the risk of SCD (Kawachi,
Colditz et al., 1994). One particularly revealing study lends support to the
premise that the increased risk in SCD observed in individuals with phobic
anxiety may be due to ventricular arrhythmias. Watkins and colleagues directly
examined the relationship between phobic anxiety and ventricular arrhythmias
(Watkins et al., 2006) and found that phobic anxiety (and depression) predicted
subsequent ventricular arrhythmias in 940 patients with CAD during a 3-year
follow-up. The phobic anxiety-arrhythmia association was independent of
comorbid depression; however, the composite (of anxiety and depression)
resulted in a larger effect size than either construct independently.
The most common type of ventricular arrhythmia (in both healthy and
diseased individuals) is the ventricular premature beat (VPB). VPBs increase
with psychological stress (Taggart, Carruthers, & Somerville, 1973; Taggart,
Gibbons, & Somerville, 1969), and VPBs have also been identified as risk factors
for electrical instability of the heart and SCD (Lown & Graboys, 1977; Lown &
Ruberman, 1970). Kubzansky and colleagues summarized much of this research
and theorized that anxiety (characterized as both an intense and acute
psychological state) may be one psychological state which predisposes
individuals to VPBs (Kubzansky et al., 1998). Indeed, one study found that
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Future Directions
Cardiovascular disease remains the leading cause of preventable mortality in
the Western world. Some 16 million Americans suffer from CHD, the most
common form of heart disease and the leading cause of death (American Heart
Association, 2006). Recent results of two large prospective studies have found
that 8090% of patients who developed clinically significant CHD and more
than 95% of patients who experienced a fatal CHD event had at least on major
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modifiable risk factor (i.e., smoking, diabetes, hypertension, and hypercholesterolemia) (Greenland et al., 2003; Khot et al., 2003). These results have focused
renewed attention on the prevention of CHD. Future research therefore must
be on examining the upstream psychosocial instigators (e.g., anxiety, mood,
physical inactivity, overeating) of the CHD epidemic. Unlike other negative
emotions, less empirical research has explored anxiety and its possible cardiotoxic influences in CHD development, progression, and outcome. Failure to
address anxiety and other psychological risk factors may be one reason that
CHD-related morbidity and mortality remain high. The potential public health
impact of preventing the development and progression of CHD is high if the
nature of the association between anxiety and CHD is appreciated and
investigated.
The explanatory strength of anxiety as a psychosocial factor influencing
CHD development and progression may be underestimated because most
past studies have used suboptimal assessments tapping selective domains of
anxiety. Symptom screenings are necessary but not sufficient in the place
of more extensive diagnostic and structured clinical interviews that may help
to identify this important emotional factor in CHD patients. Understanding
CHD risk in patients suffering from anxiety disorders may be one line of inquiry
to identify those most in need of prevention and intervention efforts. Issues of
construct definition and overlap and diagnostic classification have hampered
scientific knowledge to date, and ultimately research applying contemporary
models of anxiety is needed to understand how anxiety may or may not
influence CHD development and progression. Research is needed to more
broadly investigate the current and lifetime incidence of Axis I anxiety and
mood disorders and the underlying dimensions of emotionality (including
negative affect) in the impact these anxiety conditions may or may not have
on CHD. Similarly, research examining incidence of psychopathology and the
course of subclinical psychiatric concerns (i.e., those conditions that do not
surpass the threshold for sufficiently impairing and distressing or those conditions that do not reach full DSM-IV diagnostic criteria) may prove advantages
toward identifying those individuals more at-risk who may be targeted for
intervention. Comprehensive research examining anxiety (including worry,
anxious apprehension), the panic spectrum, and the other negative emotions
in CHD development and progression is warranted. In particular, the
CHD-fear (e.g., panic attacks, the panic spectrum) association seems
important. Also, perhaps there is a threshold at which anxiety begins to wield
its cardiotoxic effects. Moreover, there are relatively little data regarding the
additive yield of pure anxiety over that of other negative emotions.
Methods used for diagnostic evaluation of cardiac diagnoses (and therefore
group composition) have come under scrutiny, particularly with regard to
missed diagnoses in women (Buchthal et al., 2000; Bugiardini & Bairey Merz,
2005), and comparative studies tell us little about within group variability.
Studies examining psychological factors associated with the broad range of
cardiac symptoms including NCCP are needed to explore possible means
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Introduction
There is a growing body of literature that identifies the psychosocial
and behavioral factors that increase individuals vulnerability to Human
Immunodeficiency Virus (HIV) infection and that adversely impact HIV disease
management and progression among HIV-infected individuals. In this chapter
we consider the evidence that anxiety and its disorders negatively impact susceptibility to HIV infection and interfere with adaptive disease management. It is
plausible, for example, that the presence of anxiety disorders may interfere with
an individuals ability to negotiate safer sex or increase the likelihood of injection
drug use thereby increasing the risk of HIV infection. HIV disproportionately
affects men who have sex with men (MSM), communities of color, and minority
women (Centers for Disease Control and Prevention, 2005). We consider the
evidence that higher levels of anxiety disorders in these risk groups may, in part,
account for the higher HIV prevalence observed in these groups. It is also possible
that the presence of anxiety disorders or high levels of anxious affect may
contribute to poorer disease course in people already living with HIV. We review
the existent research to consider several pathways by which anxiety may compromise optimal disease management by interfering with individuals ability to
adhere to their anti HIV medications, by increasing substance and alcohol use, or
by negatively impacting physical functioning and underlying pathophysiology.
The first section of the chapter provides an overview of HIV disease course
and treatment. The second section considers the prevalence of anxiety disorders
in people living with HIV and reviews the evidence that particular anxiety
Conall OCleirigh
Massachusetts General Hospital, Psychiatry Department, Department of Psychiatry,
Behavioral Medicine Massachusetts General Hospital, 1 Bowdoin Square BS-07B, Boston,
MA 0211
cocleirigh@partners.org
This research was supported in part by the National Institute of Health, National Institute on
Drug Abuse (NIDA) grant R01-DA018603, PI. Steven Safren, Ph. D.
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An Overview of HIV
HIV is an infectious disease that is spread predominantly through sexual exposure
but also through contaminated blood products, injection drug use, or occupational exposures. It is estimated that more that 40 million adults and children are
infected with HIV worldwide and approximately two-thirds of these cases are in
Sub-Saharan Africa. Since the beginning of the epidemic, more than 18 million
people have died of AIDS. It is estimated that in the United States close to 1
million people are living with HIV. Men who have sex with men (MSM) continue
to represent the largest group of new infections in North America and AfricanAmericans comprised 49% of all new U.S. infections in 2005. Approximately
40% of all U.S. HIV cases diagnosed in 2004 progressed to AIDS within 12
months of diagnosis (Centers for Disease Control and Prevention (CDC), 2005).
HIV is a retrovirus whose principal targets of infection are CD4 cells
(t-helper cells), which play a major part in regulating immune response (Gallo
& Montagnier, 1988). The clinical presentation of acute HIV infection (e.g.,
fever, muscle weakness, and fatigue, (Boyle, McMurchie, Tindall, & Cooper,
1993) can manifest shortly following infection and persist for several weeks
during which time the immune system mounts an initial response to HIV
infection. This period is also associated with high initial rates of CD4 cell
decline and is followed by a prolonged asymptomatic phase during which the
individual remains healthy. During this phase gradual CD4 cell decline continues and in the absence of antiretroviral treatment HIV viral load increases.
CD4 cell number and HIV viral load are the principal biological measures of
disease progression and predict clinical outcomes and survival. As the CD4
cells fall to less than 500 cells/mm2, the susceptibility to infection increases and
initial presentation of Category B symptoms are observed (e.g. night sweats,
peripheral neuropathy, shingles, fatigue). When CD4 cell number falls below
200 cells/mm2 an AIDS diagnosis is made and the risk of developing Category C
(AIDS defining) symptoms or neoplasias increases (e.g., Kaposis Sarcoma,
HIV wasting syndrome, lymphoma) as the immune system becomes seriously
compromised. The insidious depletion of CD4 cells results in inverted
CD4/CD8 ratios and the functional capacity of T-lymphocytes and
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proliferative responses are progressively impaired and natural killer cell cytotoxicity (NKCC) decreases (Klimas, Baron, & Fletcher, 1991). The average
time between infection and progression to AIDS can vary as a function of
antiretroviral medication regimen (Fischl, 1995) or route of infection and a
range of psychosocial characteristics (see Leserman, 2003).
The clinical care of HIV infected individuals has improved dramatically over
the last decade. In fact, the disease course has changed from a virtual death
sentence via progressive deterioration of the immune system to a manageable
chronic condition. Treatment began with the introduction of the first antiretroviral agent, zidovudine (AZT) in 1987. With the advent of combination therapies
that include newer reverse transcriptase inhibitors and HIV-specific protease
inhibitors (PI), referred to as highly active antiretroviral therapy (HAART),
significant further improvement has been made in delaying AIDS and mortality
(Lima, Hogg, Harrigan, et al., 2007). The success of HAART has greatly increased
HIV survival with recent estimates greater than 24 years post HIV diagnosis
(Schackman, Gebo, Walensky, et al., 2006). As life expectancy increases so also
does the cost of HIV-related medical care. The life time cost of HIV medical care
has been estimated at between $385,200 and $618,900 depending primarily of the
discounts available for antiretroviral medication (Schackman, Gebo, Walensky,
et al., 2006) constituting a significant public health expense and identifying prevention of future cases of HIV infection as a continued public health concern.
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Among HIV individuals, PTSD is frequently comorbid with other psychiatric diagnosis, particularly major depression, substance abuse and other
anxiety disorders. In a study using a nationally representative probability
sample of over 1400 HIV individuals, Tsao and colleagues (2004a) found
that among those with a PTSD diagnosis, 36.5% had comorbid Major Depressive Disorder (MDD) and 28.9% had comorbid panic disorder (PD). In a
sample of individuals recently diagnosed with HIV, those with PTSD were
significantly more likely to have comorbid MDD, suicidality and social anxiety
disorder (Olley et al., 2005).
It is possible that the trauma associated with receiving a diagnosis of HIV
may contribute to PTSD symptoms. In fact, approximately one third of HIV
individuals with PTSD attribute the onset of their PTSD specifically to their
HIV diagnosis (Kelly et al., 1998; Olley et al., 2005). The higher rates of PTSD
in certain subgroups of HIV individuals, particularly minority women, also
may be attributable to both higher rates of stressful life events and childhood
sexual abuse in these groups (e.g., Kimerling et al., 1999).
HIV and Panic Disorder (PD). Estimates of the PD prevalence in HIV are
fairly consistent, ranging from 1116% across several large-scale studies (Bing
et al., 2001; Orlando, Burnam, Beckman, et al., 2001; Sherbourne et al., 2000;
Tsao, Dobalian, & Naliboff, 2004b). PD is highly comorbid with other psychiatric disorders among HIV persons, with some research indicating that
over half of those with PD have an additional diagnosis, the most common of
which are MDD and PTSD (Tsao et al., 2004b).
