Anxiety in Health Behaviors and Physical Illness PDF

Anxiety in Health Behaviors
and Physical Illness

SERIES IN ANXIETY AND RELATED DISORDERS
Series Editor: Martin M. Antony, Professor, Department of Psychology,
Ryerson University, Toronto, Ontario, Canada
ACCEPTANCE AND MINDFULNESS-BASED APPROACHES TO ANXIETY

Conceptualization and Treatment
Edited by Susan M. Orsillo and Lizabeth Roemer
CONCEPTS AND CONTROVERSIES IN OBSESSIVE-COMPULSIVE DISORDER

Edited by Jonathan S. Abramowitz and Arthur C. Houts
SOCIAL ANXIETY AND SOCIAL PHOBIA IN YOUTH

Characteristics, Assessment, and Psychological Treatment
Christopher A. Kearney
TREATING HEALTH ANXIETY AND FEAR OF DEATH

A Practitioner’s Guide
Patricia Furer, John R. Walker, and Murray B. Stein
TREATING TRICHOTILLOMANIA
Cognitive-Behavioral Therapy for Hairpulling and Related Problems
Martin E. Franklin and David F. Tolin
ANXIETY IN HEALTH BEHAVIORS AND PHYSICAL ILLNESS

Edited by Michael J. Zvolensky and Jasper A. J. Smits
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each
new volume immediately upon publication. Volumes are billed only upon actual shipment. For further
information please contact the publisher.
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
Michael J. Zvolensky, Ph.D. Jasper A. J. Smits, Ph.D.
Department of Psychology Department of Psychology
University of Vermont Southern Methodist University
John Dewey Hall 6424 Hilltop Lane
2 Colchester Avenue Dallas, TX 75205
Burlington, VT 05405-0134 USA
USA jsmits@smu.edu
Michael.Zvolensky@uvm.edu
ISBN 978-0-387-74752-1 e-ISBN 978-0-387-74753-8
Library of Congress Control Number: 2007935078
© 2008 Springer Science+Business Media, LLC

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Preface
Research has been accumulating on the prevalence and nature of the co-
occurrence 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 physi-
cal 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 anxi-
ety 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 com-
ments 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 Michael J. Zvolensky, Ph.D.

University of Vermont
Jasper A. J. Smits, Ph.D.
Southern Methodist University
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Part I: Health Behaviors and Anxiety Disorders
Tobacco Use and Panic Psychopathology: Current Status and Future

Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Michael J. Zvolensky, Theresa Leyro, Amit Bernstein,
Matthew T. Feldner, Andrew R. Yartz, Kimberly Babson, and
Marcel O. Bonn-Miller
Alcohol Use and Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Brigitte C. Sabourin and Sherry H. Stewart
Illicit Drug Use Across the Anxiety Disorders: Prevalence, Underlying

Mechanisms, and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Matthew T. Tull, David E. Baruch, Michelle S. Duplinsky,
and C. W. Lejuez
The Promise of Exercise Interventions for the Anxiety Disorders . . . . . . . . 81

Jasper A. J. Smits, Angela C. Berry, Mark B. Powers, Tracy L. Greer,
and Michael W. Otto
Anxiety and Insomnia: Theoretical Relationship and Future

Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Thomas W. Uhde and Bernadette M. Cortese
Part II: Physical Conditions and Anxiety Disorders
Anxiety Disorders and Physical Illness Comorbidity: An Overview . . . . . . 131

Tanya Sala, Brian J. Cox, and Jitender Sareen
vii
viii Contents
The Relation Between Puberty and Adolescent Anxiety: Theory

and Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Ellen W. Leen-Feldner, Laura E. Reardon, Chris Hayward, and
Rose C. Smith
Anxiety, Anxiety Disorders, and the Menstrual Cycle . . . . . . . . . . . . . . . . 181

Sandra T. Sigmon and Janell G. Schartel
Pain and Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Gordon J.G. Asmundson, Murray P. Abrams, and Kelsey C. Collimore
Asthma in Anxiety and Its Disorders: Overview and Synthesis . . . . . . . . . . 237

Lisa S. Elwood and Bunmi O. Olatunji
Cardiovascular Disease and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

Kamila S. White
HIV and Anxiety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

Conall O’Cleirigh, Trevor A. Hart, and Carolyn A. James
Physical Illness and Treatment of Anxiety Disorders: A Review . . . . . . . . . 341

Norman B. Schmidt, Meghan E. Keough, Lora Rose Hunter, and Ann
P. Funk
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Contributors
Murray P. Abrams, B.A., Anxiety Bernadette M. Cortese, Ph.D.,

and Illness Behaviours Laboratory, Department of Psychiatry, Penn State
University of Regina College of Medicine and Hershey
Medical Center
Gordon J.G. Asmundson, Ph.D.
Anxiety and Illness Behaviours Brian J. Cox Ph.D., Department of
Laboratory, University of Regina Community Health Sciences and
Department of Psychiatry,
Kimberly Babson, B.A., Department University of Manitoba
of Psychology, University of
Arkansas Michelle S. Duplinsky, Center for
Addictions, Personality, and Emotion
David E. Baruch, Center for Research and the University of
Addictions, Personality, and Emotion Maryland
Research and the University of
Maryland
Lisa S. Elwood, M.A., Department of
Psychology, University of Arkansas
Amit Bernstein, Ph.D., Veterans
Affairs Palo Alto Health Care System
and University of Vermont Matthew T. Feldner, Ph.D.,
Department of Psychology,
Angela C. Berry, M.A., Department University of Arkansas
of Psychology, Southern Methodist
University Ann P. Funk, M.A., Department of
Psychology, Florida
Marcel Bonn-Miller, B.A., State University
Department of Psychology,
University of Vermont Tracy L. Greer, Ph.D., Department of
Psychiatry, University of Texas
Kelsey C. Collimore, B.S., Anxiety Southwestern Medical Center at
and Illness Behaviours Laboratory, Dallas
University of Regina
ix
x Contributors
Trevor A. Hart, Ph.D., Mark B. Powers, Ph.D., Department

Department of Psychology, of Psychology, University of
York University Amsterdam
Chris Hayward, M.D., M.P.H., Laura E. Reardon, M.A.,

Department of Psychiatry and Department of Psychology,
Behavioral Sciences, Stanford University of Arkansas
University
Brigitte C. Sabourin, B.A.,
Lora Rose Hunter, B.A., Department Department of Psychology,
of Psychology, Florida State Dalhousie University
University
Carolyn A. James, M.A., Department Tanya Sala, M.D., FRCPC,

of Psychology, York University, Department of Psychiatry, University
Toronto of Manitoba
Meghan E. Keough, M.S., Jitender Sareen B.Sc., M.D., FRCPC,

Department of Psychology, Florida Department of Community Health
State University Sciences and Department of
Psychiatry, University of Manitoba
Ellen W. Leen-Feldner, Ph.D.,
Department of Psychology, Janell G. Schartel, M.A., Department
University of Arkansas of Psychology, University of Maine
Carl W. Lejuez, Ph.D., Center for Norman B. Schmidt, Ph.D.,

Addictions, Personality, and Emotion Department of Psychology, Florida
Research and the University of State University
Maryland
Sandra T. Sigmon, Ph.D.
Teresa Leyro, B.A., Department of Department of Psychology,
Psychology, University of Vermont University of Maine
Conall O’Cleirigh, Ph.D.,
Massachusetts General Hospital/ Rose C. Smith, B.A.,
Harvard Medical School and Fenway Department of Psychology,
Community Health University of Arkansas
Bunmi O. Olatunji, Ph.D., Jasper A. J. Smits, Ph.D.,

Department of Psychology, Department of Psychology, Southern
Vanderbilt University Methodist University
Michael W. Otto, Ph.D., Center for Sherry H. Stewart, Ph.D.,

Anxiety and Related Disorders, Departments of Psychiatry and
Boston University Psychology, Dalhousie University
Contributors xi
Matthew T. Tull, Ph.D., Center Kamila S. White, Ph.D., University

for Addictions, Personality, of Missouri-Saint Louis
and Emotion Research and the
University of Maryland
Andrew R. Yartz, Ph.D., Department
of Psychology, University of Vermont
Thomas W. Uhde, M.D.
Department of Psychiatry, Michael J. Zvolensky, Ph.D.,
Penn State College of Medicine Department of Psychology,
and Hershey Medical Center University of Vermont
Part I
Health Behaviors and Anxiety Disorders
Tobacco Use and Panic Psychopathology: Current
Status and Future Directions
Michael J. Zvolensky, Teresa Leyro, Amit Bernstein, Matthew T. Feldner,

Andrew R. Yartz, Kimberly Babson, and Marcel O. Bonn-Miller
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 pro-
blems 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, J. A. Smits (eds.), Anxiety in Health Behaviors and Physical Illness. 3

Ó Springer 2008
4 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 accom-
panied by an autonomic nervous system surge and a strong flight-or-fight
action tendency (Barlow, Brown, & Craske, 1994). Recent estimates of unex-
pected (‘‘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 devel-
oping 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 12–13 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 45–54 years
(Burke et al., 1990). Panic disorder with and without agoraphobia is associated
with a chronic, fluctuating course and high rates of both psychiatric comorbid-
ity 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
Panic and Tobacco 5
threat-relevant (e.g., anything from being in crowds to certain substances like

caffeine; Feldner et al., 2004). Although agoraphobia does not necessarily
require the presence of panic attacks or panic disorder (Fava, Grandi, &
Canestrari, 1988), researchers frequently conceptualize agoraphobia as a com-
plication of (severe) panic disorder (Barlow, 2002). However, it is noteworthy
that this approach has been increasingly called into question in recent years, as
research indicates that there may be differing forms of agoraphobic avoidance
(Hayward & Wilson, in press). Regardless, agoraphobia with or without panic
disorder often is related to higher rates of clinically significant life impairment
and severity of illness (Kessler et al., 2006). The onset of agoraphobia with or
without panic disorder is not as firmly established as that of panic attacks and
panic disorder; though research suggests it likely occurs later in life than the
onset of panic attacks and panic disorder (Lindesay, 1991).
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 interven-
tion), 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 factor’s 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).
A risk factor also can be contrasted with a maintenance factor. A mainte-

nance 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.
Tobacco Use: Definition, Nature, and Prevalence
Cigarette smoking. Cigarette smoking is widely recognized as the most popular

form of tobacco use and as a major public health problem (Windle & Windle,
1999). Indeed, cigarette smoking remains a leading preventable cause of death
and disability in the United States (Centers for Disease Control and Prevention
[CDC], 1994). Smoking is considered a key factor in various types of medical
illness, including heart disease, a variety of pulmonary diseases (e.g., chronic
obstructive pulmonary disease), and many types of cancer (CDC, 1994, 2002).
For instance, smoking is responsible for almost 31% of all cancer-related deaths
(American Cancer Society [ACS], 2006a). Although smoking increases one’s
risk for developing many of these lethal medical diseases, quitting smoking
decreases the risk of developing such problems and may increase the survival
time among persons who have already developed such medical problems
(Samet, 1992).
Despite a reduction in smoking prevalence over the past 25 years, approxi-
mately 45–48 million (approximately 22% to 25%) adults in the U.S. currently
smoke (CDC, 1996). Though nearly 70% of these smokers are motivated to quit
(CDC, 2002), approximately 90–95% of smokers who do try to quit smoking on
their own (Cohen et al., 1989), and 60–80% who attend treatment programs,
relapse to smoking (CDC, 2002). Additional work suggests that 64% of youth
(adolescents) report having tried cigarettes and 14% have smoked frequently in
the past month (i.e., 20 out of the past 30 days; CDC, 2002). Thus, there is
evidence that smoking is not only a major source of death and disability, but
that once started it is often difficult to stop.
Smokeless tobacco use. Although cigarettes are the most common type of
tobacco use, there also is a significant population of smokeless tobacco
Panic and Tobacco 7
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 18–25 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 (Hatsu-
kami, Jensen, Allen, Grillo, & Bliss, 1996). In a recent review of smokeless
tobacco treatment programs, Hatsukami and Severson (1999) estimated a 3–6
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.
Prevalence of Comorbid Tobacco Use and Panic Psychopathology
There have been both representative surveys and community-based studies

focused on addressing the extent of the co-occurrence between tobacco use
and panic psychopathology. To date, this work has largely centered on cigarette
smoking rather than smokeless tobacco. Additionally, from a historical per-
spective, the vast majority of early work in this domain did not focus on panic
or other specific anxiety conditions, but rather, addressed anxiety disorders as a
single ‘‘class of problems’’ (e.g., Breslau, 1995; Brown, Lewinsohn, Seeley, &
Wagner, 1996; Costello, Erkanli, Federman, & Angold, 1999; Degenhardt,
Hall, & Lynskey, 2001; Hughes, Hatsukami, Mitchell, & Dalgren, 1986;
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 document-
ing rates of smoking among persons with panic psychopathology. The criteria
for smoking behavior has varied across investigations. Moreover, treatment-
based recruitment strategies have been most commonly employed, perhaps
making these data somewhat less generalizable to the overall smoking popula-
tion. 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 treat-
ment-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, indi-
viduals 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 ‘‘experi-
mental’’ 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 docu-
ment mental illness (Kessler et al., 1994). Participants were 4,411 individuals aged
Panic and Tobacco 9
15 to 54 years. Among individuals diagnosed with panic attacks, panic disorder,

and agoraphobia in their lifetime, 38%, 35%, and 38% were current smokers,
respectively. These rates were significantly greater than rates of current smoking
among individuals without mental illness. By comparison, 36% of individuals
with a lifetime history of major depression and 49% of individuals with a lifetime
diagnosis of drug abuse or dependence were current smokers. Rates of lifetime
smoking among persons with a lifetime history of panic psychopathology
(i.e., panic attacks, panic disorder, or agoraphobia) ranged from 58% to 61%.
When diagnostic status in the past month was used as the grouping variable,
current rates of smoking were 46% among persons with panic attacks, 42%
among persons with panic disorder, and 48.1% among persons with agorapho-
bia. It is noteworthy that as number of mental diagnoses increased (ranging from
0 to 4 or more), the percentage of heavy (i.e., peak consumption exceeding
24 cigarettes a day) compared to relatively lighter (i.e., peak consumption less
than 24 cigarettes per day) smokers increased. Overall, these data, coupled with
the treatment-seeking data noted earlier, suggest that smoking occurs at relatively
higher rates among those with panic psychopathology compared to those with no
mental illness.
Whereas the studies just reviewed focused on smoking among those with
panic psychopathology, other investigations have sought to evaluate rates of
panic psychopathology among smokers (Black, Zimmerman, & Coryell, 1999;
Breslau, Kilbey, & Andreski, 1991; Goodwin, Zvolensky, & Keyes, 2007;
Nelson & Wittchen, 1998). All of these investigations except that by Black
and colleagues (1999), which involved community-based recruitment, involved
some sort of representative sampling strategy. In contrast to the studies
reviewed earlier, these investigations attempt to understand panic within the
context of tobacco dependence and severity. Here, across studies, results
indicate that among those persons meeting criteria for more addictive use of
cigarettes (e.g., nicotine dependence), there is a greater prevalence of panic
psychopathology (Breslau et al., 1991). For example, Breslau and colleagues
(1991) found that 6.6% of persons meeting criteria for moderate dependence,
4.8% of those with mild dependence, and 2.4% of those with no dependence
had a lifetime diagnosis of panic disorder. Nelson and Wittchen (1998) similarly
found that among participants endorsing a lifetime history of smoking (yes/no),
7.6% met lifetime diagnostic criteria for panic attacks, 2% for panic disorder,
and 4.4% for agoraphobia. These rates of panic psychopathology were
significantly greater than those reported among nonsmokers; 2.4% had a
panic attack history, 0.7% had panic disorder, and 1.6% had agoraphobia.
Smokers with a lifetime nicotine dependence diagnosis compared to smokers
without such a diagnosis evidenced greater rates of panic attacks (11.3% versus
4.0%), panic disorder (2.2% versus 1.8%), and agoraphobia (6.4% versus
2.5%). It should be noted that a similar, albeit not uniform, pattern of findings
was apparent for individuals with other psychiatric disorders (e.g., alcohol
dependence, drug dependence).
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 comorbid-
ity 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.
Panic and Tobacco 11
Second, there are a number of issues central to the generalizability of the