HIV and Generalized Anxiety Disorder (GAD). Reported rates of GAD
among HIV individuals generally range between 6.5% and 20% (Bing et al.,
2001; Haller & Miles, 2003; Sherbourne et al., 2000; Tsao et al., 2004b; Tucker
et al., 2003; Wilkins et al., 1991), with the highest prevalence rate found among
individuals attending outpatient mental health clinics. In general, these rates
seem higher than that reported in a large-scale national survey, where the 12month prevalence of GAD was 3.1% (Kessler et al., 2005). Moreover, there is
some evidence that the prevalence of GAD decreases over time. In a sample of
over 2800 HIV individuals, Tsao and colleagues (2004b) found that the
prevalence of GAD decreased significantly over a six-month period from
16% to 11%.
HIV and Other Anxiety Disorders. There is little research examining the
prevalence of other anxiety disorders among HIV individuals. In a sample
of 190 HIV individuals attending a HIV mental health clinic, 9% were found
to have simple phobia (Haller & Miles, 2003). To our knowledge, there are no
studies examining prevalence rates of other anxiety disorders such as social
anxiety disorder and obsessive-compulsive disorder among HIV individuals.
HIV MSM and Anxiety Disorders. Studies focusing on anxiety disorders
among HIV MSM have yielded inconsistent results in terms of prevalence
rates, with rates of current and lifetime anxiety disorders ranging from
312% to 719% respectively (Perkins et al., 1994; Rosenberger et al., 1993;
Sewell et al., 2000). Several studies have reported no differences in rates of
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anxiety disorders between HIV and HIV-negative MSM (Perkins, et al., 1994;
Rosenberger et al., 1993; Sewell et al., 2000). For example, a two-year longitudinal study of HIV and HIV-negative MSM who were non-intravenous
drug users found that the two groups did not differ in their rates of either
lifetime or current anxiety disorders (Sewell et al., 2000).
HIV Women and Anxiety Disorders. PTSD appears to be over-represented
in HIV-infected women, likely because of increased exposure to traumatic
stressors such as physical violence and sexual assault (Kimerling et al., 1999).
In a study of 67 inner-city African-American women beyond the initial stages of
HIV infection, it was found that over a third of the sample met DSM-IV criteria
for PTSD. More elevated rates have been reported in higher-risk samples. For
instance, in a sample of 81 HIV incarcerated women, Lewis (2005) found that
nearly three quarters of the sample met criteria for lifetime PTSD. Not only do
these rates appear higher than among community samples of women (10.4%;
Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995) but are also higher
than among incarcerated females in general (3042%; Jordan, Schlenger,
Fairbank, & Caddell, 1996; Teplin, Abram, & McClelland, 1996). Although
high-risk HIV women appear to be at greater risk for anxiety disorders,
particularly PTSD, this risk may not apply to HIV women in general. A
study comparing HIV and negative women without current substance
abuse found that the two groups did not differ in their rates of anxiety disorders,
although the HIV women were more likely to have depression (Morrison
et al., 2002).
Conclusions. Based on the current literature, it is difficult to determine
whether anxiety disorders in general are more prevalent among HIV individuals compared with normative samples. This is due to the fact that no known
large-scale studies have examined the prevalence of overall rates of anxiety
disorders in people living with HIV. Smaller studies have yielded inconsistent
results likely due to subgroup and measurement variation. However, there is
evidence that particular anxiety disorders, (i.e., PTSD and GAD) may be more
prevalent among those with HIV. Higher prevalence of PTSD may be indicative
of traumatic responses to HIV diagnoses and co-occurrence of other traumatic
stressors. Additionally, there is evidence that prevalence of anxiety disorders
may be elevated among groups with higher HIV prevalence rates than the
general population, particularly MSM and high-risk women.
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are limited by the wide range of samples and method for measuring anxiety.
Research studies also vary in choice of dependent variables, such as unprotected
intercourse (e.g., Hart & Heimberg, 2005) and behaviors associated with unprotected intercourse such as number of sexual partners (Rosario, Scrimshaw, &
Hunter, 2006). Measures of emotional stress that incorporate anxiety items and
screening measures of anxiety have demonstrated conflicting associations with
HIV risk behavior. Future research examining when anxiety exerts risky versus
protective effects, and for whom it exerts these effects, is therefore warranted.
Lastly, it would be beneficial to examine the effects of more specific types of
anxiety, as some appear to be associated with less risk (e.g., trait anxiety;
Bancroft et al., 2003) and some with more risk (e.g., social performance anxiety;
Hart & Heimberg, 2005)
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The results of these studies provide some evidence that anxiety, generally
assessed, is associated in with sub-optimal medication adherence in diverse
samples of patients with HIV. The results of these studies suggest also that
symptoms of social phobia, panic, and GAD are associated with medication
non-adherence. The largest effects were observed for GAD and panic symptoms. PTSD symptoms of avoidance and intrusion specifically related to HIV
were significantly associated with multiple measures of adherence but measures
based on diagnostic criteria of PTSD produced only weak associations. All but
one of the studies reviewed here used cross-sectional designs creating difficulties
specifying the direction of the significant effects. It is possible that the severity
of anxious symptoms interferes with adherence but it is also plausible that
adherence violations (typically assessed with in the past week) contribute to
anxious affect and other symptoms of anxiety.
Anxiety and Substance Use in HIV. Substance use in patients with HIV
confers multiple disadvantages. Substance use has been associated with both
accelerated disease progression and with poorer adherence to antiretroviral
medication (e.g., Arnsten et al., 2001; Lucas et al., 2002), with delayed response
to ART (Palepu, Tyndall, Yip, et al., 2003) and with failure to achieve HIV viral
suppression for those initiating HAART (Lucas, Cheever, Chaisson, et al.,
2001). Injection drug use in HIV has also been associated with poorer immune
(Wood, Montaner, Yip, et al., 2004) and clinical disease (Moore, Keruly, &
Chiasson, 2004) outcomes.
Although the co-occurrence of substance use and anxiety disorders has been
widely studied in the general population (e.g., Kessler et al., 2005) there is a
paucity of research examining this co-morbidity in people with HIV (Chander,
Himehoch & Moore, 2006). A recent study estimates the 1 year prevalence rates
of comorbid substance use and anxiety/mood disorder in HIV is greater than
8% (Pence, Miller, Whetten, Eron, & Gaynes 2006). Most dramatically, alcohol
and substance use disorders were 2.5 and 7.5 time more prevalent than in the
general population. These findings are broadly consistent with earlier estimates
(Bing et al., 2001) although rates of GAD (15.8%) and panic (10.5%) were
higher and drug dependence and heavy alcohol use predicted the presence of
mood or anxiety disorders.
In a large sample (n = 1168) of HIV MSM, Ibnanez, Purcell, Stall, Parsons
and Gomez (2005) reported higher rates of anxiety, childhood sexual abuse, and
hostility among injection drug users (IDUs) compared to non-IDUs and higher
rates of sexual transmission risk behavior than those reporting no drug use.
Among 355 African-American crack abusing women, general measures of
anxiety and PTSD symptom severity were significantly associated with multiple
sexual partners (Roberts, Wechsberg, Zule, & Burroughs, 2003). More recently,
among a group of 198 HAART na ve HIV patients, the probability of mood/
anxiety and substance use disorders predicted a slower rate of viral suppression
and a faster rate of overall virologic failure after suppression. Alcohol and
substance abuse/dependence also predicted faster overall virologic failure
(Pence, Miller, Gaynes, & Eron, 2007).
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and with increased utilization of health care services in the previous 9 months.
In fact, PTSD symptom severity, trauma history and stressful life events
accounted for 27% of the variance in health related functioning controlling
for CD4 cell count and HIV-viral load. Smith et al. (2002) reported that PTSD
was significantly associated with greater pain intensity and impairment. Also
within a cross-sectional design, Holmes et al. (1997) reported that the presence
of Axis 1 disorder was significantly associated with lower HRQOL domain
scores for health perceptions and mental health. General measures of anxiety
have also been related to physical functioning in HIV controlling for HIV
disease severity among men (McDaniel, Fowlie, Summerivlle, Farber, and
Cohen-Cole, 1995), women (Tostes, Chalub, & Botega, 2004), and intravenous
drug users (Lipsitz, et al., 1994).
The results of the research reviewed above provide good evidence for a
relationship between symptoms of anxiety and HRQOL and other measures
of physical functioning. Measures of anxiety based upon diagnostic criteria
appear to provide the most consistent evidence for a relationship with
health-related functioning and the strongest evidence (replication in a large
representative sample) appears to exist for the relationship between PTSD
and health-related physical functioning. The relative paucity of longitudinal
research in this area makes it difficult to specify the directionality of these
relationships. It is possible that HIV disease related decrements in physical
functioning might lead to the onset of anxiety symptoms and disorders or
exacerbate existing symptoms as the results reported by Orlando et al. (2005)
may suggest. It is also plausible that the presence of anxiety disorders may either
contribute to decrements in physical functioning (as Leserman et al., 2005
suggest) or at least incline people living with HIV to lower their estimates of
their own physical health. In any event there is sufficient evidence reported here
to conclude that diagnostic assessment of anxiety may well help inform patients
HIV symptom reports and reports of physical functioning. The application of
randomized trials of cognitive-behavioral therapy to treat anxiety disorders in
people with HIV would allow for an examination of treatment related changes
in physical functioning and HIV-symptom burden. The results of these
studies would help characterize the relationship between anxiety and HRQOL
more fully.
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Behaviors
Medication Adherence
Substance Use
Transmission Risk
Behavior (STIs,
superinfection)
Individual Resources
(e.g., trauma history,
time since HIV
diagnosis, access to
care, etc)
Anxiety Profile
Anxiety Disorder
Anxious Symptoms
Stress Hormones
Norepinephrine
Cortisol
Biological Markers
of HIV Disease
CD4+ cells
HIV Viral Load
Clinical Disease
Outcomes
Survival
Clinical Progression
Development of AIDS
Health-Related Quality
of Life (HQOL)
Fig. 1 A Depiction of the direct and mediated relationships between anxiety and health and
disease outcomes in HIV
Note: The above model describes some of the pathways by which anxiety and its disorders
may impact the disease process and health outcomes in HIV. This model is not intended to
describe all possible relationships but to suggest potential mechanisms for which there is some
initial evidence in the literature reviewed. In the model, anxiety has two main pathways by
which it exerts its impact on HIV. In the behavioral pathway the presence of anxiety disorders
negatively influence behaviors (adherence, substance use, transmission risk behavior) which
in turn can negatively impact immune control of the HIV virus and lead to poor survival and
accelerated clinical progression of the disease. In the second pathway the presence of anxiety
disorders directly impacts underlying physiology through higher levels of stress hormones
which down regulate the immune system leading to poorer immune control of HIV and less
favorable disease course.
333
The most conspicuous gap in the research on HIV and anxiety is the
absence of psychosocial or psychopharmacological clinical intervention
research designed to treat anxiety disorders in people with HIV. There is
some evidence of the efficacy of broad based coping and stress management
group interventions that have been associated with reductions in intrusion
and avoidance symptoms of anxiety in HIV patients with CSA histories
(Sikkema Hansen, Kochman et al., 2007), and with reductions in anxious
mood in MSM (Antoni, et al., 2000; Chesney, Chambers, Taylor, Johnson, &
Folkman, 2003). Most critically, there is an unmet need for efficacious and
effective interventions to treat the full range of anxiety disorders in people
with HIV. The success of adapted CBT interventions in the treatment of
depression in HIV (for review see Olatunji, Mimiaga, OCleirigh, & Safren
2006) augurs well for the generalizability of CBT procedures to treat anxiety
in HIV. It seems from this review that the development of efficacious treatments for PTSD is a priority. In particular, the development of psychosocial
interventions, or the adaptation of existing technologies, with specific application in HIV for women and MSM with CSA histories is warranted. PTSD
and related symptoms are over represented in these groups, and are associated
with increased risk for transmission risk behavior, accelerated disease progression, increased symptom burden, poorer medication adherence, and cortisol dysregulation.
There is some evidence that psychosocial intervention related changes in
anxiety have been associated with changes in norepinephrine in patients with
HIV (Antoni et al., 2000) and with reductions in HPA dysregulation in
patients with GAD (Tiller, Biddle, Maguire, & Davies 1988). The incorporation of biological measures of disease progression (CD4 cell and HIV viral
load) and stress hormones as secondary outcomes into randomized clinical
trials to treat anxiety disorders could help to specify the physiological
pathways by which anxiety exerts its influence on disease and health outcomes
in HIV.
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341
Panic
Disorder
Panic
Disroder
Panic
Disorder
Panic
Disorder
Panic
Disorder
Panic
Disorder
CCAP
Roy-Byrne,
Stein et al.,
2005
CCAP
Roy-Byrne,
Craske
et al., 2005
CCAP
Craske
et al., 2005
Schmidt &
Telch, 1997
Schmidt et al.,
2003
Klein et al.,
2006
Study
Primary
Diagnosis
Evaluated
Health
Perceptions
Health
Perceptions
Chronic
Health
Condition
Health
Perceptions
Medical
Disability
Medical
Disability
Medical
Illness
burden
Primary
Medical
Comorbidity
Treatment
CBT (delivered
via the
CBT-G
CBT-G
CBT plus
Medication
vs.
Medication
CBT plus
Medication
Management
vs. Usual
Care
CBT plus
Medication
Management
vs. Usual
Care
Randomized
Control
Randomized
Waitlist
Control
Combined
Analysis
from
Control and
Treatment
Groups
No Control
Randomized
Control
Randomized
Control
Design
(groups)
-ADIS-IV
46
55
-SCID-NP
111
(subsample
of
study
total)
71
-CIDI
-CIDI
-Fear
Questionnaire
-Anxiety
Sensitivity
Index
-CIDI
-Fear
Questionnaire
-Anxiety
Sensitivity
Index
-SCID-NP
232
232
Sample
Size
Primary
Diagnostic Tools
used to Assess
Psychopathology
-General Health
Survey
-Physical Health
Rating Form
-Self-reported number
of visits to physician
-General Health
Survey
-RxRisk-V score
Primary Diagnostic
Tools used to Assess
Physical Illness
342
N. B. Schmidt et al.
Primary
Diagnosis
Evaluated
Panic
Disorder
Anxiety
Depression
PTSD
Acute Stress
Disorder
PTSD
Anxiety
Depression
Study
Ross et al.,
2005
Kissane et al.,
2003
Bryant et al.,
2003
Shemesh
et al., 2006
Kennedy
et al., 2003
Table 1 (continued)
Spinal Cord
Injury
Myocardial
Infarction
Mild
Traumatic
Brain Injury
Breast Cancer
Medical
Usage
Asthma
Primary
Medical
Comorbidity
Cognitive
Effectiveness
Training
CBT plus
Education vs.
Education
internet or
manual)
CBT-G plus
Asthma
Education
CognitiveExistential
Group
Therapy plus
Relaxation
vs.
Relaxation
CBT vs.
Supportive
Counseling
Treatment
NonRandomized
Matched
Historic
Control
NonRandomized
Randomized
Control
Randomized
Waitlist
Control
Randomized
Control
Design
(groups)
85
14
24
303
25
Sample
Size
-Acute Stress
Disorder
Inventory
-Clinician
Administered
PTSD Scale
-Impact Event
Scale
-PTSD
Diagnostic
Scale
-SCID-P
-STAI
-BDI
-HADS
-Affect Balance
Scale
-ADIS-IV
Primary
Diagnostic Tools
used to Assess
Psychopathology
-Physician Diagnosis
-Physician Diagnosis
confirmed by study
Cardiologist
-Self-rating of physical
health
-Physician Diagnosis
Primary Diagnostic
Tools used to Assess
Physical Illness
Anxiety
Depression
Mood
disturbance
Stress
Range of
Anxiety and
Mood
diagnoses
Anxiety
Depression
Range of
Anxiety and
Mood
diagnoses
Range of
Anxiety and
Mood
diagnoses
MDD
GAD
Panic
Disorder
Study
Craig et al.,
1998
Speca et al.,
2000
Anson &
Ponsford,
2006
Suh et al.,
2002
Gothelf et al.,
2005
Creed et al.,
2005
Massand
et al., 2002
Primary
Diagnosis
Evaluated
Table 1 (continued)
Severe
Irritable
Bowel
Syndrome
Irritable
Bowel
Syndrome
Childhood
Cancer
End-Stage
Renal
Disease
Traumatic
Brain Injury
Cancer
Spinal Cord
Injury
Primary
Medical
Comorbidity
Treatment
Psychodynamic
Interpersonal
Therapy vs.
SSRI Paroxetine vs.
usual medical
cares
SSRI Paroxetine
SSRI Fluvoxamine
Regular
Exercise
Mindfulness
MeditationBased Stress
Reduction
program
CBT-G
CBT-G
257
20
No Control
Randomized
Control
15
14
31
90
58
Sample
Size
No Control
No Control
Randomized
Waitlist
Control
NonRandomized
Control
Randomized
Waitlist
Control
Design
(groups)
-SCAN
-clinician
administered
HDRS
-Profile of Mood
States
-Symptoms of
Stress
Inventory
-HADS
-Sickness Impact
Profile
-Rosenberg SelfEsteem
-Self-rating
Depression
Scale
-STAI
-K-SADS-PL
-CDI
-BDI
-SCARED
-SCID
-STAI
-BDI
Primary
Diagnostic Tools
used to Assess
Psychopathology
-Gastroenterology
Clinic Patients Rome I Criteria SF36 scores
-Current pediatric
hematologyoncology center
patients
-IBS Rome I criteria
-confirmed by flexible
sigmoidoscopy
-Current hemodialysis
treatment
-TBI rehailitation
patient
-Physician Diagnosis
Primary Diagnostic
Tools used to Assess
Physical Illness
344
N. B. Schmidt et al.
GAD
Migraine
Disorder
Primary
Medical
Comorbidity
Treatment
Selective
Serotonin
Agonist
Buspirone
Randomized
DoubleBlind
Placebo
Controlled
Design
(groups)
74
Sample
Size
-DSM-IV GAD
Criteria
-HAM-A
Primary
Diagnostic Tools
used to Assess
Psychopathology
Lee et al.,
2005
Study
Primary
Diagnosis
Evaluated
Table 1 (continued)
-International
Headache Society
criteria
-Migraine Disability
Asessment Score
(MIDAS)
Primary Diagnostic
Tools used to Assess
Physical Illness
346
N. B. Schmidt et al.
347
348
N. B. Schmidt et al.
section is organized by the strength of the research design. In the second section
we focus on comorbidity in the context of pharmacological treatments. This
section is organized according to the issues explored in the limited relevant
literature. For each study, our goal is to give a sense of the nature of both the
anxiety condition and the physical illness including how adequately each was
assessed. In addition, we clarify the nature of the intervention that was used in the
trial. Finally, we give a sense of the level of effect in terms of the outcomes that
were assessed (e.g., changes on anxiety symptoms, changes in physical illness). As
the reader will note, there are relatively few studies that have utilized strong
methodologies (e.g., large samples randomized to active treatment and control
conditions for psychological treatments, double-blind placebo controlled trials
for pharmacological interventions). As a result, we felt that we should include
weaker designs that could be informative since the state of knowledge in this area
is so nascent.
349
a medical illness burden score was calculated based on the number and type of
prescription medications participants reported taking along with their selfreports of chronic disease (Roy-Byrne, Stein et al., 2005). Based on this calculation, the participants were split into those below and above the median score for
burden of medical illness. Individuals above the median reported more anxiety
symptomatology, psychiatric comorbidity and disability than their counterparts. However, CBT and pharmacotherapy produced comparable response
rates in both groups. The authors cautioned that although both groups
responded at a similar rate, the medically burdened group continued to exhibit
more symptomatology at follow-up due to their higher baseline symptoms.
Thus, the medically burdened group might require a longer intervention to
reach the same level of symptomatology as the less medically burdened group.
In another report relevant to health ratings, number of medical visits, and
anxiety symptoms, Klein, Richards, and Austin (2006) assessed the effectiveness
of different CBT delivery methods for individuals with panic disorder (Klein
et al., 2006). Participants diagnoses were established via the clinician administered anxiety disorders interview schedule (ADIS-IV; Brown, DiNardo, &
Barlow, 1994). Participants were randomly assigned to one of three conditions;
internet based CBT, CBT manual, or information only control group. The
internet condition was composed of one introductory module, four learning
modules, and a relapse prevention module. Techniques included controlled
breathing instruction, cognitive restructuring, and interoceptive and situational
exposure. Each participant was instructed to complete one module a week for six
weeks and received support and feedback from a therapist via e-mail. Individuals
in the manual condition were mailed a copy of Mastery of Your Anxiety and
Panic: MAP-3 (Barlow & Craske, 2000). This manual included the same CBT
information as the internet modules but differed in presentation and organization. In addition, the manual group received support and guidance from a
counselor who contacted them weekly via the telephone. The information only
group was given psychoeducation regarding the nature, causes, effects and
treatment options for panic disorder. They were also contacted weekly via the
telephone by a study therapist who provided minimal support, checked their
symptoms, and encouraged them to reread the informational material. A number of standardized anxiety measures were conducted at each assessment point
(pretreatment, post-treatment and follow-up). Participants health ratings were
established during each assessment point by asking patients how many times
they had seen their general practitioner in the past month and also asking them
to rate their physical health on a scale from 0 (extremely poor) to 10 (extremely
good). The two CBT groups showed greater improvement than the control
group on all dependent variables including panic disorder symptomatology,
panic related cognitions, negative affect, number of general practitioner visits,
and physical health ratings. The gains on all of these variables were maintained
or further improved at the 3-month follow-up screening. The internet group
outperformed the manual group on health ratings at follow-up and general
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practitioner visits at both post and follow-up. Analyses were not conducted to
determine whether health status moderated treatment outcome.