reviewed investigations. The large majority of these studies have nottilized
representative samples and therefore selection biases may be operative. It also
is noteworthy that only one study (Hayward et al., 1989) focused exclusively on
youth. Therefore, it is not possible to generalize the present tobacco-panic
relations to other segments of the lifespan (e.g., adolescents) or the various
stages of tobacco use (e.g., initiation, maintenance) that would presumably be
apparent across different age ranges. Additionally, there are very limited data
on tobacco-panic psychopathology linkages from a cross-national perspective.
As factors that govern tobacco use may vary across communities and cultures,
and in conjunction with the world-wide public health impact of both smoking
and panic problems, it is important to extend work in this area to more diverse
global populations.
Finally, existing work has largely utilized limited assessments of smoking
and panic psychopathology. Due to the focus on the ‘‘presence or absence of
daily smoking,’’ little is known about the nature or topography of smoking
behavior in terms of its association with panic psychopathology (e.g., age
of onset, age of daily use, amount used when smoking the heaviest). This
work would be improved by broadening smoking assessments to include a
more detailed account of smoking history. It also may be productive to
incorporate a multidimensional approach that takes into consideration
theoretically-relevant motivational processes underlying cigarette use
(Piper et al., 2004). This type of approach could be particularly valuable when
examining linkages between smoking and panic psychopathology, whereby
motivation to smoke to avoid negative affect might be a formative psychologi-
cal process (Zvolensky, Schmidt, Antony et al., 2005).
Nature of the Associations Between Tobacco Use

and Panic Psychopathology
Developmental course. As a basis for understanding the nature of the relations

between tobacco use and panic psychopathology, it is important to first clarify
their developmental course. Representative data on the age of onset of panic
attacks and smoking provide a means to evaluate temporal sequence.
Research suggests that the onset of daily smoking typically occurs between
the ages of 15 and 20 and rarely after age 25 (Breslau, Johnson, & Hiripi, 2001).
For example, the CDC reports that in the United States, approximately 3,900
adolescents between the ages of 12 and 17 years initiate cigarette smoking each
day (CDC, 2004), and an additional 1,500 become daily cigarette smokers each
day (Substance Abuse and Mental Health Services Administration, 2005).
Early studies of smokeless tobacco use indicate a mean age of onset between
10 and 12 years (i.e., Gottlieb, Pope, Rickert, & Hardin, 1993).
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 9–17). 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 12–13 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 rela-
tively 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 devel-
opmental course and smoking-panic psychopathology is limited, extant studies
suggest that the majority of cases may involve smoking preceding panic attacks.
Future directions. Again, it is important to highlight that work in this

domain, although important for illuminating basic facets of tobacco-panic
relations, is currently limited. First, to the best of our knowledge, no studies
have examined the developmental course for smokeless tobacco. Future pro-
spective work is therefore needed to expand this area of knowledge. Second,
future study is needed to more carefully examine the putative smoking-to-panic
and panic-to-smoking developmental courses. Third, smoking often occurs in a
context of other substance use patterns. Thus, it may be useful to understand
the developmental relations of tobacco and panic within the larger develop-
mental context of panic-substance use comorbidity. In this sense, understand-
ing the relative degree of ‘‘specificity’’ of initial findings vis a vis other substance
use patterns and problems as well as health behaviors (e.g., physical exercise)
may be a fruitful next research step.
Current knowledge regarding tobacco use and panic psychopathology.
Cross-sectional studies that have utilized interview and self-report methods
have uniformly indicated that smoking, compared to non-smoking, is asso-
ciated with more panic-relevant symptoms and impairment among nonclinical
(Zvolensky, Forsyth, Fuse, Feldner, & Leen-Feldner, 2002) and clinical
(McCabe et al., 2004; Zvolensky, Eifert, Feldner, & Leen-Feldner, 2003)
samples. For example, Zvolensky, Schmidt and McCreary (2003) found that
treatment-seeking smokers with panic disorder compared to nonsmokers with
panic disorder reported more severe and intense anxiety symptoms, greater
interview-based overall severity ratings of panic symptoms, and more social
impairment. In these investigations, effects did not vary by gender, age, or other
forms of substance use. Moreover, there is emerging evidence that these types of
effects are relatively specific to panic disorder and psychopathology that
frequently co-occurs with panic (e.g., posttraumatic stress disorder; Feldner
et al., 2007). For example, Morissette and colleagues (2006) found that smokers
with anxiety disorders, as compared to their non-smoking counterparts,
reported higher levels of anxiety sensitivity (i.e., fear of anxiety and
bodily-related sensations; McNally, 2002), anxiety symptoms, and agoraphobic
avoidance. However, this association was specific to panic disorder and not
evident for any of the other studied anxiety disorders, which did not include
posttraumatic stress disorder (Morissette et al., 2006).
Laboratory studies, although less common, have yielded similar findings.
Zvolensky and colleagues (2004), for example, employed a voluntary hyperven-
tilation paradigm to examine associations between smoking and panic-relevant
fearful responding to bodily sensations. Results indicated smokers with panic
disorder reported greater levels of anxiety than smokers without panic disorder
at baseline, and also showed greater increases in anxiety during the
post-challenge assessment and recovery periods. Although smokers with, versus
without, panic disorder did not differ on baseline or post-challenge anxiety,
smokers with, compared to without, panic disorder, demonstrated slower
affective recovery from the challenge. These results indicate that smoking
compared to not smoking is related to greater affective distress in response to
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., repre-
sentative) 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 approxi-
mately 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 neuroti-
cism) 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 mod-
erate 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.
Although cross-sectional data are informative in the study of tobacco-panic

psychopathology relations, their utility also is limited. Prospective studies offer
unique insight into the nature of the observed relations over time, and by
extension, the order or temporal sequence of the associations. Researchers
have evaluated the association between smoking and risk of panic
psychopathology in a number of studies. Breslau and Klein (1999) tested the
association between daily smoking and risk for panic attacks and panic
disorder. Participants were drawn from two separate epidemiologically-defined
data sets. Across both data sets, results indicated that there was a significant
lifetime and prospective association between daily smoking and onset of panic
attacks and panic disorder; daily smokers were almost 4 times more likely to
experience panic attacks and 13 times more likely to develop panic disorder
after controlling for major depression and gender. Additionally, among
individuals who continued to smoke, compared to those who had quit, there
was a significantly increased risk for experiencing a panic attack and panic
disorder. Johnson and colleagues (2000) also found that anxiety disorders
during adolescence were not significantly related to smoking in young
adulthood. However, smoking in adolescence increased the risk for developing
agoraphobia and panic disorder during early adulthood. These effects were
observed above and beyond the variance accounted for by temperament, family
history of psychopathology, drug/alcohol use and other theoretically-relevant
factors. Specifically, adolescents who were heavy smokers were 15.6 times
more likely to develop panic disorder in early adulthood than non-smokers.
Interestingly, adolescents who smoked fewer than 20 cigarettes per day were not
at elevated risk for the development of (later) anxiety disorders,
potentially suggesting, once again, that heavier smoking levels impart greater
panic-related risk.
In another prospective study recently completed in Germany, 2,500 partici-
pants (ages 14–24 years at baseline) were evaluated over 4 years (Isensee,
Wittchen, Stein, Höfler, & Lieb, 2003). Compared with all other levels of
smoking, dependent regular smokers at baseline were significantly more likely
to develop panic attacks and panic disorder, and a similar pattern was observed
for agoraphobia. Similarly, Breslau, Novak, and Kessler (2004) evaluated daily
smoking and subsequent onset of psychiatric disorders. Results indicated
that the onset of panic disorder (odds ratio = 2.6) and agoraphobia
(odds ratio = 4.4) were associated with pre-existing daily smoking after
controlling for age, gender, ethnicity, and educational level. Additionally,
after controlling for pre-existing psychiatric disorders and sociodemographic
characteristics, current nicotine dependent smokers were significantly more
likely to have panic disorder compared to current non-dependent smokers
and former smokers. Importantly, the likelihood of panic disorder and
agoraphobia was significantly reduced as time since quitting increased; these
effects were specific to these conditions and not other psychiatric disorders
(e.g., major depressive disorder), suggesting quitting smoking likely decreases
the risk of developing panic problems, an issue that is discussed in greater detail
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 sensitiv-
ity and smoking rate significantly predicted concurrent agoraphobic avoid-
ance (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 antici-
patory anxiety. These data, in accord with cross-sectional findings (Leen-
Feldner 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 incorpora-
tion 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 implica-
tions (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
data exists on this important topic, making it a fertile area for future explora-
tion. 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 psycho-
pathology. 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 clinically-
relevant 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
smoking-related problems and processes (i.e., motivational processes) as

opposed to focusing more narrowly on rates of tobacco use. This multidimen-
sional conceptualization and measurement of smoking behavior is central to
theoretical and clinical advances relevant to tobacco-panic relations. Moreover,
it provides Moreover, it provides a means by which to further examine the role
of panic-specific, and other anxiety factors (e.g., traumatic event exposure,
negative affectivity), in smoking initiation (Bernstein, Zvolensky et al., 2007;
Feldner et al., 2007; Isensee et al., 2003).
Research has shown that affective vulnerability factors like panic psycho-
pathology may be related to problems in quitting smoking. Lasser et al. (2000),
for example, reported quit rates (i.e., proportion of lifetime smokers who were
not current smokers) in relation to psychiatric diagnosis among a representative
sample from the U.S. Using 1-month diagnostic status as a criterion point, the
quit rate was 29% for persons with panic attacks, 32% for those with panic
disorder, and 23% for persons with agoraphobia. Individuals with both panic
attacks and agoraphobia in the past month were significantly less successful in
quitting smoking compared to individuals with no mental illness (42%). Covey
and colleagues (1994) reported conceptually similar findings that panic psycho-
pathology may be related to poorer success in quitting, although it is not clear
whether this effect is more robust than the types of association(s) between
psychiatric disorders more generally and quit success. Other cross-sectional
field and laboratory work using a community sample has found that daily
smokers with a history of panic attacks, but no axis I histories, reported
significantly shorter average quit attempt histories, measured in days, com-
pared to smokers without panic (Zvolensky, Lejuez, Kahler, & Brown, 2004).
Similar results have been observed in laboratory investigations (Zvolensky,
Feldner, Eifert, & Brown, 2001). Although limited by cross-sectional design,
and by extension, possible reporting errors (e.g., recall biases), these data
provide evidence of a relation between panic psychopathology variables and
problems in quitting.
A related line of work has focused on anxiety sensitivity and success in
quitting smoking. Anxiety sensitivity tends to be elevated among individuals
who fear anxiety and arousal-related sensations such as panic disorder
(Bernstein & Zvolensky, 2007). In the earliest study in this domain, Brown,
Kahler, Zvolensky, Lejuez, and Ramsey (2001) examined a subset of data from
a randomized controlled clinical trial comparing standard smoking cessation
treatment versus standard smoking cessation plus cognitive-behavioral treat-
ment for depression in smokers with past major depressive disorder. In this
investigation, the association between anxiety sensitivity and relapse during the
early stages of a quit attempt (e.g., first week), when individuals are most apt to
experience symptoms of anxiety (Hughes, Higgins, & Hatsukami, 1990), was
examined. Anxiety sensitivity was significantly associated with increased odds
of lapsing during the first week after quit day (odds ratio = 2.0). Subsequent
work has conceptually replicated and extended the results of Brown and
colleagues (2001). For example, Zvolensky, Bonn-Miller, Bernstein, and
Marshall (2006) found anxiety sensitivity was significantly associated with

increased risk of early smoking relapse among a community sample of daily
smokers; these effects were evident above and beyond smoking rate and nega-
tive affectivity. Such work has recently been extended to low-level smokers from
Mexico, adding cross-national empirical support (Zvolensky, Bernstein, et al.,
in press). Collectively, there is a growing amount of empirical evidence suggest-
ing that panic psychopathology or pre-morbid panic-relevant variables such as
elevated anxiety sensitivity is related to early relapse problems, and possibly,
lower rates of overall success in quitting. Here again, controlled, prospective
studies are an important next research step, as they would remove concerns that
observed effects to date are attributable to reporting biases.
A closely related line of inquiry has suggested that anxiety sensitivity is
related to motivation to quit, barriers to quitting, and reasons for quitting.
For example, Zvolensky, Baker and colleagues (2004) found anxiety sensitivity
was related to higher levels of current motivation to quit smoking among adult
daily smokers (Mage = 20.4], Mcigarettes per day = 10.2); effects were not attri-
butable to other theoretically-relevant factors (e.g., gender, smoking rate;
Zvolensky, Baker et al., 2004). These findings may at first seem counterintuitive
in that it seems logical that individuals with high levels of anxiety sensitivity
would be less likely to express interest or motivation in quitting due to the
feared negative consequences related to quitting (e.g., withdrawal symptoms,
emotional dyscontrol). Yet, related work suggests that smokers who worry
about the negative health-related effects of smoking may engage in more quit-
ting behavior (Dijkstra & Brosschot, 2003). From this perspective, high anxiety
sensitivity smokers may be more apt to perceive a personal vulnerability to the
negative effects of smoking (e.g., health risks), and as such, express greater
motivation to quit (Zvolensky & Bernstein, 2005) despite their greater difficulty
in successfully doing so (Brown et al., 2001). In line with this reasoning,
Zvolensky, Vujanovic and colleagues (2007) more recently examined the rela-
tions between anxiety sensitivity and (1) motivation to quit smoking, (2) barriers
to smoking cessation, and (3) reasons for quitting smoking among 329
(160 females; Mage = 26.08 years, SD = 10.92) adult daily smokers. After
covarying for theoretically-relevant variables (negative affectivity, gender, axis
I psychopathology, non-clinical panic attack history, number of cigarettes
smoked per day, and current levels of alcohol consumption), anxiety sensitivity
was significantly incrementally related to level of motivation to quit smoking, as
well as perceived barriers to quitting smoking. Additionally, after accounting
for the variance explained by other theoretically relevant variables, anxiety
sensitivity was significantly associated with self control reasons for quitting
smoking (intrinsic factors) as well as immediate reinforcement and social influ-
ence reasons for quitting (extrinsic factors). These results provide empirical
evidence that anxiety sensitivity is uniquely related to level of motivation to quit
smoking, perceived barriers to quitting, and certain intrinsic and extrinsic
reasons for quitting.
Panic psychopathology or pre-morbid risk factors also appear to be related

to severity of acute nicotine withdrawal. In an early study in this domain,
Breslau, Kilbey, and Andreski (1992) found tobacco withdrawal symptoms in
a sample of young adults were significantly elevated among smokers with ‘‘any
anxiety disorder’’ compared to individuals without a history of such disorders;
however, specific anxiety diagnoses were not provided, rendering unclear the
specificity of such results to panic psychopathology per se. Zvolensky and
colleagues (2004) found that daily smokers with a history of panic attacks
reported significantly more intense anxiety-related withdrawal symptoms
(anxiety, restlessness, difficulty concentrating, and irritability) compared to
smokers without such a history; no differences were evident for the other
tobacco withdrawal symptoms (e.g., increased appetite). In another study,
Zvolensky, Baker et al. (2004) tested whether anxiety sensitivity predicted the
intensity of withdrawal symptoms during the first week of daily smokers’ most
recent quit attempt. Results indicated that anxiety sensitivity predicted the
intensity of nicotine withdrawal symptoms during the first week of smokers’
most recent quit attempt, and this effect was above and beyond variance
accounted for by negative affectivity, panic attack history, gender, cigarettes
per day, and age of smoking onset, accounting for 16% of unique variance in
withdrawal symptoms. This work is promising in suggesting panic-specific
factors are related to an enhanced reactivity to nicotine withdrawal symptoms.
Experimental work, which is now underway in our laboratory, is necessary to
provide an additional degree of confidence in such conclusions.
Another facet of evidence in support of a panic-tobacco relation is apparent
from motivational and outcome expectancy research. In regard to smoking-
related motivational processes, there is a large empirical literature documenting
that smokers often attribute their smoking, at least in part, to its mood-regulating
functions and believe that smoking will reduce negative affect states (Parrott,
1999). Due to their affective vulnerability, smokers with panic-relevant vulner-
abilities (i.e., high anxiety sensitivity) may be particularly motivated to smoke to
escape from emotional distress elicited by acute nicotine withdrawal or
non-withdrawal states (e.g., anticipatory anxiety; Zvolensky & Bernstein,
2005). A number of cross-sectional studies support this theory. Specifically,
studies have indicated that anxiety sensitivity is associated with coping-oriented
smoking motives among young adults with no history of psychopathology
(Novak, Burgess, Clark, Zvolensky, & Brown, 2003; Stewart, Karp, Pihl, &
Peterson, 1997; Zvolensky, Bonn-Miller et al., 2006), adolescents (Comeau,
Stewart, & Loba, 2001), and individuals with a past history of major depression
(Brown, Kahler et al., 2001). Zvolensky, Feldner, Leen-Feldner et al. (2004)
report conceptually similar findings for relations between anxiety sensitivity
and negative-reinforcement outcome expectancies for smoking. The Comeau
et al. (2001) investigation, in particular, is noteworthy in that anxiety sensitivity
moderated the relation between trait anxiety (frequency of anxiety symptoms)
and use of cigarettes to cope with affective distress, reporting a stronger relation-
ship between anxiety and use of cigarettes to cope with negative emotions
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 investiga-
tion 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 empiri-
cal 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 possibi-
lity 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
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 smok-
ing 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 pro-
blems, 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 inter-
oceptive 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 panic-
problem 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 psychopathol-
ogy. 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 dissemina-
tion of powerful clinical intervention strategies for tobacco users with
panic-related vulnerabilities or psychopathology.
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Alcohol Use and Anxiety Disorders
Brigitte C. Sabourin and Sherry H. Stewart
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 abus-
ing 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 beha-
vioral 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