Kissane et al., (2003) investigated whether cognitive-existential group psychotherapy (CEGT) among women with breast cancer improved their mood
and mental attitude toward cancer. Previous investigations have reported that
anxiety and depression are quite common among women recently diagnosed
with breast cancer (Burgess et al., 2005). Participants were recruited from nine
metropolitan hospital oncology departments and all had been diagnosed with
early stage breast cancer confirmed through histology reports. The 303 participants were randomly assigned to receive relaxation classes or CEGT plus
relaxation. During three relaxation sessions, participants were taught progressive muscle relaxation with guided imagery. CEGT was manualized and had six
goals: promoting a supportive environment, facilitating grief over losses,
reframing negative thoughts, enhancing problem solving and coping, fostering
hope, and examining priorities for the future. The CEGT was conducted in
small groups by two therapists over 20 weekly 90-minute sessions. The therapists were trained in this therapy through a series of workshops and came from
the professional fields of psychology, psychiatry, social work, occupational
therapy, and oncology nursing. Participants were assessed at baseline and
follow-up using the Hospital Anxiety Depression Scale (Zigmond & Snaith,
1983) and the Affects Balance Scale (Derogatis, 1992), a self-report measure
designed to assess a range of positive and negative affective states. CEGT group
therapy exhibited a trend toward reducing anxiety (d = 0.217) yet failed to
significantly impact negative mood (d = 0.254). Psychologists were more
successful at decreasing both negative mood and anxiety, with a moderate effect
size of d = 0.515. Analyses were not conducted to determine whether pretreatment anxiety moderated treatment effects.
Bryant, Moulds, Guthrie, and Nixon (2003) evaluated whether PTSD could
be prevented among mild traumatic brain injury patients experiencing acute
stress disorder. All patients were injured through a motor vehicle accident or a
nonsexual assault within the two weeks prior to study enrollment. Mild brain
injury was operationalized as posttraumatic anterograde amnesia of less than
24 hours and a Glasgow Coma Scale score between 13 and 15. Participants also
met criteria for Acute Stress Disorder as assessed by the Acute Stress Disorder
Interview (Bryant, Harvey, Dang, & Sackville, 1998). Patients were randomly
assigned to receive CBT or supportive therapy. Both therapies were administered individually in five weekly 90-minute sessions. CBT techniques included:
education about traumatic reactions, progressive muscle relaxation training,
imaginal exposure to traumatic memories, cognitive restructuring, and graded
in vivo exposures to avoided situations. Supportive therapy provided education
about trauma and problem-solving skills. At post-treatment and 6-month
follow-up, participants were assessed for PTSD using the clinician administered
PTSD Scale (Blake et al., 1995). Individuals in the CBT group exhibited substantially lower rates of PTSD development at both post-treatment (d = 1.16)
and at 6-month follow-up (d =0.87).
351
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N. B. Schmidt et al.
353
No Comparison Group
Schmidt and Telch (1997) directly examined whether health status and health
perception affected participants response to CBT for panic disorder. Patients
(N = 71) diagnosed with panic disorder through a diagnostic interview (SCIDNP; First et al., 1994) received 12 sessions of CBT over eight weeks. The CBT
protocol included four main components: education regarding the etiology and
maintenance of panic disorder, cognitive therapy, respiratory control techniques and interoceptive exposure. Medical comorbidity and physical health
perceptions were assessed with the General Health Survey. Both were related
to poorer outcomes post treatment, though participants perceptions proved to
be a better indicator of treatment outcome than medical status. Participants
were considered to have met PD recovery criteria if they fell within normal
range on measures of anxiety and phobic avoidance, and were no longer
experiencing panic attacks. Following treatment, 35% of participants who
viewed their health as poor met recovery criteria, whereas 71% of those who
perceived their health as good met recovery criteria.
As noted in the introduction, we generally excluded articles involving treatment of comorbid physical illness and anxiety when the latter was assessed
secondarily. Typically, they did not contribute to our understanding of the
treatment of Axis I anxiety problems. Yet we briefly summarize a few such
studies that highlight some relevant points. Holmberg, Karlberg, Harlacher,
Rivano-Fischer, and Magnusson (2006) evaluated the effects of CBT for individuals with phobic postural vertigo (PPV) which is characterized by dizziness,
avoidance and anxiety often caused by a vestibular disorder (Holmberg et al.,
2006). All study participants received education regarding the disorder and
were shown how to perform self-administered vestibular exercises, which they
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were encouraged to perform twice daily for fifteen minutes. Half of the participants also received CBT. Participants in the CBT group reported significantly
greater gains on anxiety as measured by the Hospital Anxiety and Depression
Scale (Zigmond & Snaith, 1983). This study illustrates the application of CBT in
a patient population typically not considered in collaborative health efforts.
Psychotherapy also yielded gains when Speca, Carlson, Goodey, and Angen
(2000) investigated the effects of a mindfulness meditation-based stress reduction group program on a variety of psychological symptoms among cancer
patients. Individuals in the treatment condition exhibited large to medium
reductions in anxiety, depression, anger, confusion, and stress subscales of the
Profiles of Mood States (McNair, Lorr, & Droppelman, 1971). Yet results were
mixed in another severe patient population. Anson and Ponsford (2006) studied
CBTs effectiveness in improving traumatic brain injury patients coping strategies and emotional adjustment. PParticipants reported improved competency
and understanding of emotional issues and adaptive coping strategies; however,
there were no significant changes in depression, anxiety, self-esteem or psychosocial functioning. Together these studies illustrate the issue that less specific
anxiety assessment may make it hard to distinguish the clinical significance of
any improvements.
Suh, Jung, Kim, Park, and Yang (2002) evaluated individuals with end stage
renal failure being maintained on hemodialysis, to determine if regular exercise
would affect their level of anxiety, depression and quality of life. Participants
exhibited a significant improvement in anxiety symptomatology and quality of
life but not depression following the exercise program. Exercise is one of several
typical components in behavioral health therapy. This study raises the issue that
improvementseven in more impaired populationsmay accrue from fewer
components, shorter durations, or smaller doses.
Although much research remains to be conducted, this review provides a
promising look at the effects of psychotherapy, particularly CBT, on comorbid
physical illness and anxiety. CBT was shown to improve health perceptions,
decrease anxiety symptoms, and reduce doctor visits among individuals with
panic disorder (Klein et al., 2006; Roy-Byrne et al., 2005; Schmidt et al., 2003).
CBT also significantly reduced both medical and anxiety symptoms for asthmatics who had panic disorder (Ross et al., 2005). Patients with PTSD as a
result of a myocardial infarction reported both decreased medical risk factors
and anxiety symptomatology following CBT (Shemesh et al., 2006). Individuals
with comorbid traumatic brain injury and acute stress disorder were less likely
to develop PTSD when they received CBT (Bryant et al., 2003). Similarly, a
trend toward decreased anxiety symptoms for spinal cord injury and breast
cancer patients existed following cognitive therapy, particularly when anxiety
was higher at baseline or treatment was delivered by psychologists (Craig et al.,
1998; Kissane et al., 2003).
While improvements in physical and mental health status have been demonstrated, the potential mechanisms for change are largely unclear. Very few
studies investigated the moderating effect of health status on the relationship
355
between treatment and anxiety outcome. Schmidt and Telch (1997) reported
that poor health perception had a clearly negative impact on response to CBT
among panic disorder patients. Roy-Byrne et al. (2005) indicated the medical
burden did not affect rate of response to CBT among panic disorder patients but
that due to their more severe symptomatology they would require longer treatment duration to be considered remitted. Further investigation into the moderational role of health status on treatment response is warranted to determine what
impact it has on the different medical-anxiety illness comorbidities.
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N. B. Schmidt et al.
The nature of each childs illness and treatment was well documented. Most
were inpatients at the start of the study (9 out of 15), most were receiving
chemotherapy (14 out of 15), and most had a poor prognosis, which was defined
as a less than 30% chance of survival. Patients did not alter the other medications they were receiving during the trial.
The safety, tolerability, and benefits of fluvoxamine were assessed using
biological assays, self-report measures, and clinician ratings. Measures were
taken at baseline, four weeks, and eight weeks. Blood levels of liver enzymes,
blood urea nitrogen, and creatinine were taken to assess organ response to
fluvoxamine. Patients completed the Childrens Depression Rating ScaleRevised (CDRS-R; Pozananski & Mokros, 1995) and the Pediatric Anxiety
Rating Scale (PARS; Research Unit on Pediatric Psychopharmacology Anxiety
Study Group, 2001). Additionally, the child and adolescent psychiatrist rated
Clinical Global Impressions (CGI; National Institute of Mental Health, 1985)
of severity at baseline and improvement at four and eight weeks.
Response to treatment for individuals with anxiety disorders was assessed by
PARS scores changes. Four out of five patients diagnosed with an anxiety
disorder showed over 50% improvement in total PARS scores. Decreases in
the scores were significant at four weeks, but there was no further decrease by
eight weeks. Moreover, none of the patients experienced adverse physical
consequences. While three patients reported fleeting side effects including
abdominal pain and dry mouth, none of them were lasting or required dose
reduction.
The Gothelf et al. (2005) study provided preliminary evidence that anxiety
disorders can be safely treated with psychotropic medications in children with
chronic physical illnesses. The thorough assessments of anxiety psychopathology as well as physical condition were particular strengths. However, as a
preliminary investigation there was no placebo control group with which to
compare results. Moreover, patients were only receiving active treatment for
eight weeks. The long-term effects of fluvoxamine on children with cancer could
not be determined.
In addition to the safety of using psychotropic medications in severely ill
populations, another consideration when treating individuals with comorbid
physical illness and anxiety disorders is whether the medical illness adversely
affects responses to treatment. The CCAP conducted by Roy-Byrne et al. (2005)
and mentioned in the previous section was a randomized effectiveness trial
investigating responses to combined CBT and medication treatment versus
medication alone. One goal was to investigate treatment collaborations by
community behavioral health specialists and primary care physicians. Consequently, the specific pharmacological intervention was less restricted than other
studies reviewed in this chapter. The physicians were given a one-hour didactic
about recognizing panic disorder in their patients, as well as information about
options and delivery of psychotropic medication. In both groups, the intervention consisted of six weeks of SSRIs with dose titration. However, if a participant had already had two unsuccessful trials of treatment with SSRIs, other
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CGI (National Institutes of Mental Health, 1985), and specific symptoms of IBS
including the frequency and severity of abdominal pain, constipation, diarrhea,
incomplete emptying, and bloating.
In general, both groups responded well to paroxetine. Symptoms decreased in
frequency and severity across the domains of IBS physical symptoms. Individuals with anxiety disorders experienced somewhat greater alleviation of symptoms than the group without anxiety, however the differences were not
statistically significant. For example, the criteria for full remission, greater
than 70% improvement of symptoms, was met by 7 of 10 patients with anxiety
disorders as opposed to 2 of 10 patients without anxiety disorders (p=.07).
While the small number of participants limited the power of analyses, these
tentative findings suggested a fairly dramatic difference across comorbidity
groups. This potentially underscores a significant relationship between anxiety
disorders and IBS, perhaps suggesting not only shared etiology, but that IBS can
sometimes be a physical symptom of anxiety. On the other hand, several
researchers have demonstrated that in the absence of anxiety conditions,
SSRIs are still relatively effective in treating IBS (Creed et al., 2003; Creed
et al., 2005; Masand et al., 2002).
In an initial effectiveness study, Creed and colleagues (2003) compared
psychotherapy, antidepressants, and routine gastroenterologist care for
patients with severe IBS. They found patients with severe IBS responded significantly better to either psychotherapy or pharmacotherapy. In a follow-up
study designed to target anxiety, Creed et al. (2005) compared responses of
severe IBS patients with and without psychological comorbidity on psychodynamic interpersonal therapy, paroxetine, or routine IBS care from a gastroenterologist and a general practitioner. Anxiety disorders were diagnosed using
the Schedules for Clinical Assessment in Neuropsychiatry (SCAN; World
Health Organization, 1994), a clinical interview that was administered by a
psychiatrist. In general, patients in both treatment groups experienced significant improvement in their IBS symptoms; whereas, those in the treatment as
usual condition did not. For those in the active treatment conditions, there were
no differences between patients with and without psychological comorbidity in
improvements in physical symptoms. Despite a moderate correlation between
improvement in physical symptoms and improvement in psychological symptoms, the researchers concluded that the health-related outcomes in IBS resulting from paroxetine or psychotherapy were better accounted for by factors
beyond just improvements in psychological functioning.
Similar to IBS, serotonin is believed to play a role in migraine disorders.
5-HT agonists have been found to be effective in reducing the occurrence of
migraines, called migraine prophylaxis (Pascual & Berciano, 1991). In order to
investigate the primary prophylactic effects of buspirone, Lee, Park, and Kim
(2005) conducted a randomized, double-blind, placebo-controlled study.
Seventy-four individuals were diagnosed with both GAD and migraine disorder. Anxiety disorders were diagnosed according to the Diagnostic and Statistical Manual, fourth edition (DSM-IV) criteria for GAD, in combination with a
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Future Directions
Given the limited research in this area, our conclusions must certainly be
tempered. Much research remains to be conducted to fully examine the treatment implications of the various comorbidities between medical illnesses and the
anxiety disorders. However, it appears that we can make some preliminary
statements about the treatment of patients presenting with both physical illnesses and anxiety. First, people with a wide range of physical illnesses (cardiopulmonary, brain injury, cancer) that are treated for their anxiety problems
appear to benefit from empirically supported treatments like CBT or certain
classes of psychotropic medications. Moreover, these patients appear to benefit
in terms of their anxiety and to an extent, their physical health as well. Some
limited data hint that this physical improvement may occur directly (i.e., as a
result of the intervention) as well as indirectly (i.e., through changes in anxiety
symptoms). Although some data suggest that comorbid patients may not benefit
quite as much as those without physical illness, these patients do show some
gains. Unfortunately, there are few studies or even speculation about how to
handle comorbid patients differently to improve responsiveness. One idea is to
simply provide them with more treatment, though dose response studies in the
anxiety literature are not clear that more is always better. We would suggest that
clinicians consider incorporating interventions within existing CBT protocols
that are specific to the comorbid physical illness. For example, treating asthmatics with panic disorder could involve specific discussions of the respiratory
physiology of asthma and how anxiety affects asthma symptoms, specialized
interoceptive techniques designed to assess and tease apart asthma and panic
symptoms, and evaluation and discussion of potential medical safety aids such
as carrying inhalers.
Stanley et al. (2005) created such a protocol by designing CBT-RADAR, an
integrated cognitive behavioral treatment for reducing anxiety and depression
among patients with Chronic Obstructive Pulmonary Disease (COPD). They
noted that differential assessment and treatment is complicated by symptom overlap between medical and mental health symptoms, such as shortness of breath,
chest pain, weakness, sleep disturbance, decreased energy, fatigue,. As a result, they
integrated two intervention models with documented efficacy and potential utility
for medical patients. The first model is CBT-GAD/PC: an approach targeting
treatment of generalized anxiety in later life consisting of education/awareness,
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these studies have largely focused on treatments aimed at the psychiatric condition. As we noted in the introduction, very few studies using empirically supported medical treatments that are designed to intervene on a physical illness
appear to be concerned with the co-occurrence of Axis I anxiety psychopathology. This is certainly a fertile ground for future work.
The final consideration is analytic. We suggest that researchers should
consider: (1) treatment effects on both physical illness and anxiety, (2) moderator effects, and (3) mediator effects. Our review found that often studies failed to
measure changes in both physical illness and anxiety domains, which is certainly
unfortunate since changes in both arenas are of considerable interest. A few
studies assessed for moderator effects, for example, whether having a certain
physical illness influenced how anxious patients responded to the treatment.
Evaluation of such effects is very important for the identification of individuals
who may not respond well to standard treatment protocols. Mediator effects are
useful in determining whether changes in one domain (e.g., anxiety) are responsible for changes in the other domain (e.g., physical illness). Such analyses have
been conducted in only a small minority of the studies evaluated but could be
very important in beginning to identify mechanisms that are critical to change
among patients with comorbidity.
We hope that this review will inspire additional work in this area. Despite
highly efficacious treatments for anxiety, there is room for improvement and
there are some suggestions that patients respond less optimally because of
comorbid physical illnesses. In sum, much can be done to improve our understanding of the interplay between physical illnesses and anxiety and how this
impacts treatment interventions.
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Renal Failure, 24, 337345.
Tollefson, G. D., Tollefson, S. L., Pederson, M., Luxenberg, M., & Dunsmore, G. (1991).
Comorbid irritable bowel syndrome in patients with generalized anxiety and major
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Weissman, M. M., Markowitz, J. S., Ouellette, R., Greenwald, S., & Kahn, J. P. (1990). Panic
disorder and cardiovascular cerebrovascular problems results from a community survey.
American Journal of Psychiatry, 147, 15041508.
Wells, K. B., Golding, J. M., & Burnam, M. A. (1989). Affective, substance use, and anxiety
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Psychiatrica Scandinavica, 67, 361370.
Index
disorders involving, 35
effects of pharmacological treatment for1
anxiety on, 45
among HIV patients, prevalence of, 328
psychological effects of, 35
symptoms of alcohol use disorders, 37
Allergic asthma, 239
Amnesia, 350
Anaerobic exercise, effects of, 96
Anal intercourse, 323, 324
Angina
development of, 283
microvascular, 290
Anhedonic depressive symptoms, 69
Anti-basal ganglia antibodies (ABGA), 142
Antiretroviral therapy (ART)
goal of, 327
side effects of, 326
viral replication, suppression of, 327
Anxiety
in asthma
cognitive behavioral model, 269
cognitive behavioral treatment,
268270
in asthmatic adults, see Asthma and
anxiety
in asthmatic children/adolescents, see
Asthma and anxiety
and CHD, see Coronary heart disease
(CHD), and anxiety
and depression
in cardiac events, effects of, 285
in CHD, comorbidity of, 294
comorbidity of, 280
as predictive of hypertension, 297
STAI and BDI for, 352, 353
and HIV, see HIV (Human
immunodeficiency virus), and
anxiety
367
368
Anxiety (cont.)