Ó Springer 2007
30 B. C. Sabourin, S. H. Stewart
Symptomatic and Syndromal Levels of Enquiry

in the Anxiety – Alcohol Relationship
Anxiety and alcohol use can both be characterized at two different levels: sympto-
matic and syndromal. An association at the former level would entail a clear
relationship, for example, between feelings of anxiety and drinking behavior.
That is, one would expect that higher levels of anxiety would be related to higher
quantities and/or frequency of drinking behavior. In a classic paper, Persons
(1986) describes the advantages of studying psychological phenomena at the
symptomatic level rather than at the diagnostic category (or syndromal) level.
The symptom approach allows for study of important phenomena that may be
ignored by examining only the diagnostic category in question. For example, level
of alcohol consumption is not considered in the diagnosis of alcohol abuse or
dependence according to the fourth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV; American Psychiatric Association
[APA], 1994), although there have been some recommendations for incorporating
heavy drinking behaviors in the diagnostic definitions in future editions (Helzer,
Bucholz, & Bierut, 2006). Nonetheless, level of consumption may be an important
risk factor for alcohol problems (Dawson & Archer, 1993) and thus may be of
interest as a ‘‘symptom’’ when considering the anxiety – alcohol relation from the
symptom perspective. Also, the symptom approach recognizes the continuity of
clinical phenomena and behaviors with normal phenomena and behaviors. This is
a crucial point in the study of both drinking behavior and anxiety. For example,
some argue that drinking problems are best viewed as lying on a continuum
ranging from normal, non-problematic social drinking on one end to severe and
pathological alcohol dependence on the other extreme (Sobell et al., 1996).
In addition to the arguments presented above in favor of focusing on symptoms
rather than diagnostic categories, Chilcoat and Breslau’s (1998) discussion of
criteria for establishing causation between anxiety and alcohol abuse also demands
a symptom-focused approach rather than a syndromal- focused approach.
According to Chilcoat and Breslau, one of the criteria for causation includes a
‘‘gradient of effect’’, or dose response relationship between the two phenomena of
interest. That is, as the level of exposure to the causal agent increases, a resulting
increase in the level of the causal outcome should be expected. The gradient of
effect relationship can be studied as it pertains to the relation of any anxiety-related
symptom (e.g., number of panic attacks; severity of cognitive re-experiencing) with
any alcohol-related symptom (e.g., severity of negative consequences resulting
from alcohol use; usual number of alcohol beverages consumed per week).
The relationship between anxiety and alcohol can also be considered at the
syndromal level. At this level, a relationship between alcohol and anxiety would
be demonstrated if a diagnosis of one of the two disorders (i.e., anxiety disorder
or alcohol use disorder) was associated with an increased likelihood of a diag-
nosis of the other disorder. The DSM IV (APA, 1994) distinguishes between two
distinct types of alcohol use disorders: alcohol abuse and alcohol dependence.
Alcohol and Anxiety 31
Alcohol abuse is characterized by ‘‘recurrent and significant adverse conse-

quences related to the repeated use of alcohol’’ (p. 198), whereas alcohol depen-
dence 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.
Epidemiological Findings on the Anxiety – Alcohol Relationship
The relationship between anxiety and alcohol can be described using the concept
of comorbidity, which can be defined as diagnosable, problematic alcohol use and
anxiety symptoms that are both present at some point in a person’s lifetime, but
not necessarily at the same time (Kushner et al., 2000a). Comorbidity rates can be
estimated using either clinical or community samples. Because individuals with
more than one disorder are more likely to seek treatment, clinical samples may in
fact inflate comorbidity estimates (Berkson, 1949). It is believed that community
surveys provide more accurate reflections of the anxiety disorder – alcohol use
disorder relationship. We will review the two most recent large-scale community
surveys, which are representative of the results of these types of surveys.
In this chapter, we will present odds ratios (ORs) to quantify the comorbid
relationship between anxiety disorders and alcohol use disorders. An OR
reflects the odds that individuals will display a second disorder if a first disorder
is present versus if it is not present. An OR of 1.0 reflects a lack of relationship,
with higher ORs reflecting more significant relationships between two disor-
ders. ORs of less than 1.0 reflect a decreased probability of having the second
disorder given the presence of the first disorder.
The National Comorbidity Survey (NCS: e.g., Kessler et al., 1996) reported
12-month ORs for individuals with alcohol dependence and alcohol abuse of
also having suffered from panic disorder (1.7 and 0.5 respectively), social
phobia (2.8 and 2.3), generalized anxiety disorder (4.6 and 0.4), posttraumatic
stress disorder (2.2 and 1.5), and specific phobias (2.2 and 1.2). The 12-month
ORs associated with alcohol dependence are significant for all anxiety disorders
with the exception of panic disorder (although the lifetime OR of alcohol
dependence is significant for panic disorder). On the other hand, although
having any anxiety disorder leads to a significant OR of developing alcohol
abuse, the only specific anxiety disorder with a significant OR is social phobia.
More recently, the National Epidemiologic Survey on Alcohol and Related
Conditions (NESARC; e.g., Grant et al., 2004) reported 12-month ORs for
individuals with alcohol dependence and abuse to also display any anxiety
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. How-
ever, 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 signifi-
cantly 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 (Paa-
vola, 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 etiologi-
cal 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.
Etiological Models of the Relationship
In order to gain a better understanding of the relationship between anxiety and

alcohol use, it is important to explore the mechanisms that may affect the
etiology of the co-occurrence of symptoms of both of their disorders. There
1
The NESARC did not specify significance of reported 12-month ORs.
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.
Common Underlying Variables
There is some evidence, provided by two main lines of research, to support the
hypothesis that certain common, underlying factors are causing both anxiety
symptoms and problematic alcohol use (Kushner et al., 2000a). First, family
and twin studies have provided some evidence of possible common genetic
contributions to the correlation between anxiety symptoms and alcohol con-
sumption (e.g., Tambs, Harris, & Magnus, 1997). Family and twin studies have
also examined the heritability of common underlying personality traits asso-
ciated with both anxiety and alcohol use disorders. For example, several cross-
sectional and longitudinal studies have linked the highly heritable personality
trait of neuroticism (Jang, Livesley, & Vernon, 1996) with anxiety and its
disorders (e.g., Jorm et al., 2000; Weinstock & Whisman, 2006). Neuroticism
has also been linked to alcohol use disorders (Cox, 1987). Another personality
dimension that is closely related to neuroticism, negative emotionality, has been
associated with alcohol use disorders (Swendsen, Conway, Rounsaville, &
Merikangas, 2002). In a study by Swendsen et al. (2002) examining heritability
of negative emotionality, non-alcoholic individuals with alcoholic relatives did
not differ significantly on scores of negative emotionality than those without
alcoholic relatives. If negative emotionality were a heritable risk factor, non-
alcoholic individuals with alcoholic relatives would score higher on this trait
than those without alcoholic relatives. These findings suggest that negative
emotionality may indeed be an individual risk factor rather than a heritable
risk factor for alcohol use disorders. The inconsistent results between these two
related personality traits (i.e. both associated with negative emotional states)
demonstrates that common heritability for some of the personality traits rele-
vant to the anxiety – alcohol relationship is still in need of further investigation.
Conversely, another personality risk factor for both anxiety disorders and
alcohol use disorders, anxiety sensitivity (i.e. fear of anxiety; Stewart & Kushner,
2001), does have a strong heritable component that accounts for nearly half of
the variance in scores on anxiety sensitivity measures (Stein, Lang, & Livesley,
1999). Therefore, it appears that some, but not necessarily all, underlying
personality risk factors associated with both alcohol use disorders and anxiety
disorders have a shared heritable component.
Second, results from some prospective studies suggest a possible common ‘‘third
variable’’ contribution to the alcohol – anxiety relationship. For example, Zimmer-
man 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). Unfortu-
nately 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 envir-
onment 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.
Alcohol Use Causes Anxiety
The second hypothesis dealing with the relationship between anxiety and
alcohol use posits that prolonged drinking is actually a causal factor in anxiety
symptoms and disorders. This alcohol-induced anxiety can occur through
either psychosocial or physiological mechanisms. Psychosocially, it is hypothe-
sized that alcohol may interfere with normal adaptation to stressful stimuli
or that negative consequences produced by problematic drinking (e.g., loss
of job or relational problems) can lead to anxiety symptoms and increased
vulnerability of developing anxiety disorders (Kushner et al., 2000a).
Physiologically, alcohol withdrawal can often produce anxiety symptoms
such as shakiness (see Kushner et al., 2000a) or increased startle, a common
symptom of PTSD (Stewart et al., 1998). In addition, neural adaptation occurs
with frequent and excessive alcohol use over time such that repeated alcohol
withdrawals actually sensitize this withdrawal-induced anxiety (Breese, Over-
street, & 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 individual’s 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.
Anxiety Causes Alcohol Use
It has been hypothesized that anxiety symptoms and anxiety disorders promote
alcohol use, as individuals drink to self-medicate their anxiety. The ‘‘self-med-
ication hypothesis’’ (and the related tension reduction hypothesis) as applied to
the understanding of the relationship between anxiety and alcohol posits that
the pharmacological and/or psychological effects of alcohol lead to decreases in
aversive anxiety symptoms, thereby motivating anxious individuals to increase
their quantity and/or frequency of alcohol use via the process of negative
reinforcement (Kushner et al., 2000a). Although the self-medication and ten-
sion reduction hypotheses clearly do not account for all drinking behavior
(Greeley & Oei, 1999), there has been a good deal of empirical evidence to
support these hypotheses as they apply to the understanding of comorbid
anxiety and alcohol use disorders (Kushner et al., 2000a).
Anxiety disordered individuals do in fact self-report using alcohol to manage
their anxiety (Kushner, Abrams, Thuras, & Hanson, 2000b; Thomas, Randall,
& 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 dose-
response 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 prospec-
tive research conducted with both clinical and non-clinical populations
converge to provide some evidence for a relationship between anxiety sym-
ptoms 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 examin-
ing 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
disorder diagnoses should precede alcohol disorder diagnoses. In the cases

of social phobia, panic disorder, and PTSD diagnoses, the anxiety disorder
usually preceded the onset of the alcohol use disorder in comorbid individuals
(Cox, Norton, Swinson, & Endler, 1990; Kushner, Sher, & Beitman, 1990;
Stewart & Conrod, 2002).Furthermore, a cross-national investigation by
Merikangas et al. (1998) confirmed that anxiety disorders preceded alcohol
use disorders for the majority of participants. Assessing temporality or relative
order of onset of symptoms of alcohol use disorders and anxiety disorders
among comorbid cases can also help elucidate the anxiety – alcohol
causal relationship. For example, a recent study by Bernstein, Zvolensky,
Sachs-Ericsson, Schmidt, and Bonn-Miller (2006) found that the symptom of
panic attacks predated the onset of heavy drinking behaviors for the vast
majority of participants with both panic attacks and heavy drinking in a
community sample. Although many anxiety disorders and their symptoms
predate alcohol use disorders and heavy drinking, this relationship is normally
inverse for individuals with generalized anxiety disorder (GAD). For the
majority of individuals with GAD, alcohol use disorder predated the GAD
(Kushner et al., 1990), suggesting that, for those cases, anxiety could not have
been the cause of the alcohol use disorder. Thus, as can be seen from the
findings above, for most comorbid individuals (excluding a majority of GAD
individuals), the order of onset supports the possibility that anxiety may play a
causal role in the development of alcohol use disorders. And conversely, for
those with GAD, the alcohol use may play a causal role in the development of
the anxiety disorder. However, Chilcoat and Breslau (1998) clarify that the
temporality criterion is necessary but not sufficient for determining a causal
association between disorders.
Finally, the prospective study by Kushner and colleagues (1999) mentioned
earlier in the chapter that found an increased risk of future anxiety disorders for
individuals with alcohol dependence also found the converse. That is, having a
diagnosis of anxiety at baseline increased the risk three- to five-fold for a new
onset of alcohol dependence three to six years later (see also Goodwin et al., 2004).
The study demonstrates that the causal relationship between anxiety and alcohol
is potentially bi-directional in nature. Overall, the evidence presented above does
seem to support the fact that, at least in some instances, anxiety symptoms and
anxiety disorders do precede and possibly promote problematic alcohol use.
Moderating and Mediating Variables in the Anxiety – Alcohol

Relationship
More recent work has focused on finding specific variables that either moderate
or mediate the causal relationship between anxiety and alcohol use. A mod-
erator variable is a qualitative (e.g., sex) or quantitative (e.g., anxiety level)
variable that affects the direction and/or strength of the relation between two
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 comor-
bid 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 dis-
order 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 experi-
mental manipulation of expectancies via the placebo-controlled design. If
expecting alcohol were to induce a cognitive or placebo-induced anxiety redu-
cing 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 alcohol’s physio-
logical 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
on alcohol consumption. In addition, socially related alcohol expectancies have

been associated with higher levels of alcohol dependence in socially anxious
individuals (Ham, Carrigan, Moak, & Randall, 2005).
These studies demonstrate that different expectancies affect alcohol con-
sumption depending on the particular type of anxiety-related psychopathology
involved. For individuals with panic disorder or PTSD, the research until now
appears to indicate that general tension reduction expectancies provide suffi-
cient motivation for increasing alcohol consumption. However, for individuals
with social anxiety, it appears that specific social-related alcohol expectancies,
but not general tension reduction expectancies, tend to motivate these indivi-
duals to drink, resulting in greater risk of developing alcohol dependence. As
has been done with social anxiety, increasingly directed research in other types
of anxiety-related psychopathology is needed to determine more precisely the
kinds of expectancies that help explain each group’s increased risk for alcohol
problems in order to target these more specifically in treatment.
Self-efficacy. Self-efficacy has been defined by Bandura (1977) as the con-
viction that one can successfully execute a behavior required to produce a
certain outcome. Research conducted with socially anxious individuals suggests
that self-efficacy may act as a link between alcohol expectancies, social anxiety
and heavy drinking behaviors. Positive socially related alcohol expectancies
and low self-efficacy to avoid heavy drinking interact with one another in
increasing problematic drinking among socially anxious individuals (Burke &
Stephens, 1997; Gilles, Turk, & Fresco, 2006). Thus, increasing individuals’
self-efficacy in refusing alcohol or avoiding heavy drinking could be incorpo-
rated when developing treatment programs for comorbid individuals, at least in
the case of social phobia comorbidity. More research is needed to determine the
relevance of the self-efficacy construct to the comorbidity of alcohol use dis-
orders with anxiety disorders other than social phobia.
Drinking motives. Problematic drinking can arise because of maladaptive
drinking motives (reasons for drinking) even in the absence of particularly
elevated levels of alcohol consumption (Stewart et al., 2006). For some indivi-
duals who experience fear or anxiety, avoidance behaviors, such as drinking to
self-medicate, become negative reinforcement strategies used to attenuate or
cope with anxious states. Because such avoidance strategies are negatively
reinforcing through their effects in alleviating anxiety, the drinking behavior
continues over time and the individual comes to rely on drinking as a primary
coping strategy. For example, in many cases, social anxiety is not associated
with higher drinking levels (Tran et al., 1997), but it is with problematic reasons
for drinking, such as drinking to cope with negative emotional states, as well
as with greater risks of developing alcohol problems (Thomas, Randall, &
Carrigan, 2003; Stewart et al., 2006). A further problem with coping-related
drinking is that, as an avoidance behavior, it may serve to maintain anxiety by
preventing habituation of the anxiety response.
Research by Cooper (1994; see also Cooper, Russell, Skinner, & Windle,
1992) exploring drinking motives and their relation to problematic drinking
uncovered four factors explaining motivation for drinking. Two of these

motives involve positive reinforcement from drinking: social (i.e. to obtain
social rewards) and enhancement (i.e. to enhance positive mood or well
being), whereas the other two motives involve negative reinforcement from
drinking: coping (i.e. to cope with negative emotions), and conformity (i.e. to
avoid negative social consequences such as social rejection). Only the negative
reinforcement motives of coping and conformity predict alcohol problems after
controlling for quantity and frequency of alcohol use.
A study by Stewart and colleagues (2006) also found that for undergraduate
students, problem-drinking symptoms were positively associated with the nega-
tive reinforcement motives of coping and conformity drinking. The study also
found that coping and conformity drinking motives mediated the relationship
between social anxiety (specifically, fear of negative evaluation) and drinking
problems. That is, individuals with social anxiety experienced drinking pro-
blems because they drank either to cope with negative emotions (i.e. coping
drinking motives), or to avoid negative social consequences (i.e. conformity
drinking motives). In addition, the study found either no association or even a
negative direction association between social anxiety measures and drinking
quantity and frequency. Together, research by Cooper and her colleagues and
Stewart and her colleagues support the notion that drinking to cope with
anxiety or to conform with peer pressure confers additional risk for problem
drinking over and above the risks associated with level of alcohol consumption.
Additional support for coping and conformity drinking motives as impor-
tant factors in the anxiety – alcohol relationship has been provided by studies
conducted with non-clinically anxious participants. For example, Deacon and
Valentiner (2000) found a significant association between scores on the Beck
Anxiety Inventory (BAI, a widely-used measure of anxiety symptoms) and
coping motivated drinking but not social or enhancement motivated drinking.
In addition, Thomas et al. (2003) found that socially anxious individuals more
often reported drinking before and during social situations in an effort to feel
more comfortable (i.e. to cope with their social anxiety) than non-socially
anxious individuals.
Anxiety sensitivity has been associated with greater drinking levels and
argued to be a potential risk factor for alcohol use disorders (Stewart &
Kushner, 2001), as we describe in greater detail in the next section. Results
from a study by Stewart et al. (2001) supported coping and conformity motives
as mediators in the relationship between AS and higher drinking levels. That is,
high AS individuals’ greater drinking behavior was at least partially explained
by high coping and conformity motive scores.
Anxiety sensitivity. Anxiety sensitivity (AS) is an important individual dif-
ference that may mediate the anxiety – alcohol relationship. It is possible that
anxiety disordered patients are at increased risk of alcohol problems because
of their higher levels of AS (i.e., higher levels of fear of anxiety), which, in turn,
promote greater motivation and behaviors (e.g., alcohol use) to escape or avoid
the feared symptoms (Stewart & Kushner, 2001). Thus, consistent with the
self-medication hypothesis, it is possible that individuals high in AS use alcohol

for its anxiolytic or arousal dampening effects. In fact, high AS individuals have
been found to prefer alcohol and other ‘‘depressants’’ over ‘‘stimulant’’ type
drugs (DeHaas, Calamari, & Bair, 2002; Norton, Rockman, & Ediger, 1997).
Additionally, elevated levels of AS have been associated with increased drink-
ing behavior, including increased typical weekly drinking frequency, and yearly
excessive drinking frequency (Stewart, Peterson, & Pihl, 1995; Cox & Klinger,
1988; Stewart, Zvolensky, & Eifert, 2001). Moreover, Stewart, Conrod,
Samoluk, Pihl, and Dongier (2000) found evidence for the mediating role of
AS in explaining the association between PTSD symptoms and negative rein-
forcement drinking.
Stewart et al. (2001) also examined the relationship between lower-order
components of AS and drinking behavior. AS consists of three lower-order
factors: AS physical concerns (e.g., worrying that a rapidly beating heart is a
sign of having a heart attack), AS psychological concerns (e.g., worrying that
not being able to keep one’s mind on a task is a sign of going crazy), and AS
social concerns (e.g., worrying about appearing nervous in front of others; see
Zinbarg, Mohlman, & Hong, 1999). After controlling for the other two factors,
AS social concerns emerged as the only significant predictor for weekly drink-
ing frequency and yearly excessive drinking frequency. Thus, it is possible that
AS also plays an important role in the relationship between social anxiety and
drinking problems given the elevation of AS social concerns among those with
social phobia (Zinbarg et al., 1999).
Summary. Although these mediating and moderating variables are typically
studied in isolation, as can be seen above, alcohol expectancies, self-efficacy,
drinking motives, and anxiety sensitivity may interact with each other or inter-
vene with one another in explaining problematic alcohol use in anxious indivi-
duals. For example, people with certain anxiety disorders may be more likely to
drink to cope with their anxiety sensations (coping motives) because of their
fear of these sensations (anxiety sensitivity), thereby increasing their risk for
drinking problems. Additional research exploring the interplay between the
different variables affecting the anxiety-alcohol relationship would provide
important steps toward creating more effective treatments for comorbid
individuals.
Anxiety, Alcohol Use, and Other Health Behaviors
Alcohol consumption has been shown to be highly related to risky health

behaviors, such as smoking and illicit drug use (Paavola, Vartiainen, &
Haukkala, 2004; Tolstrup et al., 2005). In a longitudinal study (Paavola et al.,
2004), earlier alcohol use was associated with later smoking, and smoking in
adolescence predicted alcohol use in adulthood. Despite this close association
between alcohol use and smoking, combining the two behaviors does not
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 disor-
ders 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.
Maintenance of Comorbid Anxiety and Alcohol Problems
Empirical findings supporting all three causal hypotheses suggest the possibility
of multiple causal pathways involved in the etiology of comorbid alcohol use
disorders and anxiety disorders. The specific causal pathway involved may vary
across people or across anxiety sub-types. Regardless of the etiology of the
comorbid anxiety symptoms and problematic alcohol use, there have been
countless studies confirming that, once comorbid, anxiety and alcohol use do,
in fact, exert important influences on each other (see Kushner et al., 2000a).
Furthermore, processes involved in the initiation of the comorbidity may differ
from those involved in the maintenance of problematic alcohol use and anxiety.
A feed-forward model has been proposed (Kushner et al., 2000a) in which once
both alcohol use and anxiety are present, each promotes the maintenance or
exacerbation of the other. For example, anxious individuals may resort to
alcohol to decrease feelings of anxiety, which might be an effective strategy in
the short term, providing reinforcement for this pattern. However, alcohol, and
especially withdrawal from alcohol, increases anxiety-like symptoms in the
longer run via physiological mechanisms such as kindling. Alcohol may also
worsen anxiety levels because of the negative familial, social or occupational
consequences of heavy drinking. Individuals will then increase their drinking
behavior in an attempt to alleviate these worsening feelings of anxiety because
drinking has become a learned strategy for dealing with these symptoms,
especially if there is a failure to recognize that the alcohol may actually be
promoting the anxiety in the medium to long term.
Finally, in individuals with PTSD, alcohol that is used to cope with anxiety
may prevent normal ‘‘habituation’’ of the anxiety symptoms following trauma
exposure. On the other hand, for individuals who are not drinking, anxious
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).
Treatment Outcome and Relapse
When individuals who suffer from both anxiety disorders and alcohol use dis-
orders enter treatment for either disorder, their treatment outcome is often nega-
tively affected by their comorbidity. Alcohol use disorders have been found to
predict poorer anxiety disorder treatment outcomes for patients with both PTSD
(Forbes, Creamer, Hawthorne, Allen, & McHugh, 2003), panic disorder with
agoraphobia, social phobia, and generalized anxiety disorder (Bruce et al., 2005).
Comorbid anxiety problems also increase the likelihood of relapse in
treated or abstinent alcoholics (e.g., Driessen et al., 2001; Kushner et al.,
2005; Willinger et al., 2002). For example, if a comorbid PTSD – alcoholic
individual does not know how to cope with flashbacks and nightmares of the
traumatic event in ways other than through drinking, then continued re-
experiencing symptoms can serve as a major risk factor for return to problem
alcohol use following initially effective alcohol abuse treatment. Not all
studies have shown this relationship, however. In one study (LaBounty,
Hatsukami, Morgan, & Nelson, 1992), alcoholics with comorbid panic dis-
order did not differ in their rates of relapse to drinking problems from non
comorbid alcoholics. However, in a recent review, Bradizza et al. (2006) noted
some methodological issues with this paper, including the absence of a valid
and reliable diagnostic measure and the failure to define relapse, limiting the
conclusions that could be drawn from the study. Moreover, despite the
similar relapse rates, the study did find that more comorbid alcoholic and
panic disordered patients reported relapsing to cope with negative emotions
than non comorbid alcoholics. Thus, these observed differences in the relapse
process might be useful for improving treatments for this group.
Another study compared relapse rates for alcoholic individuals with comor-
bid social phobia, or panic disorder with agoraphobia, or agoraphobia without
a history of panic attacks to relapse rates for alcoholics without any comorbid
anxiety disorder (individuals with other anxiety disorders were excluded) fol-
lowing treatment for alcoholism (Marquenie et al., 2006). The results suggested
that the comorbid anxiety disorders did not have a significant impact on either
relapse rates or days to relapse. Nonetheless, some methodological problems
may account for this study’s failure to support higher alcoholism relapse among
treated alcoholic patients with comorbid anxiety disorders. First, the study used
a retrospective design. Participants were contacted for the study an average of
20.3 months (and up to 42 months) after baseline assessment, even though the
majority of participants who relapsed did so within the first few months post
baseline, raising issues concerning potential inaccuracy in the self-reports due to

retrospective memory bias. Also, compared to the non comorbid group, the
comorbid group had less chronic alcoholism and a shorter period between the
initial and follow-up assessments, which could have led to underestimates of the
rate of relapse in the comorbid group. Although the authors stated the failure to
observe group differences in alcoholism relapse persisted when these group
differences were statistically controlled in the analyses, statistical control of
possible confounds is never definitive, (and in fact may even produce biased
parameter estimates) especially when the confounding variables are correlated
with the predictor of interest, again limiting any firm conclusions that can be
drawn from the Marquenie et al. study.
Several studies, on the other hand, have found higher relapse rates in
comorbid patients. Driessen et al. (2001) found that treated alcoholic patients
with comorbid anxiety had 29% higher alcoholism relapse rates than did
alcoholics without comorbid anxiety. Furthermore, a study examining the
relationship between trait anxiety and relapse in a sample of abstinent alcohol
dependent patients found that higher trait anxiety was significantly predictive
of relapse to uncontrolled drinking (Willinger et al., 2002). Finally, in the best-
controlled study to date, Kushner et al. (2005) found that alcoholic patients
with an anxiety disorder (especially those with comorbid panic disorder or
social phobia) were significantly more likely to relapse to problem drinking
(using multiple criteria for drinking relapse) than alcoholic patients without an
anxiety disorder. These finding are particularly convincing given the methodo-
logical soundness of the study. For example, the study used a prospective design
where all participants were contacted between 90 and 120 days after the begin-
ning of treatment, thus increasing reporting accuracy by reducing reliance on
long-term retrospective memory. Also, all participants were given the same
standardized treatment and assessed at a consistent time following treatment.
Taken together, it appears that comorbid alcohol and anxiety may have a
negative effect on treatment outcome and relapse but with some mixed results.
The methodologically superior studies do seem to suggest such a negative effect. In
addition, although a couple of studies failed to show differences in relapse rates,
one of these negative studies did provide some evidence for the self-medication
hypothesis through highlighting the importance of coping with anxiety in explain-
ing relapse to alcohol use among patients with comorbid alcohol and anxiety
disorders. These differences could be useful in developing specific relapse preven-
tion types of treatments (see Marlatt & Donovan, 2005) for comorbid patients.
Treatments of Comorbid Anxiety and Alcohol Use Disorders
Individuals who suffer from both anxiety problems and alcohol use problems
present a special and challenging population with regards to treatment. As was
shown above, this population often suffers worse anxiety and alcohol treatment
outcomes than populations experiencing symptoms in only one of the two

domains. Although the study of specific treatments for anxiety – alcohol
comorbidity is still in its infancy, this area is growing and there are now several
promising approaches to treating comorbid anxiety and alcohol use disorders
(Stewart & Conrod, in press).
There have been mixed findings regarding the effects of pharmacological
treatment for anxiety on drinking outcomes with some studies finding improve-
ments in alcohol outcomes and others finding more equivocal results (see review
by Kushner et al., 2000a). One study (Randall et al., 2001) found that treating
individuals with comorbid social phobia and alcohol use disorder with parox-
etine (a selective serotonin reuptake inhibitor) did improve anxiety, but did not
result in significant decreases in drinking frequency and quantity. Relative to
placebo, paroxetine treatment did, on the other hand, lead to improvements on
the Clinical Global Index for alcohol. Other studies have found that successful
treatment of anxiety with buspirone was also associated with a reduction in
alcohol use (Tollefson, Montague-Clouse, & Tollefson, 1992; Kranzler et al.,
1994). These mixed findings are partially consistent with the self-medication
hypothesis, although the paroxetine study does suggest that there is more to the
maintenance of problematic drinking behavior in anxious individuals than just
the self-medication process.
There have also been mixed findings for the effectiveness of cognitive beha-
vioral therapy (CBT) to improve anxiety and problematic drinking symptoms
in comorbid patients. Thevos et al. (2000) found that, for female patients with
comorbid social phobia and alcohol use disorders involved in project MATCH
(the largest treatment-matching trial to date), CBT treatment for alcohol was
more effective in delaying return to drinking than Twelve-Step Facilitation
(TSF). It was hypothesized that TSF, which encourages participation in Alco-
holics Anonymous (AA), a group-based treatment modality that heavily
involves public speaking as patients share their experiences, may be too intimi-
dating for women with social phobia. Subsequently, Randall, Thomas, &
Thevos, (2001) examined whether conducting parallel CBT treatments aimed
at decreasing social anxiety and at addressing problematic drinking behaviors
would have additional benefits for comorbid patients compared to treatment of
the alcohol disorder alone. For patients receiving the parallel treatments, the
sessions consisted of CBT treatment for alcohol followed immediately by CBT
for social anxiety (i.e. the two treatments are offered simultaneously, but
independently of each other). Surprisingly, they found that patients who parti-
cipated in the parallel treatment had worse drinking outcomes, as assessed by
drinking quantity and frequency measures, than did patients who participated
in the alcohol only treatment. There are several possible explanations for these
unexpected findings. It is possible that clients in the parallel treatment group
engaged in more social situations as a consequence of their social phobia
treatment, resulting in more opportunities to drink. Additional research needs
to be conducted that would include other types of outcome measures that are
not specifically linked to frequency or quantity of drinking. As was mentioned
earlier in the chapter, coping drinking motives and problematic consequences of

drinking are useful therapy targets for comorbid individuals, particularly in the
case of social phobia. It is also possible that the lack of integration of the two
treatments or the excessive demands of combining two already intensive treat-
ments may have affected results. The parallel treatment did in fact lead to
somewhat higher drop out rates than the alcohol treatment alone, suggesting
that the parallel treatment may have been too much for comorbid patients to
handle (Conrod & Stewart, 2005).
On the other hand, another study (Bowen, D’Arcy, Keegan, & Senthilselvan,
2000) found that parallel CBT for panic disorder and standard alcohol treat-
ment in a group of comorbid panic disordered and alcoholic patients did not
result in significantly different treatment outcomes than standard alcohol treat-
ment alone. Both treatments resulted in significant decreases in anxiety and in
drinking behaviors. The authors noted that the relaxation training and stress
management components of the standard alcohol treatment might have limited
the ability to distinguish between treatments as these components may have
been useful in targeting the comorbid anxiety.
A recent randomly-controlled study conducted by Schade and colleagues
(2005) compared standard alcohol treatment alone to standard alcohol treat-
ment with anxiety treatment consisting of CBT plus optional fluvoxamine (a
selective serotonin re-uptake inhibitor) treatment (again, a parallel approach)
in patients with a primary diagnosis of alcohol dependence and a comorbid
diagnosis of panic disorder, agoraphobia, or social phobia. There were no
differences in alcohol outcome measures between both groups of patients.
The additional anxiety treatment did, on the other hand, improve anxiety
symptoms. It can be speculated that improved anxiety scores are significant
for this population, as decreased anxiety may serve as a protective factor for
longer-term outcomes. The study examined outcome results 32 weeks after
initial assessment, but did not look at longer- term outcomes (1 year or later)
in these patients. Future studies should examine longer-term treatment out-
comes in comorbid anxiety and alcohol patients.
Few studies, however, have reported outcomes for truly integrated treat-
ments. Integrated treatment models recognize the complex relationship between
anxiety disorders and alcohol use disorders and their possible mutual mainte-
nance (Zahradnik & Stewart, in press). Furthermore, their aim is to create a
hybrid of the treatments that work best for each disorder separately, and also
include in the treatment strategy an understanding of the reciprocal influences
each disorder has on the other (Zahradnik & Stewart). Integrated treatments
have been developed and tested for certain anxiety disorder – substance use
disorder combinations, but until now only one study (Kushner et al., 2006) has
investigated an integrated treatment focusing on comorbidity with alcohol use
disorders in particular. The treatment integrated CBT for panic disorder with
content focusing on the interaction between alcohol use and panic symptoms.
The integrated treatment was provided on top of treatment as usual (TAU) for
the alcohol use disorder and compared to a group who received only the TAU.
The trial was conducted on a sample of comorbid panic disorder – alcoholic