and hostility, as predictive of
atherosclerotic disease, 297
and its disorders in asthma, see Asthma
and anxiety disorders
in NCCP patients, 289291
and physical illness, see Physical illness
and anxiety
and risk for HIV infection or
transmission, 322326
role in CHD, 292
role in HIV, 332
See also HIV (Human immunodeficiency
virus), and anxiety
and sleep disorder, primary classification
for diagnosis, 106
Anxiety and insomnia
criteria for support
different disorders, 109
single-spectrum disorder, 108
third factor models, 109110
evidence supports to models
age of onset, 110111
course, 112113
gender distribution, 111
neuroanatomy and pharmacology,
113117
symptoms and sleep EEG, 111112
Anxiety and menstrual cycle disorders
anxiety sensitivity, 189, 190
assessment measures, 184, 185
and biological factors, 193
health behaviors, 196, 197
premenstrual exacerbation and
comorbidity, 185, 186
premenstrual symptoms and disorders,
182, 183, 190192
researches on, 197199
retrospective and prospective studies,
183
treatments and therapies, 194196
Anxiety and physical illness link, method of
assessment
generalized anxiety disorder (GAD),
141142
obsessive-compulsive disorder (OCD),
142143
panic disorder (PD), 136140
posttraumatic stress disorder (PTSD),
132136
social anxiety disorder, 143144
specific or simple phobia, 144145
See also Physical illness and anxiety
Index
Anxiety disorders
alcohol role in development of, 37
and alcohol use disorders, odds ratios
(ORs) to quantify relationship
between, 31
and alcohol use, etiological theories of
relationship between, 29
anxiety symptoms and increased
vulnerability of developing, 35
in CHD patients, prevalence of, 281, 282,
287289
and chronic pain
assessment methods, 223225
associations, 215217
course of, 214, 215
issues and researches on treatment,
227229
physiological arousal, 220222
prevalence of, 209214
treatment and therapies, 225227
comorbid anxiety, 329
in context of mood disorder, 64
diagnosis of, 42
exercise role in, 81
GAD, prevalence of, 321
HADS anxiety score, 327
health anxiety and sexual behavior,
324325
and health behaviors, link between, 131
and HIV infection risks, 322326
in HIV patients, prevalence of, 319, 332
generalized anxiety disorder (GAD), 321
MSM and anxiety disorder, 321
panic disorder (PD), 321
PTSD, 320321
women, anxiety disorders in, 322
illicit drug use comorbidity, 71
panic disorder, prevalence of, 321
pathophysiology of stress hormones in,
330331
and physical illness
comorbidity, 129
treatment of, see Physical illness and
anxiety
in prediction of development of alcohol
dependence, 34
prevalence and impact among asthmatic
patients, 241
prevalence in
HIV individuals, 319
HIV MSM, 320322
programmatic research in, importance of,
331333
Index
PTSD, 324
prevalence rates of, 320321
relationship between anxiety and
alcohol, 31
relationships with illicit drug use, 58
screening measures, 319
semi-structured interviews, 223, 224
social anxiety, 323324
specific rates of co-occurrence for, 8
stress hormones, dysregulation of, 331
symptomatic and syndromal levels of
enquiry in, 2931
temporal order of, 64
tobacco use on, 3
trait anxiety, 323
treatment outcome and relapse in, 43
Anxiety disorders and specific illnesses, 129
observed relationships, explanations for
direct and indirect causal relationship,
130
shared risk factors, 131
Anxiety disorders interview schedule
(ADIS), 293
for DSM-IV, 351
Anxiety management, in asthma
treatment, 269
Anxiety neurosis, 286
atherosclerosis among, 296
Anxiety-premenstrual cycle phase
interaction models, 192194
Anxiety psychopathology
assessment of, 361
and physical illness, 341, 346
studies on, 342345
treatment of, 346348
Anxiety-related HIV sexual risk,
mechanisms of, 325
Anxiety sensitivity (AS), 40, 67
and adolescent anxiety, 171
in asthma-anxiety association, 264265
in chronic musculoskeletal pain and
PTSD patients, 218, 219
in premenstrual disorder, 189190
treatment for heroin users, 72
Anxiety symptoms, 131132
Anxiolysis, 116
Arrhythmias
anxiety in, examination of, 285
occurrence of, 297
ventricular
anxiety in, 295
susceptibility to, 299
Aspirin treatment, for improved PTSD, 352
369
Asthma, 341
adults with, anxiety in, see Asthma and
anxiety
anxiety-asthma relation, specificity of,
265266
and anxiety disorders, 237
prevalence and impact of, 241
anxiety in, CBT for, 268270
anxiety vulnerabilities on, 264265
Atopy syndrome in, 240
bronchoconstriction, 262, 264, 266
children/adolescents with anxiety in, see
Asthma and anxiety
classification, 238
dysfunctional beliefs, 267268
and mental health, 240241
non-psychological risk factors for,
239240
occurrence and symptoms, 237, 238
and panic differentiation in asthma
treatment, 269
panic disorder in, specificity of, 260261
P-F levels in, 264
and psychopathology, relation
between, 259
related QoL, effect of anxiety on, 263
self management, in asthma
treatment, 269
symptom severity, and anxiety, 262263
Asthma and anxiety
in adults, 247, 259
outcomes of various studies, 259
relation between, 248258
in children/adolescents, 241, 247
relation between, 242246
cognitive-behavioral model of cooccurrence of, 266268, 269
extant research, 270271
limitations, and future directions,
271272
Asthma Symptom Checklist (ASC), 260, 264
Astrand-Ryhming ergometer test, 83
Atherosclerosis
in anxiety-CHD association, 296297
anxiety for progression of, 295
cause of, 281
inflammatory cytokines in, role of, 301
product of, 280
risk factors of, 297
Atopy syndrome, in asthma, 240
Autonomic nervous system (ANS)
dysregulation, in PTSD and
chronic pain, 221, 222
370
Average sleep duration, 118
Axis I anxiety disorder in NCCP, 291
Beck Anxiety Inventory (BAI), 40
Beck depression inventory (BDI), for
depression and anxiety, 352, 353
Benzodiazepines, 347, 357
efficacy of, 93
Blood pressure
changes, as symptom of partial
seizures, 138
elevated, in pain and anxiety, 220
high
as cardiovascular risk factor, 133, 282
endothelial damage in atherosclerosis
due to, 281
as factor contributing to
atherosclerosis, 296
influence of CBT over, 352
in panic disorder patients, 136, 300
Brain injury, 354, 360
Breast cancer, 354
CEGT for, 350
Breathing, diaphragmatic, 351
Bronchitis, chronic, 240
Buspirone, effects on migraine disorder,
358, 359
CAD, see Coronary artery disease (CAD)
Cancer, 360
breast, 354
CEGT for, 350
in youth, fluvoxamine for treatment
of, 355
Cardiac anxiety, in NCCP, 289
Cardiac death, and anxiety, association
between, 284
Cardiac function, altered, in anxiety-CHD
association, 297300
Cardiac morbidity, negative impact of
depression on, 302
Cardiorespiratory disorders, 341
Cardiovascular disease (CVD) and anxiety, 279
future directions, 303305
increased risk for CHD, 281287
See also Coronary heart disease (CHD),
and anxiety
past studies on, caveats in interpretation
of, 291
conceptualizations of anxiety,
292293
construct definition overlap, 293294
directionality, 294
Index
patients with NCCP, anxiety in,
289291
terminology and background in,
280281
Causal risk factor, and puberty, 159
CBT, see Cognitive behavioral therapy
(CBT)/ Cognitive-behavioral
treatment (CBT)
CCAP study, see Collaborative care for
anxiety and panic study (CCAP),
for effectiveness of CBT
CD4 cell and HIV infection, 318
CDI, see Childrens Depression Inventory
CEGT, see Cognitive-existential group
psychotherapy (CEGT)
Central nervous system (CNS),
hyperexcitability of, 35
Central neurotransmitter function, 92
CHD, see Coronary heart disease (CHD)
Chest pain (CP), 279
non-cardiac (NCCP), anxiety in patients
with, 289291
Childhood sexual abuse
among IDUs, rates of, 328
and PTSD, prevalence of, 325
Children, with asthma and anxiety
disorder, relations between, 241,
242246, 247
Childrens Depression Inventory, 355
Chronic insomniacs, 117
Chronic musculoskeletal pain
and anxiety disorders, 208212
exposure therapy and graded activities,
226, 227
Chronic obstructive pulmonary disease
(COPD), 137, 138, 341, 360
patients with anxiety and depression,
CBT for, 360
Chronic Pain Coping Inventory (CPCI),
in anxiety disorder assessment, 225
Chronic pain, in PTSD patients, 213, 214
Cigarette smoke, 281
See also Smoking
Clinical anxiety, exercise training programs
for, 8992
Clinical Global Index, 45
Cognitive behavioral therapy (CBT), 136
for anxiety, 346
anxiety disorder and pain treatment, 225
for depression, efficacy of, 333
for improved QoL among individuals
with asthma, 270
for PMS treatment, 195, 196
Index
randomized trials for anxiety disorders in
HIV patients, 330
to improve anxiety and problematic
drinking symptoms in comorbid
patients, 45
Cognitive-behavioral treatment (CBT)
for anxiety disorders, 346, 347
in HIV patients, 330
of anxiety in asthma, 268279
CBT-RADAR for reducing anxiety and
depression among COPD
patients, 360
CCAP for effectiveness of, 348
for depression in HIV, 333
for depression in smokers, 18
for GAD and primary insomnia, 120
for obsessive compulsive disorder, 92
for panic disorder, 349
for panic disorder target anxiety
sensitivity, 90
for PPV and panic disorder, 353
for PTSD, 350
for substance dependence, 72
Cognitive-existential group psychotherapy
(CEGT), 350
for women with breast cancer, 350
Cognitive refocusing and self-efficacy, 94
Cognitive strategies in anxiety, and pain
treatment, 226
Collaborative care for anxiety and panic
study (CCAP), for effectiveness of
CBT, 348
Concurrent treatment of PTSD and cocaine
dependence (CTPCD), 72
Confidence interval (CI), 239
Congenital analgesia, 208
Conjunctivitis, allergic, 240
COPD, see Chronic obstructive pulmonary
disease (COPD)
Coronary artery disease (CAD), 137, 280
pathophysiology of, 301
patients with PD
morbidity and mortality among, 298
myocardial perfusion defects in, 300
prevalence of, 288
Coronary heart disease (CHD)
family history of, 290
morbidity
predictive of, 291
weighty influence on, 293
occurrence of, 294
patients with, prevalence of anxiety
disorders in, 287289
371
psychosocial influences on, 279
risk factors in, 281
NCCP patients, 291
ventricular arrhythmia, 299300
Coronary heart disease (CHD), and anxiety
association between, potential
mechanisms in
altered cardiac function in, 297300
atherosclerosis in, 296297
health-compromising behaviors in,
295296
pathophysiological mechanisms of,
300302
increased risk for, 281
epidemiological studies on, 282284
studies in psychiatric samples, 286287
studies in samples with known CHD,
284285
pathophysiological mechanisms of,
300302
therapeutic approach for targeting of,
302303
Corticotrophin releasing factor (CRF), 67
Cortisol
dysregulation of, 331
role in HIV, 331
Dehydroepiandrosterone (DHEA), 158, 188
Depression
in asthma, prevalence of, 237
on cardiac morbidity, negative impact
of, 302
in HIV, CBT for, 333
sertraline for, 303
severity of, 327
Depression and anxiety
in cardiac events, effects of, 285
in CHD, comorbidity of, 294
comorbidity of, 280
as predictive of hypertension, 297
STAI and BDI for, 352, 353
Depressive disorders, in CHD, rate of, 287
Dermatophystosis, 110
Diabetes mellitus, 281, 288, 290, 304
Diabetes, type, 2, 110
Drugs
properties of drowsiness and
sedation, 116
use in diagnoses, 56
Z, for reducing anxiety, 116
DSM-IV (Diagnostic and Statistical
Manual of Mental Disorders,
fourth edition)
372
DSM-IV (cont.)
ADIS for, 351
anxiety disorder of PD with
agoraphobia, 61
anxiety disorders, 59, 60, 85
as classification system for diagnosis of
anxiety and sleep disorders,
106, 116
criteria for GAD, 120, 358, 359
diagnosis of alcohol abuse or dependence
according to, 30
diagnosis of PTSD, 132, 135, 322
diagnostic criteria for CHD, 304
for disorder classification, 59
on illicit drugs, 55, 56
inclusion of PMDD in, 182
for PD, 286, 348
structured clinical interview (SCI) for, 352
symptoms of a panic attack listed
in, 136
Dysthymia, asthma with, 259
Early Adulthood Research Project
(EARP), 62
Eczema, 240
EEG-assessed sleep, 117
Emotional stress, measures of, 326
Emphysema, 240
Enhancing Recovering in Coronary Heart
Disease (ENRICHD), 303
Epidemiological Catchment Area (ECA), 56
Epilepsy, 138
Exercise anxiolysis, mechanisms of, 92
Exercise interventions, parameters of, 89
Exposure therapy in PTSD and pain
treatment, 226, 227
Fluvoxamine
safety and benefits of, 356
in youth cancer, treatment of, 355
Follicle stimulating hormone (FSH) in
puberty, 158
Forced expiratory volume in 1 second
(FEV1), 238
Framingham heart study of anxiety-CHD
link, 283
GABAergic-benzodiazepine-chloride
(GBC), 115
GABAergic systems, for biological
functions, 114, 115
GAD, see Generalized anxiety disorder
(GAD)
Index
Generalized anxiety disorder (GAD)
assessment of, 359
with asthma
diagnoses of, 247
presence of, 259
cardiovascular and gastrointestinal
disease, 141
diagnostic criteria for, 327
endocrine/metabolic/autoimmune
disease, 141142
in HIV, prevalence of, 321
in menstrual cycle, 185, 191, 192
NE reactivity in patients with, 331
obsessive-compulsive disorder (OCD),
142143
in pain patients, 209212
in risk of CHD, presence of, 291
Group A-Hemolytic Streptococcus
(GABHS), 142, 143
HAART, see Highly active antiretroviral
therapy (HAART)
HADS, see Hospital anxiety and depression
scale
Headache index (HI), 359
Headaches, migraine, 341
Health behaviors, and HIV and anxiety,
327329
Health-compromising behaviors
in anxiety-CHD association, 295296
spectrum of, 305
Health Professionals Follow-up Study of
anxiety-CHD link, 283
Health-related quality of life (HRQOL),
and HIV and anxiety, 329330
Heart attacks, PTSD symptoms as risk
of, 283
Heart deaths, 286
Heart disease, anxiety in, 292
Heart-focused anxiety, in NCCP, 289
Heart problems, psychological factors
in, 279
Heart-rate variability (HRV), reduced, in
anxiety disorder, 298
Highly active antiretroviral therapy (HAART)
anxiety and substance use, 328
autonomic nervous system activity
response to, 331
health-related quality of life (HQOL), 329
and HIV survival, 319, 329
Histamine, role in asthma, 262
HIV (Human immunodeficiency virus)
and anxiety, 317
Index
disease management, 326
disorder specific anxiety symptoms,
impact of, 327328
future research in, 331333
health and disease outcomes in, direct
and mediated relationships
between, 332
and health behaviors, 327329
and HRQOL, 329330
management of, 326
medication adherence in, 327328
overview of, 318319
prevention, comorbid psychosocial
issues in, 332
prevention interventions, traditional,
332
psychosocial and behavioral factors,
326
risk of infection or transmission,
322326
and self-reported adherence,
relationship between, 326
stress hormones in, pathophysiology
of, 330331
substance use and disease progression,
328
anxiety disorders in HIV patients,
prevalence of, 319322
See also Anxiety disorders in HIV
patients, prevalence of
association with heterosexual sex, 320
CD4 cell decline in, 318
clinical presentation of, 318
disease management, 326
and GAD, 321
infection risks, role of anxiety in
emotional stress, 326
PTSD, 324
social anxiety, 323324
trait anxiety, 323
and panic disorder (PD), 321
programmatic research in, importance of,
331333
and PTSD, 320
retrovirus, 318
screening measures, 319
sexual risk behavior
abuse history associated with, 325
anxiety, 323
stress hormones in, 330331
HIV MSM and anxiety disorders, 321322
HIV wasting syndrome, 318
Hospital anxiety and depression scale
373
HADS anxiety score, 327
HIV screening measures, 319
Hospital anxiety and depression scale
(HADS), for anxiety disorders in
HIV patients, 319
Hostility, 279, 325
HPA systems, see Hypothalamic pituitary
adrenocortical systems,
dysregulation of
HRQOL, see Health-related quality of life
(HRQOL), and HIV and anxiety
5-Hydroxyindoleacetic acid (5-HIAA), 170
5-Hydroxytryptamine (5-HT), 301
Hypercholesterolemia, 110, 281, 288, 304
Hypertension, 281, 288, 290, 304, 341
anxiety and depression as predictive of
prescription treatment in
normotensive individuals, 297
Hypothalamic pituitary adrenocortical
systems, dysregulation of, 331
Hypothalamic pituitary axis (HPA), 188
in depression, dysregulation of, 301
IBS, see Irritable bowel syndrome (IBS)
ICD-10 (International Classification of
Diseases, tenth edition), as
classification system for diagnosis
of anxiety and sleep disorders, 106
IDUs, see Injection drug users (IDUs),
childhood sexual abuse among,
rates of
IgE role in asthma, 238
IHD, see Ischemic heart disease (IHD),
chronic
Illicit drugs
categories of, 56
in context of mood disorder, 64
factors associated with vulnerability
for, 69
lifetime prevalence rates of, 60
reinforcing effects of, 66
relationships with specific anxiety
disorders, 59
temporal order of, 64
usage relationships with anxiety
disorders, 58
Imagery exposure, problem solving, and
relapse prevention in asthma
treatment, 269
Immune system response, HIV infection, 318
Immunoglobulin E (IgE), mediated asthma, 238
Injection drug users (IDUs), childhood
sexual abuse among, rates of, 328
374
Insomnia
age of onset for, 111
risk factor, gender distribution, 111
with secondary anxiety, 112113
Intercourse, anal, 323, 324
Irritable bowel syndrome (IBS), 139, 140
and asthma, individuals with, 261
SSRIs for treatment of, 357, 358
Ischemic heart disease (IHD), chronic, 280
Kaposis Sarcoma, 318
Kindling-stress hypothesis, 35
Late Luteal Phase Dysphoric Disorder
(LLPDD), 182, 183
biological factors, 193, 194
biopsychosocial factors, 194
Leutinizing hormone (LH), in puberty, 158
Locus ceruleus (LC), 114
Lung functioning assessment, in asthma, 238
Lymphoma, 318
Major depressive disorder (MDD)
with asthma, presence of, 259
comorbidity of, 293
in HIV, prevalence of, 321
for psychiatric comorbidity, 296
MAOIs, see Monoamine oxidase inhibitors
(MAOIs)
Marijuana withdrawal symptoms, 68
MDD, see Major depressive disorder (MDD)
Medical illness, burden of, 349
Medical utilization, 341
Medication adherence, 326
in HIV, anxiety and, 327
Menstrual cycle and anxiety disorders, 181
anxiety sensitivity, 189, 190
assessment measures, 184, 185
biological factors, 193
biopsychosocial factors, 194
health behaviors, 196, 197
premenstrual exacerbation and
comorbidity, 185, 186
premenstrual symptoms and disorders,
182, 183
researches on, 197199
retrospective and prospective
assessments, 183
treatments and therapies, 194196
Menstrual distress and health behaviors,
196, 197
Menstrual reactivity hypothesis, 190
Mental disorders, DSM for, 30
Index
See also DSM-IV (Diagnostic and
Statistical Manual of Mental
Disorders, fourth edition)
Mental health and asthma, 240, 241
Mental illness, forms of, 341
Methamphetamine, use among MSM, 324
Migraine disorders
buspirone effects on, 359
role of serotonin in, 358
Migraine headaches, 341
Minnesota Multiphasic Personality
Inventory (MMPI), 263, 300
MI-related PTSD, 133
Mitral valve prolapse, 341
Monoamine oxidase inhibitors
(MAOIs), 346
Mood disorders
comorbidity of, 292, 300
in NCCP patients, prevalence of, 290
Mood symptom fluctuation in women,
reproductive hormones role, 193
MSM (men who have sex with men), 317
HIV, and anxiety disorders, 321
methamphetamine use among, 324
prevalence of anxiety disorder, 320
Multiaxial Assessment of Pain (MAP), 220
Multidimensional Pain Inventory (MPI) in
anxiety disorder assessment, 224
Multiple sclerosis, single-spectrum
disorder, 108
Multiple sleep latency testing (MSLT), 106
Mutual maintenance model for pain and
anxiety disorders, 215, 216
Myocardial infarction (MI), 280, 352, 354
anxiety in, examination of, 285
anxiety with, 283
chest pain suggestive of, 289
trigger onset of, 300
NAS, see Nucleus accumbens septi
National Comorbidity Survey (NCS), 131
National Epidemiological Survey on
Alcohol and Related Conditions
(NESARC), 57, 60
NCCP, see Non-cardiac chest pain (NCCP)
anxiety in patients, 289291
axis I anxiety disorder, 291
risk factors, 290
Neurobiological disorder, 108
Neurobiological models, of drug addiction, 66
Neuropathy, peripheral, 318
Neurotransmitter-neuromodulatory
receptor systems, 113
Index
Night sweats, 318
Non-cardiac chest pain (NCCP), 280
CVD patients with, anxiety in, 289291
Non-psychiatric medical services, utilization
of, 341
Norepinephrine (NE)
in patients with HIV, changes in, 333
in patients with PTSD, levels of, 331
Normative aging study of anxiety-CHD
link, 283
Northwick study of anxiety-CHD link, 282
Nucleus accumbens septi, 93
Nurses health study of anxiety-CHD
link, 283
Obesity
in adulthood with asthma symptoms, 239
for psychiatric comorbidity, 296
Obsessive compulsive disorder (OCD), 347
CBT for, 92
in menstrual cycle, 190
in pain patients, 209212
Pain
and anxiety disorders
assessment methods, 223225
associations, 215217
course of, 214, 215
issues and researches on treatment,
227229
physiological arousal, 220222
prevalence of, 209214
treatment and therapies, 225227
concept of, 208, 209
prevalence in anxiety disorder patients,
213, 214
-related emotion and ANS responses, 221
-related stimuli, attention, 219, 220
Pain Anxiety Symptoms Scale (PASS), in
anxiety disorder assessment,
224, 225
Panic attack management in asthma
treatment, 269
Panic disorder (PD), 341, 347
in adolescent anxiety, 169
mediators of, 170
moderators of, 171, 172
with agoraphobia and anxiety disorder,
DSM-IV for diagnosis of, 61
application of exercise interventions
for, 89
association with
cancer, 140
375
cardiovascular disease, 136137
endocrine/metabolic disease, 140
gastrointestinal (GI) disease, 139140
neurological disease, 138139
respiratory disease, 137138
asthma with, 259
diagnoses of, 247
specificity of, 260261
CAD patients with
morbidity and mortality among, 298
myocardial perfusion defects in, 300
prevalence of, 288
CBT for, 90, 349, 353
in CHD-anxiety association, 286
CHD patients with, prevalence of, 289
comorbidity of, 293
diagnostic criteria for, 327
drinking frequency and quantity in nonalcoholic drinkers with, 38
DSM-IV for diagnosis of, 286, 348
efficacy of aerobic exercise for, 91
in HIV, prevalence of, 321
in incidence of cardiovascular morbidity,
294
NCCP patients with, prevalence of, 291
norepinephrine reactivity in patients
with, 331
in pain patients, 209212
for psychiatric comorbidity, 296
related symptoms for, 62