patients, with promising results. The group receiving the integrated treatment
showed better anxiety and alcohol outcomes than the TAU alcohol only treat-
ment group.
It is hoped that integrated treatments will provide a more effective strategy in
treating comorbid patients. Integrated treatments appear to be the most recom-
mended by ‘‘expert opinion’’; however few of the recommendations are sup-
ported by randomized controlled trials, or even quasi-experimental designs
(Watkins, Hunter, Burnman, Pincus, & Nicholson, 2005). More research
needs to be conducted to develop and test integrated treatment strategies and
to compare them against parallel or sequential approaches.
Prevention and/or Early Intervention
Another treatment approach receiving recent research attention involves tar-

geting the vulnerability factors (e.g., AS) associated with problematic drinking
in cases with, or at risk for, comorbid anxiety disorders (Conrod, Stewart,
Comeau, & MacLean, 2006, Watt et al., 2006). A study by Watt et al. found
promising results for brief CBT targeted at reducing AS in a sample of uni-
versity women. Three 50-minute CBT sessions led to a decrease in the propor-
tion of women with high AS who engaged in negative consequence drinking
(based on elevated scores on the Rutgers Alcohol Problem Index; RAPI; White
& Labouvie, 1989), as well as a decrease in conformity-motivated drinking (a
high-risk drinking motive; Cooper et al., 1992; Cooper, 1994) and in emotional
relief alcohol expectancies (i.e. a positive alcohol expectancy similar to tension
reduction expectancies described earlier). The treatment also significantly
reduced AS levels (Watt et al., 2006). Another similar AS-focused brief CBT
delayed drinking onset in young at-risk adolescents (mean age = 14; Conrod,
Castellanos, & Mackie, in press). Later drinking onset has been shown to be a
factor protecting against the development of later alcohol use problems (Grant,
Stinson, & Harford, 2001). The intervention also reduced panic attacks in high
AS adolescents (Castellanos & Conrod, 2006). Together, these results suggest
that brief CBT focused on reduction or management of AS may be a useful
strategy for prevention of or early intervention with anxiety – alcohol use
disorder comorbidity.
Conclusion
Although there is ample evidence supporting the existence of a strong relation-

ship 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
likely to self-medicate needs to be conducted, with a focus on potential differ-

ences 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 treat-
ments 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 treat-
ments 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 circum-
stances 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 Drug Use Across the Anxiety Disorders
Prevalence, Underlying Mechanisms, and Treatment
Matthew T. Tull, David E. Baruch, Michelle S. Duplinsky, and C. W. Lejuez
An increasing number of studies are beginning to recognize the heightened risk

for the development of substance use disorders among individuals with an anxiety
disorder diagnosis, and the possible interplay between these disorders is receiving
more attention in theoretical, clinical, and empirical spheres (e.g., Goodwin et al.,
2002; Morissette, Tull, Gulliver, Kamholz, & Zimering, 2007; Stewart, 1996;
Zvolensky & Schmidt, 2004; Zvolensky, Schmidt, & Stewart, 2003). As the
majority of this attention has been focused on nicotine or alcohol use, the goal
of this chapter is to review the extant work specific to illicit drug use across the
anxiety disorders. In keeping with this focus, we will consider only illicit drugs
and refer interested readers to chapters 4 and 5 in this volume for reviews specific
to nicotine and alcohol. We begin by providing a brief list of the drugs that would
fall under the larger category of illicit drugs, as well as prevalence rates of illicit
drug use within the general population. We then move to discuss prevalence rates
of illicit drug use within the anxiety disorders and among individuals with
anxiety-disorder relevant symptoms (e.g., non-clinical panic attacks). Of note,
this chapter will focus primarily on illicit drug use within the anxiety disorders as
opposed to anxiety disorder diagnoses among individuals who use illicit drugs.
Next, we present theories and data pertaining to the temporal progression of illicit
drug use and anxiety disorders. The chapter then concludes with a brief review of
treatments that specifically address comorbid anxiety and illicit drug use.
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: 301-405-
3281, 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).

Ó Springer 2008
56 M. T. Tull et al.
4th Edition (DSM-IV; American Psychiatric Association [APA], 1994),

include opioids (e.g., heroin, morphine), cocaine and its variants (e.g.,
crack), amphetamines (e.g., crystal methamphetamine), hallucinogens (e.g.,
LSD, PCP), inhalants, and marijuana. Drug use diagnoses include abuse and
dependence. Abuse refers to a pattern of drug use leading to significant
functional impairment, as evidenced by one of the following within a
12 month period: 1) recurrent use leading to failures to fulfill major obliga-
tions at work, school, or home; 2) recurrent use in situations where it may be
physically hazardous to do so; 3) legal problems resulting from use; or 4)
continued use even when the drug use results in social or psychological
problems (APA, 1994). Dependence refers to a history of drug use marked
by: 1) substance abuse; 2) continued use despite problems associated with that
use; 3) drug tolerance; and 4) withdrawal symptoms (APA, 1994). Specific
reference to use, abuse, and dependence often differ across studies, which can
limit more broad conclusions across studies. Therefore, throughout this
chapter we refer more broadly to use and will refer specifically to abuse and
dependence when appropriate.
In regard to rates of illicit drug use within the general population, the
National Comorbidity Survey (NCS; Kessler et al., 1994), a nationally repre-
sentative household survey of 8,098 adults aged 15–54 in the United States,
found that 4.4% (5.4% of men and 3.5% of women) of respondents met
criteria for lifetime drug abuse and 7.5% (9.2% of men and 5.9% of women)
met criteria for lifetime drug dependence. In regard to 12-month prevalence,
0.8% (1.3% of men and 0.3% of women) met criteria for 12-month drug
abuse and 2.8% (3.8% of men and 1.9% of women) met criteria for 12-month
drug dependence. Data from the NCS Replication (NCS-R; Kessler, Chiu,
Demler, & Walters, 2005), a nationally representative household survey of
adult English-speaking individuals in the United States, provides more recent
12-month prevalence rates. Specifically, the NCS-R found that 1.4% and
0.4% of 5,692 respondents met criteria for drug abuse or dependence (respec-
tively) in the past 12 months (prevalence rates as a function of gender were
not provided).
A limitation of the majority of epidemiological surveys is the examination
of prevalence rates across drugs, with limited specificity to particular drugs.
As a notable exception, the Epidemiological Catchment Area (ECA) study, a
representative household survey of 20,291 adults in the United States,
provides 6-month and lifetime prevalence rates for drug use disorders, as
well as rates for specific illicit drug use disorders (rates are collapsed across
abuse or dependence)(Reiger, et al., 1990). In particular, 2% and 6.1% of the
sample met criteria for a 6-month or lifetime drug use disorder respectively.
In regard to specific drug use disorders, prevalence rates were provided
for marijuana dependence-abuse (1.2% 6-month, 4.3% lifetime), cocaine
dependence-abuse (0.0% 6-month, 0.2% lifetime), opiate dependence-abuse
(0.1% 6-month, 0.7% lifetime), amphetamine dependence-abuse (0.2%
Drug Use and the Anxiety Disorders 57
6-month, 1.7% lifetime), and hallucinogen dependence-abuse (0.0% 6-month,

0.3% lifetime) (Reiger et al., 1990).
The National Epidemiological Survey on Alcohol and Related Conditions
(NESARC; Conway, Compton, Stinson, & Grant, 2006), a representative
household and group quarters survey of 43,093 adults in the United States,
provides a more recent estimate of lifetime prevalence rates of drug use dis-
orders, as well as rates for specific illicit drug use disorders, than the ECA.
Within their sample (which over-sampled for minorities and young adults
between 18–24 years of age), 7.74% (10.6% for men and 5.1% for women)
met criteria for lifetime drug abuse and 2.59% (3.3% for men and 2.0% for
women) for lifetime drug dependence. In regard to specific illicit drug use
disorders: 1.08% (1.6% men, 0.6% women) and 0.34% (0.4% men, 0.3%
women) met criteria for lifetime opioid abuse and dependence respectively,
1.40% (1.9% men, 0.9% women) and 0.60% (0.6% men, 0.6% women) met
criteria for lifetime amphetamine abuse and dependence respectively, 1.45%
(2.1% men, 0.9% women) and 0.24% (0.4% men, 0.1% women) met criteria for
lifetime hallucinogen abuse and dependence respectively, 1.83% (2.7% men,
1.0% women) and 0.98% (1.2% men, 0.7% women) met criteria for lifetime
cocaine abuse and dependence respectively, 7.16% (10% men, 4.5% women)
and 1.30% (1.7% men, 0.9% women) met criteria for lifetime marijuana abuse
and dependence respectively, and 0.30% (0.5% men, 0.1% women) met criteria
for lifetime inhalant/solvent abuse (Conway et al., 2006).
In terms of racial/ethnic differences in drug use disorders, Smith et al. (2006)
found in the NESARC that, in general, Native Americans evidenced the highest
12 month prevalence rates of drug abuse or dependence as compared to all other
racial/ethnic groups. Rates of drug use disorders across racial/ethnic groups
were as follows: White (1.93%), Black/African-American (2.39%, significantly
different from rates for White participants), Native-American (4.91%, signifi-
cantly different from rates for White and Black/African-American partici-
pants), Asian/Asian-American (1.39%, significantly different from rates for
Black/African-Americans and Native-Americans), and Latino (1.74%, signifi-
cantly different from rates for Black/African-Americans and Native-
Americans).
Not surprisingly, illicit drug use is associated with a variety of health
compromising behaviors including risky sexual behavior (Brook et al.,
2004; Loxley, Bevan, & Carruthers, 1998), licit substance use such as smoking
(Zvolensky, Bonn-Miller et al., 2006) and alcohol abuse or dependence
(Stinson et al., 2005), and poor self-care including poor dietary (Benedict,
Evans, & Calder, 1999; Morabia et al., 1989) and sleep patterns (Pace-Schott
et al., 2005). Combined with an anxiety disorder (which may develop inde-
pendently of, prior to, or as a result of a drug use disorder), the interactive
effects of a co-morbid drug use and anxiety disorder may place an individual
at risk for more severe and extensive health consequences than those with
either disorder alone.
Illicit Drug Use in the Anxiety Disorders
A number of studies have demonstrated that prevalence rates of anxiety dis-

order diagnoses among illicit drug users are generally higher than what has been
found among individuals from the general population (e.g., Kessler, Berglund,
Demler, Jin, & Walters, 2005; Grant et al., 2004). For example, Kessler, et al.
(1996), in examining the 1-year prevalence of anxiety disorders among 5,877
individuals with a substance use disorder from the NCS, found that 24% of
individuals with drug use without dependence also met criteria for some anxiety
disorder and 45.5% of individuals with an illicit drug use disorder met criteria
for an anxiety disorder. Beyond evidence of anxiety disorders among substance
users, a growing literature focuses on illicit drug use among those with an
anxiety disorder.
General Relationships Between Anxiety Disorders

and Illicit Drug Use
Reiger et al. (1990), in analyzing data from the ECA study, found that
individuals with any anxiety disorder (as determined by DSM-III criteria)
were 2.5 times as likely to also exhibit a comorbid drug use disorder (Odds
Ratio [OR] = 2.4 for drug dependence and OR = 2.3 for drug abuse).
Specifically, 11.9% of participants with any anxiety disorder diagnosis also
met criteria for a drug use disorder, and this rate was significantly greater than
that found among participants without an anxiety disorder diagnosis. Grant
et al. (2004) found slightly higher ORs in examining data from the NESARC.
Individuals with any anxiety disorder were 4.58 times as likely to also exhibit a
comorbid drug use disorder (OR = 2.15 for drug abuse and OR = 2.43 for drug
dependence).
In another large scale study of comorbidity, Merikangas et al. (1998) ana-
lyzed data from six international epidemiological study sites (Germany,
Mexico, Netherlands, Ontario, and two sites in the United States). They
found that, across all sites, approximately 24.9% of individuals with any life-
time DSM-III-R anxiety disorder diagnosis also exhibited lifetime drug use
(e.g., marijuana, opioids, stimulants, sedatives, or inhalants, but not alcohol),
35.8% exhibited lifetime drug problems (met at least one DSM-III-R abuse
criteria for any drug), and 45.8% met criteria for lifetime DSM-III-R drug
dependence.
Lopez, Turner, and Saavedra (2005) analyzed data from 1,747 young adults
(92% aged 19–21) from Miami-Dade county (Florida) public schools, and
examined drug dependence among individuals with pure anxiety disorder diag-
noses (i.e., the occurrence of one or more anxiety disorders that is not accom-
panied by any additional psychiatric disorder) or an anxiety disorder that
was comorbid with some other psychiatric disorder (depression, dysthymia,

conduct disorder, or attention deficit/hyperactivity disorder) (DSM-IV diag-
nostic criteria was used for disorder classification). Of the 4.9% with a pure
anxiety disorder diagnosis (75.3% met diagnostic criteria for posttraumatic
stress disorder [PTSD], 16.5% for social anxiety disorder [SAD], 5.9% for
panic disorder [PD], and 3.5% for generalized anxiety disorder [GAD]),
13.9% also exhibited drug dependence. Further, more men (20.8%) than
women (10.9%) with a pure anxiety disorder diagnosis also met criteria for
drug dependence. Among the 10.2% with a comorbid anxiety disorder diag-
nosis (76.4% met criteria for PTSD, 18% for PD, 15.7% for SAD, 12.4% for
GAD, and in terms of non-anxiety disorder comorbid psychiatric diagnoses,
62.9% met criteria for depression/dysthymia, 53.5% for conduct disorder,
36.5% for antisocial personality disorder, and 28.1% for attention deficit
hyperactivity disorder), 29.2% met criteria for drug dependence. Again, more
men (33.3%) than women (26.9%) with a comorbid anxiety disorder diagnosis
also met criteria for drug dependence.
Studies have also been conducted among adolescent populations and pro-
duced similar findings regarding high prevalence of drug use disorders among
adolescents with anxiety disorder diagnoses. For example, Swadi and Bobier
(2003) examined 62 adolescent patients (Mage=16.35) from an inpatient mental
health facility in New Zealand. Of the 16% of these patients who had a
diagnosable anxiety disorder, 63% also exhibited a drug use disorder (primarily
marijuana, stimulants, and hallucinogens). Goodwin, Fergusson, and
Horwood (2004) examined DSM-IV anxiety disorder and illicit drug depen-
dence comorbidity among 1265 16–18 year-olds from the New Zealand
Christchurch Health and Development Study (CHDS). Of the 175 participants
who met criteria for an anxiety disorder at the age of 16–18, 12% also met
criteria for illicit drug dependence, compared to 3.4% among those without an
anxiety disorder diagnosis. Participants were then assessed again at age 18–21.
Of the 130 who met criteria for an anxiety disorder within this age range, only
9.2% met criteria for illicit drug dependence. Interestingly, this rate was not
significantly different from rates obtained among participants without an anxi-
ety disorder diagnosis (7%).
Relationships Between Specific Anxiety Disorders

and Illicit Drug Use
In addition to examining general relationships between anxiety and drug use

disorders, studies have also focused their attention on examining the relation-
ship between specific anxiety disorders or anxiety disorder-related symptoms
(e.g., non-clinical panic attacks) and the use of specific drugs. Although these
studies are limited, more focused attention on the relationship between specific
anxiety disorder diagnoses and drugs of abuse may further our understanding
of the functional relationship between disorders. That is, depending upon

the type of anxiety disorder present, an individual may be at risk for the
development of a particular drug use disorder. We will first present data from
the NESARC that provides an overview of 12-month and lifetime prevalence
rates of various illicit drug use disorders among individuals with specific anxiety
disorder diagnoses. We will then direct more focused attention on additional
research that examines illicit drug use within specific anxiety disorders.
The National Epidemiological Survey on Alcohol and Related Conditions.
Conway et al. (2006) have recently presented data from the NESARC
on lifetime prevalence rates of illicit drug use disorders across the DSM-IV
anxiety disorders (with the exception of PTSD and obsessive-compulsive dis-
order [OCD]). In doing so, Conway et al. (2006) have provided the most
comprehensive overview of anxiety disorder-illicit drug use disorder comorbid-
ity to date2. Among respondents with PD with agoraphobia, 6.2% met criteria
for a lifetime opioid use disorder, 9.2% for amphetamine use disorder, 8.1% for
hallucinogen use disorder, 25.6% for marijuana use disorder, 11.5% for cocaine
use disorder, and 0.8% for inhalant/solvent abuse. Among respondents with
PD without agoraphobia, 4.9% met criteria for a lifetime opioid use disorder,
5.8% for amphetamine use disorder, 4.3% for hallucinogen use disorder, 17.7%
for marijuana use disorder, 7.6% for cocaine use disorder, 1.1% for inhalant/
solvent abuse. Of respondents with SAD, 3.6% met lifetime criteria for an
opioid use disorder, 5.5% for amphetamine use disorder, 4.1% for hallucinogen
use disorder, 17.8% for marijuana use disorder, 6.3% for cocaine use disorder,
and 0.7% for inhalant/solvent abuse. In regard to specific phobia, 2.8% of
respondents with a lifetime diagnosis of specific phobia also met lifetime criteria
for an opioid use disorder, 4.9% for amphetamine use disorder, 3.9% for
hallucinogen use disorder, 14.9% for marijuana use disorder, 4.8% for cocaine
use disorder, and 0.5% for inhalant/solvent abuse. Finally, among respondents
with GAD, 3.7% also met lifetime criteria for an opioid use disorder, 6.2% for
amphetamine use disorder, 4.6% for hallucinogen use disorder, 18.5%
for marijuana use disorder, 7.1% for cocaine use disorder, and 0.7% for
inhalant/solvent abuse.
Conway et al. (2006) also examined gender differences in the ORs of illicit
drug use disorders across the anxiety disorders. Few differences were observed.
However, women with SAD (OR = 4.4) were significantly more likely than
men with SAD (OR = 2.3) to exhibit comorbid lifetime opioid use disorder. In
addition, men with PD with agoraphobia (OR = 8.7) were significantly more
likely than women with PD with agoraphobia (OR = 6.5) to exhibit comorbid
lifetime cocaine dependence.
Grant et al. (2004) also provide 12-month anxiety disorder-illicit drug use
disorder co-morbidity prevalence data from the NESARC, although
2
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).
prevalence rates pertaining to specific illicit drug use disorders were not exam-
ined. 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 depen-
dence and specific anxiety disorders across racial/ethnic groups. Significant
associations were found for drug dependence and all anxiety disorders exam-
ined (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 asso-
ciations were found for PD without agoraphobia and SAD. Asian/Asian-
American respondents demonstrated significant associations between drug
dependence and PD without agoraphobia, SAD, and GAD, and Latino respon-
dents 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)
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, barbitu-
rates 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 polysub-
stance 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
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 investi-
gated 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 dif-
fered 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 exam-
ined 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).
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 co-
occur 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) exam-
ined 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.
Temporal Order of Anxiety Disorders and Illicit Drug Use
Many of the studies discussed above are cross-sectional in nature, and

therefore, it is impossible to determine the temporal progression of the
disorders. In regard to the specific relationship between anxiety and drug
use disorders, three temporal paths are possible. First, the use of specific
drugs may increase the risk for the onset of an anxiety disorder. Second,
illicit drug use may follow the development of an anxiety disorder diagnosis,
consistent with a self-medication model of illicit drug use. Finally, there may
be an underlying third factor that increases the risk for both anxiety dis-
orders and illicit drug use. That is, there may be a common underlying
mechanism for the comorbid development of these disorders (Goodwin
et al., 2002).3
3
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.
Illicit Drug Use Precedes Anxiety Disorder Onset
In regard to the first hypothesis, Zvolensky, Bernstein et al. (2006) found that a
lifetime history of marijuana dependence was significantly associated with an
increased risk for panic attacks, even when controlling for polysubstance use,
alcohol abuse, and relevant demographic variables. Further, Cottler, Compton,
Mager, Spitznagel and Janca (1992) found evidence for the high-risk hypothesis
of comorbid PTSD-substance use disorder development. This hypothesis essen-
tially states that drug use increases the likelihood of traumatic exposure (due to
the high risk behaviors drug use is often associated with), thereby increasing
risk for PTSD. Using data from the St. Louis Epidemiologic Catchment Area
study, Cottler et al. (1992) examined the order of onset of PTSD and drug use
within the 2,663 respondents. Cottler et al. (1992) found that drug use tended to
precede the development of PTSD. However, it is important to note, that rates
of PTSD in this sample were low (1.35% overall).
In another study, Compton, Cottler, Phelps, Abdallah, and Spitznagel
(2000) examined the temporal relationship of drug dependence and DSM-III-
R psychiatric diagnoses among 425 individuals in drug treatment. In the major-
ity of cases (90%), drug dependence was found to follow the onset of a phobic
disorder (the authors did not indicate whether this referred to SAD, specific
phobia, or both). However, among individuals with a diagnosis of GAD, in
65% of the cases, the onset of the anxiety disorder followed the onset of the drug
dependence, suggesting that, at least with GAD, the diagnosis may be second-
ary to drug dependence.
Illicit Drug Use Follows Anxiety Disorder Onset
Studies have also provided support for the hypothesis that illicit drug use
follows an anxiety disorder diagnosis. This hypothesis has most extensively
been studied in PTSD. For example, Chilcoat and Breslau (1998) found that a
PTSD diagnosis greatly increased the risk for the subsequent development of a
SUD; however, traumatic exposure not resulting in PTSD did not have this
effect, suggesting that the relationship between traumatic exposure and sub-
stance use is unique to those individuals who develop PTSD. They also found
that substance abuse/dependence did not increase risk for traumatic exposure
or PTSD (thus not providing support for the high-risk hypothesis). Consistent
with a self-medication model of illicit drug use where drug use develops in an
attempt to alleviate anxiety disorder symptoms, it has been demonstrated that
exposure to trauma cues among PTSD-SUD patients is associated with sub-
stance craving, suggesting that the experience of PTSD-related symptoms may
increase motivation to use substances in an attempt to relieve those symptoms
(Coffey et al., 2002; Saladin et al., 2003).
Additional support for the hypothesis that the presence of an anxiety dis-
order 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 neuro-
biological 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 transmis-
sion of anxiety and illicit drug use disorders, this is likely an important area for
further pursuit. Specifically, the interaction between life stress and a poly-
morphism 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 body’s 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 contri-
butes 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,
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 func-
tioning 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 vari-
able 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
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 psycho-
pharmacological 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 exten-
sively 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 benzo-
diazepine (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 McNally’s
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, mar-
ijuana 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,
anxious arousal, and anhedonic depressive symptoms. These conflicting results

indicate that future research is needed to better clarify the interactions between
AS, marijuana, and other variables such as age and co-occurrence with other
addictive substances. This research will aid in determining potential confound-
ing factors, as well as facilitate the identification of more complex relationships
between factors associated with vulnerability for illicit drug use and anxiety
disorders. Further, given evidence that AS may be associated with the severity
of marijuana withdrawal symptoms (Bonn-Miller, Zvolensky, Marshall, &
Bernstein, 2007), it will be important for future research to examine whether
AS may function to maintain drug use (due to fears of withdrawal symptoms)
and/or increase risk for relapse for certain drugs during periods of attempted
abstinence.
Limited research has also been conducted that investigates the relationship
between AS and heroin use. Lejuez et al. (2006) investigated AS among pri-
marily African-American inner city substance users receiving treatment in a
residential treatment facility. Specifically, measures of AS were collected among
heroin users, crack/cocaine users, users of both heroin and crack/cocaine, and
those that used neither. It was found that even when controlling for demo-
graphic variables, depressive symptoms, and the use of other drugs (e.g.,
alcohol, marijuana), primary heroin users evidenced higher levels of AS than
all other groups, suggesting a unique relationship between heroin use and AS.
Elevated AS has also been found to be a risk factor for worse treatment
outcomes among heroin users in residential substance use treatment. Specifi-
cally, Lejuez, et al. (2007) examined AS as a predictor of residential substance
use treatment drop-out among heroin and crack/cocaine users. Heightened
levels of AS were found to predict residential substance use treatment drop-
out among heroin users but not crack/cocaine users.
Prospective studies are needed to determine the specific role AS may play in
the concurrent development of both anxiety and drug use disorders, as well as to
identify the particular mechanisms through which AS may lead to these dis-
orders. In regard to the pathogenesis of an anxiety disorder such as PD,
heightened AS may be associated with attempts to avoid anxiety-related phy-
sical symptoms, thereby preventing functional exposure to the feared stimulus
and maintaining anxious responding. Likewise, in regard to the pathogenesis of
drug use, motivational models acknowledge the influence of positive conse-
quences factoring into substance use yet posit a special role for the removal or
avoidance of negative internal invents especially among chronic users (Cooper,
1994; Simons, Correia, Carey, & Borsari, 1998; Simons, Gaher, Correia,
Hansen, & Christopher, 2005; Tate, Pomerleau, & Pomerleau, 1994). Baker,
Piper, McCarthy, Majeskie, and Fiore (2004) comprehensively reviewed the
basic experimental learning literature and concluded that negative reinforce-
ment remains the primary mechanism behind addiction. Of utmost interest to
the role of AS in addiction, Baker et al. (2004) argue that addiction is main-
tained by the avoidance and or escape of negative affect and other associated
interoceptive cues (i.e. cognitive processes) that signal withdrawal symptoms.
This is consistent with Hayes and colleagues proposal to reconceptualize psy-

chopathology, including substance use, as a behavior that serves an experien-
tially 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 con-
struct 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 conceptua-
lizations 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 build-
ing) 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 rele-
vance 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 con-
sequences associated with a loss of independence in the service of avoiding
smaller yet immediate discomfort associated with leaving home alone.
Combining both the reinforcer and reciprocal aversive conceptualizations of

delay discounting provides a unique approach for understanding anxiety
disorder-illicit drug use comorbidity. This may be particularly powerful in
individuals where drug use is not only positively reinforcing (drug induced
euphoria, social interaction) but also highly negatively reinforcing in regard to
anxiety (the removal of overwhelming anxiety). It is also of note that although
discounting is typically considered in terms of delay as discussed here, it is quite
difficult to have a delay without also adding a degree of uncertainty. In this way,
the extent to which delayed positive reinforcers and delayed aversives also are
not perceived as guaranteed, their impact on keeping an individual from making
an impulsive choice is further diminished. For example, while benefits of sobri-
ety participating in exposure-based anxiety treatments seem strikingly powerful
(good health, job security, trust, family), the delay to attaining the rewards are
often long and relatively uncertain (will trust ever be fully returned? Will
employers give you the benefit of the doubt if something goes missing? Will
the anxiety ever really go away?), while pain (anxiety, withdrawal) remains
immediate and certain. Thus, delayed discounting provides a framework to
conceptualize the myriad of environmental factors influencing preference
between two alternatives and suggests intervention implications (i.e., increasing
the immediacy and certainty of alternative behaviors).
Treatment for Anxiety and Drug Use Disorder Comorbidity
Given the high rates of comorbidity between anxiety disorders and substance
use disorders, as well as suggestions that comorbid anxiety and substance use
disorders may be better characterized as a single unique disorder (Hien, Cohen,
Miele, Litt, & Capstick, 2004; Morissette et al., 2007), specialized treatments
designed to specifically target this comorbidity are beginning to be developed.
Of those treatments that are available, the majority are focused on the comor-
bidity between PTSD and substance use disorders.
Seeking Safety. Najavits (2002) developed Seeking Safety to specifically
target comorbid PTSD and substance use disorders. Seeking Safety is a
24-session cognitive behavioral group therapy protocol treatment that teaches
individuals with this comorbid symptom presentation a variety of cognitive,
behavioral, and interpersonal skills particularly applicable to individuals with
both PTSD and substance use difficulties, all of which are designed with the
idea that safety is the top priority in recovery from each disorder (Najavits,
Weiss, & Liese, 1996). That is, coping skills are focused on maintaining absti-
nence, reducing self-destructive and high-risk behavior, and establishing sup-
port. Seeking Safety has been found to be effective, with patients exhibiting
significant reductions in substance use behavior, trauma-related symptoms,
suicide risk, suicidal thoughts, depression, and thoughts about substance use,
and improvements in social adjustment, family functioning, and problem
solving (e.g., Hien et al., 2004; Najavits et al., 1996; Zlotnick, Najavits, Rohse-
now, & 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 Brady’s (2001) Concurrent Treat-
ment 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 symp-
toms, 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 Sensi-
tivity 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 indivi-
duals to attempt to avoid these sensations through the use of heroin. Therefore, we
developed a six session adjunctive treatment where individuals engage in inter-
ceptive exposure exercises in order to facilitate acceptance of, and tolerance for,
aversive internal sensations, with the goal of preventing the use of heroin for self-
medication of these sensations. In an initial examination of this treatment’s
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 dis-
order 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
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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The Promise of Exercise Interventions
for the Anxiety Disorders
Jasper A. J. Smits, Angela C. Berry, Mark B. Powers, Tracy L. Greer, and

Michael W. Otto
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 demonstrat-
ing 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

Ó Springer 2008
82 J. A. Smits et al.
may confer protective or anxiolytic effects. We conclude this chapter with

suggested avenues for further research in this area.
Physical Activity Defined
Caspersen, Powell, and Christenson (1985) defined physical activity as ‘‘any

bodily movement produced by skeletal muscle that results in energy expendi-
ture.’’ As such, physical activity encompasses a variety of activities,
including occupational work, leisure activities and exercise, which is defined
as a physical activity that is planned for fitness or health purposes (Caspersen
et al., 1985). Exercise can be further sub-divided into aerobic or anaerobic
exercise. Aerobic exercise includes activities such as walking, swimming,
cycling and running, all of which require maintenance of increased heart
rate. The American College of Sports Medicine (ACSM, 2005) defines aerobic
exercise as a physical activity that lasts longer than three minutes during
which glycogen is consumed with oxygen. In contrast, anaerobic exercise,
which includes activities such as weight training and sprinting, lasts less
than three minutes during which glycogen is consumed without oxygen
(ACSM, 2005).
Physical fitness has been defined as a set of attributes related to the ability to
engage in physical activity (Caspersen et al., 1985). It is a multidimensional
construct (President’s Council on Physical Fitness, 2000) that includes
skill-related (e.g., agility, balance, speed, reaction time), health-related
(e.g., cardiorespiratory endurance, muscular endurance, muscular strength,
body composition, and flexibility) and physiologic components (e.g., glucose
tolerance, blood lipid and cholesterol profiles, fatness, and bone mass). The
latter two components have been more directly linked with physical health and
evidence suggests that they can be more easily improved, relative to the other
component of physical fitness, by engaging in regular physical activity
(ACSM, 2006).
Quantifying the level of physical activity involves the determination of
energy expenditure, which is typically expressed in kilocalories, or the
amount of heat required to increase the temperature of 1 kg of water by
18C. Energy expenditure is best measured by a method called ‘‘doubly labeled
water’’ (Schoeller, 1988). This procedure involves several steps, starting with
the administration of water labeled with stable isotopes of hydrogen and
oxygen. Participants are then subjected to regular urine sampling to track the
loss of these isotopes over a 7- to 14-day period. This procedure allows for an
estimation of daily carbon dioxide production, which can be converted to
total daily energy expenditure in kilocalories. However, instead of determin-
ing energy expenditure, most investigations of the relationship between
physical activity or exercise and anxiety have relied on less expensive and
more practical methods such as self-report questionnaires and interviews.
Promise of Exercise Interventions for the Anxiety Disorders 83
These instruments typically assess several dimensions of physical activity

including type, intensity, frequency, and duration, thereby allowing research-
ers to estimate the total expended kilocalories during a given time
point (e.g., week, month). Such instruments are also often used merely to
categorize participants’ physical activity habits (e.g., engaging in regular
exercise versus not engaging in regular exercise, active versus non-active,
sedentary versus non-sedentary).
Research examining the link between anxiety pathology and fitness has
mostly focused on cardiorespiratory fitness, which is operationalized as the
volume of oxygen consumed while exercising at maximum capacity
(i.e., VO2max). VO2max can be expressed in absolute values (liters/minute) or
relative values (ml/kg/min). The values tend to be higher among men compared
to women and decline with age. According to the ACSM (2006), mean absolute
values for men over age 20 range from 44.2 to 34.6 ml/kg/min, whereas mean
absolute values for women in the same age range are between 37.8 to 26.7 ml/
kg/min.
VO2max can be measured directly using open-circuit spirometry, or indir-
ectly by means of maximal or submaximal exercise tests. Since open-circuit
spirometry and maximal exercise testing require specialized settings, submax-
imal exercise tests are more commonly employed. One of the most widely
used submaximal exercise tests is the Astrand-Ryhming ergometer test
(Astrand & Ryhming, 1954). During this 6-minute protocol, participants
peddle at 50 rotations per minute at a work rate (i.e., watts) that is deter-
mined by the participant’s gender and fitness status. The objective is to reach
a steady-state heart rate between 125 and 170 beats per minute. A nomogram
is then used to estimate VO2max based on the average heart rate during
minutes 5 and 6.
Because it provides an index of cardiorespiratory fitness, VO2max can be
used to guide the prescription of exercise intensity. Specifically, the intensity of
exercise (e.g., very light, light, moderate, vigorous, very hard, maximal) can be
Table 1 Physical activity intensity