and symptoms in menstrual cycle, 185,
190, 191
treatment-seeking smokers with, 13
Panic psychopathology
addictive use of cigarettes, rates of
occurrence in, 9
behavior pattern characterized by
consistent avoidance of
threatening situations in, 4
current knowledge regarding, 13
development of, 16
diagnostic criteria for agoraphobia, 4
distinction from other anxiety disorders, 8
lifetime estimates of panic disorder, 4
persons with, rates of smoking among, 8
prevention programs for, application
to, 17
and tobacco use
co-occurrence rates between, 10
nature of associations between, 5, 11
prevalence of, 711
Panic-specific emotional symptoms, degrees
of, 14
376
PD, see Panic disorder (PD)
Peak expiratory flow (PEF), 238
Pediatric anxiety rating scale (PARS), for
anxiety disorder, 356
Pediatric autoimmune neuropsychiatric
disorders associated with
streptococcus infection
(PANDAS), 142, 143
Peptic ulcer disease (PUD), 141
Peripheral neuropathy, 318
Pharmacotherapy, in PTSD and pain
treatment, 227
Phobias, 110
social phobia, 328
Phobic anxiety, 293
anxiety-CHD for construct of, 293
CHD risk factors associated with,
284, 291
as risk of SCD, 282, 299
Phobic disorders, prevalence of, 283
Phobic postural vertigo (PPV), effects of
CBT for, 353
Physical functioning, health-related,
relationship between PTSD
and, 330
Physical illness and anxiety
future directions for, 360361
future methodological considerations for,
361362
pharmacological treatment of, 355360
psychosocial treatment of, 348
no comparison group, 353355
nonrandomized with control group,
352353
randomized with treatment
comparison group, 348350
randomized with waitlist, 351
Physiological arousal, in pain and anxiety
disorders, 220, 221
Pittsburgh Sleep Quality Index (PSQI),
117, 118
Polymorphous light eruption (PLE), 110
Pontine nucleus locus ceruleus, 114
Poor sleep, 117, 118
Postsynaptic serotonin receptors, downregulation of, 93
Posttraumatic stress disorder (PTSD), 283
association with
cancer, 135136
cardiovascular disease, 133
endocrine/metabolic/autoimmune
disease, 134135
neurologic disease, 133134
Index
asthma with, diagnoses of, 259
in CAD patients, prevalence of, 288
CBT for, 350
and childhood sexual abuse, prevalence
of, 325
childhood sexual abuse and, 325
and chronic musculoskeletal pain
patients, 207216
assessment methods, 223225
hypoalgesia/analgesia in, 222
physiological arousal, 220, 221
symptom overlap and anxiety
sensitivity, 218, 219
treatments and therapies, 225227
concurrent treatment of, 72
depression, substance abuse and anxiety
disorders, 321
diagnostic criteria for, 59
drug use disorder, 61
and health-related physical functioning,
relationship between, 330
in HIV-infected women, 322
in HIV patients, prevalence of, 320
and HIV risk, 324
in menstrual cycle, 192
NE in patients with, levels of, 331
prevalence rate in HIV individuals, 320
symptoms of, 283
treatments for, 333
PPV, see Phobic postural vertigo (PPV),
effects of CBT for
Premenstrual anxiety
health behaviors, 196, 197
research
in normal women, 187188
in women with PMDD, 189
in women with PMS, 188189
treatments and therapies, 194196
Premenstrual Dysphoric Disorder
(PMDD), 182
assessment measures, 183186
cognitive-behavior therapy, 195, 196
diagnosis of, 183
research on, 189
selective serotonin reuptake inhibitor,
196
Premenstrual exacerbation (PME), and
comorbidity, 185, 186
Premenstrual symptoms, and anxiety
disorders
assessment measures, 182186
interaction models, 192194
OCDs and GADs, 191, 192
Index
panic disorder, and symptoms, 190, 191
PTSD, 192
Premenstrual syndrome (PMS), 182
and biological factors, 193
cognitive-behavior therapy, 195, 196
research on women, 188, 189
selective serotonin reuptake
inhibitor, 196
Present pain index (PPI), in SF-MPQ, 224
Primary anxiety disorder, observations, 106
Primary insomnia, 106
Progressive resistance training (PRT), 96
Prototypical panic psychopathology, 14
Pseudoseizure, and psychogenic seizure, 133
Psychedelic abuse, and dependence, 62
Psychiatric comorbidity, 349
obesity, PD and MDD for, 296
Psychiatric illness, and NCCP, relationship
between, 290
Psychocardiology, 280
Psychoeducation, in anxiety and pain
treatment, 225
Psychogenic nonepileptic seizure (PNES),
133, 134
Psychological distress
in asthma, importance of, 241
in HIV risk, role of, 322
Psychopathology
of anxiety
assessment of, 361
physical illness and, 341
treatment of, 346348
and asthma, relation between, 259
Psychosocial clinical intervention research,
importance of, 333
Psychosocial treatment, for physical illness
and anxiety, 348
Psychotherapy
effects of, 354
in premenstrual anxiety, 195
PTSD, see Posttraumatic stress disorder
(PTSD)
Pubertal hormones
and anxiety, 162, 163
in puberty assessment, 158, 159
Pubertal status
and anxiety, 160162
in puberty assessment, 157
Pubertal timing
and anxiety, 163166
in puberty assessment, 157159
Puberty
and risk factor, 159, 160
377
role in adolescent anxiety: theory and
evidence, 155
conceptually-driven suggestions,
167172
future perspectives, 167
operationalization and assessment,
156160
psychological problems, 155, 156
pubertal status and timing effects
puberty assessment, 156160
research, 166, 167
undesirable bodily events, 156
Puberty-anxiety association, researches,
166169
QT interval variability (QTV), 298
Quality of life (QOL)
anxiety disorders for negative impact
on, 241
asthma related, effect of anxiety on, 263
and HIV, 329330
Reduced heart-rate variability (HRV),
298299
Reductions, in anxiety with exercise, 87
Relaxation training in anxiety and pain
treatment, 226
Renal failure, 354
Rhinitis, treatment of, 240
Rutgers Alcohol Problem Index (RAPI), 47
SAM systems, see Sympathetic adrenal
medullary systems,
dysregulation of
Schedules for clinical assessment in
neuropsychiatry (SCAN), for
anxiety disorders, 358
Schizophrenia, 355
Screen for Child Anxiety Related Emotional
Disorders (SCARED), 355
Seizure, 138
Selective serotonin reuptake inhibitors
(SSRI), 117
in PMS and PMDD treatment, 196
Serotonergic receptor system, 114, 116
Serotonin, role in migraine disorders, 358
Serotonin selective reuptake inhibitors
(SSRIs), 346
for treatment of IBS, 357, 358
Sertraline, for depression, 303
Sexual activity, among HIV-infected
adolescents, 324
Sexually transmitted disease (STD), 323
378
Shared vulnerability/stress models for pain
and anxiety disorders, 216, 217
Shingles, 318
Short Form McGill Pain Questionnaire
(SF-MPQ), in anxiety disorder
assessment, 224
Simple phobia (SP) in premenstrual
anxiety, 185
Single spectrum disorder model, anxiety and
insomnia, 107, 108
Sleep deprivation, 110, 117, 118, 156
panic induced by, 118
Sleeping difficulties, and insomnia-like
symptoms, 111
Sleep polysomnography (PSG), 117
Sleep restoration, mechanism of, 9394
Sleep restriction, 118
Slow wave sleep (SWS), 94
Smokeless tobacco, developmental course
for, 13
Smoking, 287, 304
for development of asthma, 240
Smoking behavior, conceptualization and
measurement of, 18
Smoking cessation, 291
Smoking-panic relations
cross-sectional tests to clarify factors
affecting, 14
psychopathology of, 12
study of, 15
tests for examining moderating factors
affecting, 16
Social anxiety
and HIV risk
gay and bisexual youth, 323
unprotected sex, 324
impact on drinking behavior of
undergraduate student, 40
Social anxiety disorder
autoimmune disease, 144
endocrine/metabolic disease, 143144
gastrointestinal disease, 143
in pain patients, 209212
Social phobia (SP), 118
asthma with, 259
diagnoses of, 247
Specific anxiety disorders, relationships with
illicit drug use, 59
Specific or simple phobia
cancer, 145
endocrine/metabolic disease, 144145
gastrointestinal disease, 144
respiratory disease, 144
Index
Spinal cord injury (SCI), 354
with depression and anxiety, 352
Spirometry role, in FEV1 measurement, 238
SSRIs, see Serotonin selective reuptake
inhibitors (SSRIs)
State trait anxiety inventory (STAI), for
anxiety and depression, 352, 353
Stress
cardiomyopathy, 300
for low SES and asthma symptoms, 239
Stress hormones in anxiety
HIV and pathophysiology of, 330331
HPA and SAM systems, dysregulation
of, 330331
Structured clinical interview diagnostic
(SCID)
for assessment of anxiety disorders, 329
for DSM, 293
Subacute cutaneous lupus erythematosus
(SCLE), 109
Substance use, 317, 322, 325, 326
in HIV, anxiety and, 328
Substance use disorders (SUD), 71, 328
anxiety and medication adherence,
relationships with, 326327
and anxiety-related HIV sexual risk, 325
in asthma, prevalence of, 237
comorbidity of, 329
in HIV patients, 328
Sudden cardiac death (SCD), 280
anxiety for, 295
emotion of anxiety in development
of, 280
occurrence of, 297
due to phobic anxiety, 282, 299
predictor of, 298
Suicidal ideation, in asthma, 241
Suicidality, 325
Sympathetic adrenal medullary systems,
dysregulation of, 331
Tachycardia, ventricular, 298
Tanner staging system, in pubertal status
assessment, 157
T-helper cells, and HIV infection, 318
Third factor model, anxiety and insomnia,
108, 109
apolipoprotein E gene polymorphism, 110
cardiovascular disease, 110
Threat-related stimuli, attention, 219, 220
Thyroid disease, 341
Tobacco-panic comorbidity, nature of, 10
Tobacco-panic psychopathology linkages, 11
Index
Tobacco use, 281, 290
cigarette smoking, 6
co-occurrence rates between panic
psychopathology and, 10
current knowledge regarding, 11
effects on persons with a lifetime history
of panic psychopathology, 9
lifetime nicotine dependence diagnosis, 9
multiple forms of, 10
nature of associations between panic
psychopathology and, 11
nature of association with panic
psychopathology, 5
smokeless application, 67
See also Smoking
Tourettes syndrome, 142
Trait anxiety, 326
and cardiac events, relation between, 284
in CHD patients, 294
and HIV risk, 323
prediction of, 260
Transtheoretical Model (TTM), 84
Traumatic event exposure, in adolescents, 155
Treatment rationale and education, in
asthma treatment, 269
Tricyclic antidepressants (TCAs), 346
Triiodothyronine (T3), arousal features in
PTSD, 134
Twelve-Step Facilitation (TSF), 45
379
Ultraviolet light/sun exposure, 109
Variable risk factor, and puberty, 159
Ventral lateral preoptic nucleus (VPLO), 114
Ventricular arrhythmia
anxiety for, 295
in CHD, 299300
Ventricular premature beat (VPB), as risk of
SCD, 299
Veterans Administration Normative Aging
Study of anxiety-CHD link, 283
Veterans Administration (VA) Health Care
System, 214
Visual analogue scale (VAS), in SF-MPQ, 224
Vulnerability nomenclature, risk factors
associated with, 56
Wakefulness-promotion, 114
Women
with breast cancer, CEGT for, 350
HIV, and anxiety disorders, 322
increase in CHD risk for, 283
World Mental Health Survey (WMH),
110, 111
on relation between asthma and
psychopathology, 259
Worry cognitive process, 106
Z drugs, reducing anxiety, 116