Intensity VO2R (%) HRR (%) HR Max (%) RPE
Very Light <20 <50 9
Light 20–39 50–63 11
Moderate 40–59 64–76 13
Hard 60–84 77–93 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)
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 person’s heart rate reserve, maximal heart rate, or subjective ratings
of perceived exertion (i.e., RPE; Borg, 1998).
Physical Activity in the United States
Data from the 2002–2004 National Health Interview Survey (NHIS), which
included a representative sample of 93,222 U.S. adults, indicated that 62% of
adults engaged in at least in some leisure-time physical activity over the past year
(i.e., light, moderate or vigorous activity episodes that last at least 10 minutes;
Adams & Schoenborn, 2006). Physical activity status further varies as a function
of several demographic factors. For example, physical activity is significantly
more prevalent among men compared to women (64% versus 60.2%) and among
White and Asian adults (63.7% and 62.1%) compared to Black and Hispanic
adults (51.3% and 47.6%). Likewise, physical activity decreases with age and
increases with education and family income (Adams & Schoenborn, 2006).
Developmental Stages of Adopting Physical Activity
Understanding contributors to the adoption and maintenance of physical

activity is critical to the implementation of physical activity interventions
(see for review Marcus et al., 2000). The Transtheoretical Model (TTM) or
‘‘Stages of Change’’ (Prochaska & DiClemente, 1983) has been applied to many
health-related activities, including physical activity, to describe the process
of adopting a new behavior. The model describes five stages as follows:
1) precontemplation, in which there is no intent to change behavior within
6 months; 2) contemplation, in which there is intent to change behavior within
6 months; 3) preparation, in which there are small or inconsistent changes in a
behavior; 4) action, in which there is active involvement in a behavior for less
than 6 months’ duration; and 5) maintenance, in which a behavioral change is
sustained for 6 months or more. Utilization of the stages in intervention
management frequently involves assessment of individuals’ readiness to change,
evaluation and contributors to stage transition, and stage-targeted strategies
that target behaviors and issues specific to that stage. For example, in the
PACEþ study (Calfas et al., 2002), behaviors such as targeting a specific
exercise behavior (e.g., setting a goal to increase moderate or vigorous physical
activity) was associated with a greater likelihood of moving to the next stage of
change. Self-efficacy has also been shown to be an important factor in transition
to subsequent stages (Plotnikoff, Hotz, Birkett, & Courneya, 2001). Marshall
et al. (2003) reported that a stage-targeted physical activity intervention was
associated with significantly greater increases in amount of post-baseline
physical activity (78 minutes) compared to a control group receiving no inter-

vention (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 comple-
tion 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.
Population-based Studies of the Relationship Between

Physical Activity and Anxiety
There have been several large-scale studies providing evidence for the negative
association between physical activity and anxiety. For example, Stephens
(1988) collapsed data from four national health surveys conducted in the
United States and Canada between 1971 and 1981 (e.g., the National Health
and Nutrition Examination Study, Canada Health Survey, National Survey of
Personal Health Practices and Consequences, and the Canada Fitness Survey).
This procedure yielded a total sample size of approximately 55,000 persons
between ages 10 and 74. Both mental health and level of leisure time exercise
were assessed by self-report. The findings supported the hypothesis that physi-
cal activity is associated with good mental health, including fewer symptoms of
depression and anxiety, even after controlling for education and physical health
status. Interestingly, the strength of this relationship varied as a function of age
and sex, where a stronger link was observed among women and among those
over age 40. Recently, Schmitz and colleagues (Schmitz et al., 2004)
extended these findings by showing a link between physical activity and
enhanced psychological and health-related well-being among persons suffering
from DSM-IV anxiety disorders. They used data from the German National
Health Interview and Examination Survey (GHS) which comprised a represen-
tative sample of approximately 7,000 persons between ages 18 and 79.
Diagnoses (12-month prevalence) were determined by a combination of
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.
Clinical Studies of the Relationship Between

Physical Fitness and Anxiety
The linkage between phobic anxiety and cardiovascular disease and mortality
(Coryell, Noyes, & House, 1986; Coryell, Noyes, & Clancy, 1982; Gomez-
Caminero, Blumentals, Russo, Brown, & Castilla-Puentes, 2005; Kawachi
et al., 1994; Kawachi, Sparrow, Vokonas, & Weiss, 1994; Kawachi, Sparrow,
Vokonas, & Weiss, 1995; Weissman et al., 1990; see also White et al. in Chapter
11 in this volume) has prompted research on physical fitness among individuals
suffering from pathological anxiety, and particularly panic disorder. There
have been several studies that have employed standardized exercise testing
protocols to determine cardiorespiratory fitness among individuals with panic
disorder (Broocks et al., 1997; Gaffney, Fenton, Lane, & Lake, 1988; Martinsen,
Raglin, Hoffart, & Friis, 1998; Meyer, Broocks, Bandelow, Hillmer-Vogel, &
Ruther, 1998; Schmidt, Lerew, Santiago, Trakowski, & Staab, 2000; Taylor et
al., 1987). For example, Martinsen and colleagues (1998) subjected 35 patients to
a submaximal bicycle ergometer test and found that their VO2max was on
average at 82% (1.9 liters/min) of the expected value. Similarly, Brooks and
colleagues (1997) reported that, relative to a group of non-psychiatric partici-
pants (n = 24), individuals with panic disorder (n = 38) showed significantly
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 partici-
pants 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 particu-
larly poor among panic disorder suffers with elevated levels of anxiety sensitiv-
ity. 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 consid-
ering 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 mea-
sures 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.
Reductions in Anxiety with Exercise
Although the studies discussed above support the hypothesis that physical
activity plays a role in the etiology, maintenance and treatment of anxiety
pathology, the cross-sectional nature of many of these investigations leave
open several alternative explanations for the observed relationships. In this
section, we will discuss a number of studies that have experimentally manipu-
lated physical activity, providing some evidence for the causal effects of physical
activity on anxiety.
The Effects of Acute Exercise on Anxiety
Evaluation of the beneficial effects of single episodes of exercise on anxiety

has been the focus of numerous quantitative and qualitative reviews
(e.g., Ekkekakis & Petruzzello, 1999; Petruzzello, Landers, Hatfield, Kubitz,
& Salazar, 1991; Schlicht, 1994). For example, Petruzzello and associates (1991)
conducted a meta-analysis of 119 studies that examined the pre- to post-exercise
reductions in self-reported state anxiety. The mean controlled effect size was
d = 0.23, although randomized controlled studies yielded smaller effect sizes
(d = 0.16). In a more recent review, Ekkekakis and Petruzzello (1999) aptly
pointed out that many of the studies examining the effect of acute exercise on
anxiety lack the methodological rigor (e.g., adequate sample sizes and control
conditions) necessary to significantly advance knowledge regarding the dose-
response relationship. They did, however, observe some robust findings. First,
the duration of exercise session is not predictive of anxiety reduction beyond the
effects explained by the degree of exercise intensity. Second, the degree of
benefit is linked to the degree of fitness; in non-clinical samples, demanding
exercise tasks result in greater anxiety reductions among high-fit individuals
versus low-fit individuals (Ekkekakis et al., 1999). In addition to fitness level,
the participant’s baseline anxiety level appears to be predictive of the degree of
benefit. Long and Stavel (1995) reported that effect sizes for studies that
employed high-anxious samples were significantly larger than those that
employed low anxious samples (d = 0.51 and 0.28, respectively). One implica-
tion of this finding is that the degree of benefit from exercise may be much more
profound in clinical samples.
In addition to reducing state anxiety, single exercise sessions also appear to
buffer the effects of social stressor tasks. Using a counterbalanced design,
Rajeski and colleagues (Rejeski, Thompson, Brubaker, & Miller, 1992) asked
48 low-to-moderate physically fit women to exercise or rest prior to completing
two stressor tasks. The experimental sessions began with either 40 minutes of
cycling at 70% heart rate reserve or 40 minutes of rest after which participants
rested 30 minutes. Following this 30 minute period, participants completed a
Stroop mental challenge and a 3-minute impromptu speech on a controversial
topic (e.g., abortion, role of women in society). Relative to rest, exercise was
associated with less blood pressure reactivity following psychosocial stress, and
reduced anticipatory anxiety prior to speech task.
Similar findings have been observed in studies using biological challenge
procedures. Biological provocations such as caffeine ingestion, inhalation
of carbon dioxide-enriched air, and lactate infusion have been shown to
reliably increase bodily and subjective symptoms of anxiety and panic in
healthy controls (Zvolensky & Eifert, 2001). A series of recent studies (Esquivel,
Schruers, Kuipers, & Griez, 2002; Strohle et al., 2005; Youngstedt, O’Connor,
Crabbe, & Dishman, 1998) has demonstrated that emotional responding to
these challenges is significantly attenuated when preceded by a single brief
(e.g., 12–30 minutes) intense exercise session (e.g., 70% of max HR; 60–70%
VO2max, >6mm of blood lactate). Together, these findings suggest that single
exercise sessions result in anxiolysis in non-clinical participants.
Parameters of Exercise Interventions
Petruzzello and colleagues (1991) reviewed 62 studies of exercise interventions

that were at least four weeks in length. Most studies involved non-clinical
(n = 48) or non-clinical high anxious (n = 11) individuals. Less than half of
the studies (n = 25) employed a randomized controlled design; the other
37 studies were non-experimental or quasi-experimental in nature. Comparison
groups involved waitlist control, relaxation or motivational control conditions
and anxiety was generally measured using the trait version of the State-Trait
Anxiety Inventory (STAI-T; Spielberger, Gorsuch, Lushene, Vagg, & Jacobs,
1983). The average controlled effect size for anxiety reduction with exercise
training was (d = 0.34). However, post-hoc analyses revealed that the effect size
significantly varied as a function of characteristics of study design and the
exercise intervention. Specifically, randomized controlled studies yielded larger
effects sizes (d = 0.54). Moreover, length of training was significantly
associated with the degree of improvement in anxiety; interventions with a
minimum length of 10 weeks were associated with greater effect sizes
(d =0.36 to 0.90) compared to interventions with a duration of less than
10 weeks (d = 0.14 to 0.17). Similarly, only interventions with session durations
between 21 and 30 minutes or greater than 40 minutes yielded significant
effect sizes.
Exercise Training Programs for Clinical Anxiety
Despite the wealth of studies devoted to the application of exercise interven-

tions to stress and non-clinical anxiety, to our knowledge, there are only two
randomized controlled clinical trials of exercise interventions for
individuals meeting criteria for anxiety disorders. This limited evidence stands
in stark contrast to studies of exercise interventions for major depression. For
depression, exercise interventions are associated with reliable benefit.
For example, a recent meta-analysis of 11 controlled studies of the efficacy
of exercise interventions for depression yielded a controlled effect size of
(d = 1.42) (Stathopoulou et al., 2006). For anxiety disorders, the available
evidence for the efficacy of exercise interventions is limited to the treatment of
panic disorder.
Panic disorder is a particularly apt disorder for the application of exercise
interventions (see for review Smits et al., 2007) given that fears of somatic
sensations of anxiety (i.e., anxiety sensitivity) are central to the etiology and
maintenance of the disorder (McNally, 2002; Smits, Powers, Cho, & Telch,
2004). Cognitive-behavioral treatments for panic disorder target anxiety sensi-
tivity 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 proce-
dure 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 con-
trols. 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 pro-
vocation 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 (60–90% 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 interven-
tion (pre- to posttreatment raw score mean reductions of 9.14 and 2.88, respec-
tively). 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 anxio-
lytic properties for patients with panic disorder. Using a counterbalanced
design, O’Connor (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
reductions in anxiety after both maximal and submaximal exercise testing.

Importantly, these reductions were evident within 5 minutes following exercise.
A much broader study of the efficacy of aerobic exercise for panic disorder
was conducted by Broocks et al. (1998). These investigators examined the
efficacy of aerobic exercise relative to clomipramine and pill placebo in a
sample of patients with panic disorder (N = 46). Patients randomized to
clomipramine were prescribed the medication following evidence-based guide-
lines. Patients in the aerobic exercise condition were medication-free and
underwent a 10-week endurance training program. Specifically, patients were
asked to find a four-mile route (forest or park) that was easily accessible from
their home, and complete this entire route at least three times a week, where
walking was allowed during the first six weeks, and running was expected
during the last four weeks. Patients also met with a trainer once each week to
run together. Exercise led to significantly more benefit than placebo treatment
at week 10, and clomipramine yielded significantly greater effects compared to
placebo after four weeks. At posttreatment, both active treatments outper-
formed the placebo condition and were equally effective in reducing anxiety.
Additionally, clomipramine yielded greater changes in global improvement
ratings compared to aerobic exercise. In discussing the magnitude of the effects
observed for exercise in their study, Broocks et al. (1998) hypothesized that
additional cognitive interventions would have enhanced the benefits among
participants in the exercise condition. Specifically, therapists could have
assisted patients in preparing to reappraise some of the feared consequences
of exercise-induced sensations. This type of preparation could have potentially
prevented avoidance of more intense exercise that was evident in a subset of the
patients (Broocks et al., 1998).
The findings reported by Broocks and colleagues (1998) comport well with
an earlier report (Martinsen, Hoffart, & Solberg, 1989). Martinsen et al. (1998)
randomly assigned in-patient participants with panic disorder with agorapho-
bia (n = 56), social phobia (n = 13), or generalized anxiety disorder (n = 10) to
either an aerobic or non-aerobic exercise treatment program. Both programs
were conducted in group format, were eight weeks in length, and involved three
weekly one-hour sessions, of which thirty minutes were devoted to exercise. The
aerobic program involved walking or running at 70% of maximal aerobic
capacity, whereas the intensity of the anaerobic program, which comprised
muscular strength training, was unspecified. The study attrition rate was 11%
and involved only panic disorder patients (n= 9) in the aerobic exercise condi-
tion. Although aerobic exercise was associated with greater improvements in
physical fitness, both conditions showed comparable significant pre- to post
treatment improvements on interviewer and self-report measures of anxiety.
Based on these results, the authors concluded that exercise programs are
effective for reducing pathological anxiety and that this effect cannot be
accounted for by enhanced cardiorespiratory fitness.
Initial feasibility data also supports the application of exercise to obsessive-
compulsive disorder (OCD). Brown and colleagues (Brown et al., 2007) recently
completed an open trial of an exercise intervention with 15 patients who

were also on a stable dose of cognitive-behavioral treatment, pharmacotherapy,
or their combination. The exercise intervention involved a combination of
supervised and home-based aerobic exercise at 55 to 69% of age predicted
maximal heart rates. Over the course of the 12-week protocol, participants
progressed from 20-minute to 40-minute sessions three to four times a week.
Prior to each supervised group session, participants participated in a 30-minute
meeting with a clinical psychologist and an exercise physiologist to discuss
topics related to compliance with the intervention program (e.g., benefits
of exercise, goal setting, identifying and overcoming barriers to exercise).
Compliance was further stimulated by providing monetary remuneration for
adherence. The Cohen’s d effect size for reductions in Y-BOCS scores was
d = 1.69 from pre- to posttreatment, and d = 1.11 for pretreatment to
6-month follow-up. Moreover, clinically meaningful changes were observed
for 69% and 50% of patients at posttreatment and 6-month follow up,
respectively.
The initial successes of the application of exercise interventions to the treat-
ment of clinical anxiety problems encourage a more in-depth study of the
feasibility and efficacy of exercise protocols for patients with anxiety disorders.
In addition to large-scale randomized controlled trials, these efforts should
include investigations of the mechanism underlying the effects of exercise on
anxiety.
Mechanisms of Exercise Anxiolysis
There is little research on the mechanism by which exercise exerts its ameliora-
tive effects on anxiety. In this section, we will discuss several proposed
physiological and psychological mechanisms of exercise anxiolysis for which
there is some preliminary supporting evidence.
Central Neurotransmitter Function
Several animal studies have demonstrated that physical activity results in

alterations in many neural systems that are also presumed to underlie the
reductions in depression and anxiety with pharmacological treatments. For
example, increased release of serotonin has been observed in animals both
during (Wilson & Marsden, 1996) and following treadmill running (Dunn &
Dishman, 1991; Meeusen & De Meirleir, 1995). Based upon other animal
studies showing that physical activity leads to increased serotonin metabolism
(Broocks, Schweiger, & Pirke, 1991; Chaouloff, 1997), Broocks and colleagues
(Broocks et al., 1999; Broocks et al., 2001; Broocks et al., 2003) posited that
physical activity may result in down-regulation of postsynaptic serotonin
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 pro-
duces 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 (48–72 hours), and that correspond-
ing 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
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 ubi-
quitous 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 under-
lying 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).
Cognitive Refocusing and Self-efficacy
There is some evidence suggesting that exercise may exerts its effect on anxiety
by enhancing perceived coping ability. Steptoe and colleagues (Moses, Steptoe,
Mathews, & Edwards, 1989) observed parallel decreases in perceived coping
and anxiety in anxious individuals who initiated an exercise program. Similarly,
Bodin and Martinsen (2004) found that exercise that targeted self-efficacy
(e.g., 45 minutes of martial arts) corresponded with significantly greater
improvements in positive affect and state anxiety compared to exercise that
did not target self-efficacy (e.g., 45 minutes of stationary bike exercise). As an
alternative to enhanced self-efficacy, some have suggested that physical exercise
may only serve as distraction from ruminations, worries, and anxiety (Bahrke &
Morgan, 1978; Leith, 1994). Interestingly, Goode and Roth (1993) found that it
is not distraction per se but the content of the distraction techniques in which
people engage that is associated with changes in emotional well-being. They
found that that runners who focused on nonassociative thoughts (those not
related to exercising) showed less fatigue and in some cases decreases in tension
and anxiety, compared to runners who focused on associative thoughts
(monitoring the body and the exercise itself).
Exposure
Recently, Stathopoulou and colleagues (2006) proposed that, among other

effects, exercise may exert positive effects on mental health by teaching persis-
tence in the presence of negative somatic or emotional states. Indeed, the
modification of some of the self-perpetuating patterns in affective disorder
(e.g., social withdrawal and inaction in response to feelings of depression, and

avoidance in response to feelings of anxiety), by facilitation of adaptive pursuit
of goals regardless of the presence of aversive thoughts or emotions, is increas-
ingly being discussed as a general feature of adaptive change in therapy
(Barlow, Allen, & Choate, 2004). Accordingly, by training persistence with
exercise, despite the presence of the physical and emotional symptoms of
exertion, exercise interventions may have more general effects on returning
participants to adaptive activity.
As we discussed above, this persistence in the presence of symptoms may
take on special meaning in the case of panic disorder. We discussed exercise,
with its induced array of symptoms that are similar to many of the symptoms of
anxious arousal, as a form of interoceptive exposure – exposure to the somatic
symptoms of anxiety under controlled circumstances. As suggested by the
research to date, inclusion of specific preparation and cognitive coaching for
the symptoms to be induced both mimics typical interoceptive exposure proce-
dures used in cognitive behavior therapy (Smits et al., 2007) and appears to lead
to more optimal outcomes for exercise interventions (Smits et al., 2005; Broocks
et al., 1998).
Conclusions and Future Directions
The application of exercise interventions to clinical anxiety is in the early stages

of development, but the few trials completed to date, as well as the wealth of
evidence for the effects of exercise on non-clinical anxiety, encourage further
study. Although most work to date has been completed with persons suffering
from panic disorder, preliminary findings with respect to the mechanisms of
exercise anxiolysis suggest that exercise of may also offer significant benefits for
those suffering from other forms of anxiety psychopathology. This hypothesis
awaits testing in large-scale randomized controlled trials.
The development of exercise interventions for the anxiety disorders will
likely benefit from studies focused on identifying intervention parameters cri-
tical to efficacy of exercise. There is evidence from the depression literature
suggesting that high intensity exercise provides superior results compared to
lower intensity exercise. For example, Dunn and associates (Dunn, Trivedi,
Kampert, Clark, & Chambliss, 2005) reported that the public health recom-
mended dose of aerobic exercise (total energy expenditure of 17.5 kcal/kg/week)
was more effective in reducing depression relative to low dose aerobic exercise
(total energy expenditure 7.0 kcal/kg/week) or flexibility exercise. A public
health dose of exercise has also yielded reductions in depressive symptom
severity and improvements in quality of life in a preliminary study of exercise
augmentation to antidepressant treatment (Trivedi, Greer, Grannemann,
Chambliss et al., 2006a) and is currently being investigated in the context of a
larger randomized controlled trial (Trivedi, Greer, Grannemann, Church 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 impor-
tance 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
these data are encouraging, systematic research on issues related to the

dissemination and adoption of exercise interventions for the anxiety disorders
is needed.
From a public health perspective, examining the potential role for physical
activity interventions in the prevention of anxiety pathology may be as impor-
tant as determining its effectiveness for the treatment of anxiety disorders.
Certainly, growing evidence for the efficacy of exercise for reducing anxiety
sensitivity indicate promise for exercise interventions for preventing
panic-related pathology (Schmidt, Lerew, & Jackson, 1997; Schmidt, Lerew,
& Jackson, 1999; Wilson & Hayward, 2005). However, there is a need for
studies that clarify the role of physical (in)activity in the development of anxiety
pathology. When testing the direction of this relationship, it is important to
consider the potential interplay between physical activity and other established
risk factors of anxiety pathology as well as the potential moderating effects of
gender (Stephens, 1988). In this context, it may also be important to assess other
health factors (e.g., fitness, nutrition, substance use, sleep) that have shown to
be linked to physical activity (Aaron, Dearwater, Anderson, & Olsen, 1995).
Similarly, the importance of investigating the impact of exercise on psychoso-
cial function and quality of life should be underscored. Impaired psychosocial
function is associated with increased risk of recurrence of anxiety disorders
(Rodriguez, Bruce, Pagano, & Keller, 2005), and these symptoms must there-
fore be addressed in addition to primary symptoms in order to fully manage the
anxiety disorders.
Finally, we have limited the discussion in this chapter to a unidirectional
model. It should be noted, however, that the evidence to date may point to a
more complex relationship between physical activity and anxiety and panic
psychopathology. Of particular importance to public health would be the
investigation of the potential impact of anxiety and mood problems on the
adoption and maintenance of physical activity.
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Anxiety and Insomnia
Theoretical Relationship and Future Research
Thomas W. Uhde and Bernadette M. Cortese
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 under-
standing of the pathophysiology and causal relationships between anxiety
and insomnia. The physiological and neurobiological relationships between
anxiety and insomnia remain one of medicine’s mysteries. Given the promi-
nence 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 non-
specific 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 dis-
orders 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
Ó Springer 2008
106 T. W. Uhde, B. M. Cortese
Definitions
Anxiety and insomnia are multidimensional phenomena that largely rely on

impairment criteria to achieve status as a disorder. There are two primary classi-
fication systems used by clinicians for the diagnosis of anxiety and sleep disorders:
Diagnostic and Statistical Manual (DSM-IV) and Tenth Revision of the Interna-
tional 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 percep-
tion 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 under-
lying 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 down-
stream development of secondary complications (Fig. 2) and c) anxiety and
insomnia are each caused by another critical, independent factor (Fig. 3). Each
Anxiety and Insomnia 107
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 abnorm-
ality) 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
Fig. 3 In the third factor

model, anxiety and insom-
nia are each caused by a cri-
tical, independent factor(s)
that separately influences
each disorder. These third or
‘‘other’’ factors might be
psychosocial/environmen-
tal, endogenous/neurobiolo-
gical or familial/genetic in
nature, or possibly involve
contributions from any or
all of these elements
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.
What criteria would support a single (spectrum) versus different

disorders versus third factor models for anxiety and insomnia?
A. Single-Spectrum Disorder: In a single-spectrum disorder model, there is

really just one underlying neurobiological disorder that is characterized by
modest variations in clinical presentation. If anxiety (or one of its diagnostic
subtypes) and insomnia are the same basic disorder, one should be able to
document identical pathological mechanisms or neurobiological abnormal-
ities in each of the two clinical syndromes. Thus, either the anxiety or an
anxiety diagnostic subtype (e.g. panic disorder) and insomnia syndromes
would share common neurobiological abnormalities. A medical analog of a
single-spectrum disorder might be multiple sclerosis, wherein a common
underlying pathological process (e.g. demyelization) leads to different symp-
toms at different phases of illness (Fig. 1).
In terms of investigating whether two apparently different clinical
syndromes (i.e. anxiety and insomnia) actually represent a single disease
entity, one would study and expect to find similar ages of onset of illness,
gender distributions, type of symptoms, course of illness, and response to
treatment for the two candidate conditions. One would also predict that
cultural, education, and related expectancy biases might largely contribute to
whether people with the ‘‘same’’ disorder identified themselves as having a
‘‘sleep’’ versus ‘‘anxiety’’ problem. The single-spectrum disorder theory,
therefore, suggests that ‘‘insomnia’’ and ‘‘anxiety’’ (or one or more diagnostic
subtypes of anxiety) are the same single-spectrum disorder and that
non-biological, socio-cultural factors largely determine whether patients
self-identify themselves as having an anxiety or sleep disorder.
B. Different Disorders: In contrast to a single-spectrum disorder, distinctly

different disorders would have different underlying abnormalities and be
highly likely to reflect dissimilarities in onset and course of illness, medical
complications and treatment response. However, depending on the under-
lying diathesis or etiology of illness, one might anticipate downstream com-
plications that result in overlapping clinical symptoms. If these are truly
different disease entities, the initial presentation and associated clinical
features would be different. Nonetheless, two different diseases could be
associated with increasingly similar symptoms during later stages of illness
insofar as secondary complications might recruit common neuro-anatomical
substrates or neurobiological systems. Thus, either anxiety or a diagnostic
anxiety subtype and insomnia might each increase the likelihood of devel-
oping secondary complications, which, when the initial and secondary com-
plications are taken together, produce similar clinical profiles. A medical
disease analog might be hypertension leading to impaired renal function
which would share many of the same symptoms as primary renal disease
associated with secondary hypertension (Fig. 2).
To explain high rates of co-morbid anxiety and insomnia wherein each
(i.e. anxiety and insomnia) are fundamentally different disorders would
suggest that we could identify two syndromes: a) patients presenting with
initial insomnia followed by the development of pathological anxiety (or one
of its diagnostic subtypes) and b) patients that present initially with anxiety
or an anxiety disorder subtypes which is later associated with insomnia.
Furthermore, one would predict different (particularly early in the course
of illness) but overlapping (especially in later stages of illness) neuro-
biological abnormalities in the anxiety-insomnia versus insomnia-anxiety
syndromes. Moreover, one would predict that these two syndromes would
have differential responses to treatment, as well as dissimilarities in age of
onset and other demographic variables.
C. Third Factor Models: High comorbid rates of anxiety and insomnia could
also be explained on the basis of an unknown third factor or factors that have
a direct but independent impact on anxiety and insomnia. In this circum-
stance, third factor(s) would be necessary or contributory but insufficient
alone to produce anxiety and insomnia. Like the single-spectrum and sepa-
rate diagnoses models, the third factors model could explain high co-rates of
insomnia and anxiety, respectively, in people seeking treatment in mental
health (or an anxiety subspecialty program) versus sleep medicine clinics.
These third or ‘‘other’’ factors might be psychosocial/environmental, endo-
genous/neurobiological or familial/genetic in nature, or possibly involve
contributions from any or all of these elements (Fig. 3).
An example of an exogenous-external factor that has an impact on two
separate medical but co-morbidly associated disorders is ultraviolet light/sun
exposure. Data suggest a higher than expected association between patients
with subacute cutaneous lupus erythematosus (SCLE) and polymorphous
light eruption (PLE) (Millard, Lewis et al., 2001; Millard, Kondeatis et al.,
2001). Although thought to be different medical conditions, both are

made more evident or severe by sun exposure. Still other third factors
(e.g. genetic polymorphisms) (Millard, Kondeatis et al., 2001) may contribute
to the co-morbid associations of SCLE and PLE, as has been similarly
proposed for apolipoprotein E gene polymorphism in patients with high
HDL-cholesterol levels and dermatophystosis (Tursen et al., 2004). Likewise,
hypercholesterolemia can be conceptualized as playing a third factor role in
the co-morbid association of cardiovascular disease and type 2 diabetes.
Such third factors might be hypothesized for insomnia and anxiety dis-
orders, wherein each is a truly separate neurobiological disease entity but
both suffer an exacerbation of severity due to external factors (e.g. sleep
deprivation) or, in fact, might even share a common genetic polymorphism.
If third factor(s) are contributing to the high prevalence of co-morbid
anxiety and insomnia, we should be able to identify differences in course of
illness and treatment responses in direct relation to the degree to which that
outside ‘‘third’’ factor distinctly and separately influences the essential
qualities of anxiety and insomnia. It should be noted that an outside factor
may affect different components (e.g. symptoms, severity) of anxiety versus
insomnia, although the impact of the third factor should have a consistent,
predictable, and identifiable role in explaining one or more common and
critical feature(s) of anxiety and insomnia.
What Evidence Supports a Single (Spectrum) Versus Different

Disorders Versus Third Factor Models for Anxiety and Insomnia?
A. Age: Age of onset could help to distinguish anxiety and insomnia as separate
and distinct disorders if it was found to be considerably different for these
two disorders. Recent data from the World Mental Health Survey (WMH)
describes an early age of onset for some anxiety disorders, with a later onset
for others. For example, phobias and separation anxiety disorder was found
to have a median age of onset in the range of 7–14 years (interquartile range
[IQR] = 4–20 years). The age of onset distributions for panic, generalized
anxiety, and posttraumatic disorders, on the other hand, ranged from 25 to
53 years (IQR = 15–75 years; Kessler et al., 2007). The NCS-R median age
of 11 for the onset for anxiety reported by Kessler et al. (2005) and a 7 year
(IQR = 7 years) median age of onset for a first anxiety disorder reported by
Johnson, Roth, and Breslau (2006) are consistent with the WMH results and
further demonstrate the early age of onset for anxiety.
With respect to insomnia, the evidence supports the view that older
individuals are most at risk (Morphy, Dunn, Lewis, Boardman, & Croft,
2007). In fact, several studies reveal that nearly half of individuals over the
age of 65 report sleeping difficulties and insomnia-like symptoms (Monane,
1992; Foley et al., 1995; Ganguli, Reynolds, & Gilby, 1996).
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 &
O’Connor, 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 gen-
eralized 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 com-
plaints 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 insom-
nia 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 polysomno-
graphic findings; sleep architecture and REM measures are normal whereas
both syndromes have EEG evidence of increased sleep latency and distur-
bances in maintaining sleep (for reviews, see Papadimitriou & Linikowski,
2005; Uhde, 2000).
Of interest, patients with GAD, when awakened under experimental

conditions after several minutes of EEG-documented stage 2 sleep, report
not having been asleep or experiencing any drowsiness whatsoever. These
observations, combined with our ongoing studies in patients with recurrent
sleep paralysis indicate that some individuals find it nearly impossible to
distinguish between awake and sleep states, including REM-stage sleep. We
have reported that patients with recurrent sleep paralysis, as well as some
patients with GAD and PD (especially those with nocturnal panic attacks)
find it difficult to separate at the experiential level the difference between
sleep versus wakeful states (Uhde et al., 2006). Thus, the study of sleep in
patients with primary insomnia, as well as patients with selective anxiety
disorders and recurrent sleep paralysis may be of interest to neuroscientists
investigating the neurobiological and theoretical basis of consciousness. In
fact, the impressive degree of self-awareness reported by patients with recur-
rent sleep paralysis during sleep has been described by our research team as
‘‘consciousness intruding upon REM stage sleep’’ or as ‘‘sleep consciousness’’
(Uhde et al., 2006).
Taken together, these observations suggest that GAD and panic disorder,
particularly patients with nocturnal panic attacks, share many symptomatic
and sleep EEG characteristics with chronic insomnia sufferers. On the other
hand, certain other anxiety disorders such as social phobia (Brown, Black, &
Uhde, 1994) can be easily distinguished from chronic insomnia on a number
of clinical and physiological criteria (for review, see Uhde, 2000), largely
based on the absence of either impressive clinical or EEG findings.
D. Course: Anxiety and insomnia are, in many cases, both disabling and
chronic conditions that put a significant number of individuals with these
disorders at risk for developing secondary complications. The high
co-morbidity between anxiety and insomnia suggests a strong relationship
between the two but information on the temporal relationship is lacking.
Some research on insomnia and anxiety has assessed the longitudinal course
of illness in relation to each other. The findings, however, are limited and
inconsistent, with important questions remaining as to whether insomnia
typically precedes anxiety or if insomnia more often develops subsequent to
anxiety.
1. Insomnia, with secondary anxiety.
Some findings suggest that anxiety symptoms/disorders can develop from
primary insomnia. For example, longitudinal data from the National
Institute of Mental Health Epidemiologic Catchment Area Study (ECA)
revealed that adults with uncomplicated insomnia (i.e., defined as insomnia
without the lifetime presence of a psychiatric disorder) at baseline were
5 times more likely to experience a panic attack in addition to being at a
significant increased risk for developing panic disorder by a follow-up inter-
view, one year later, compared to individuals without baseline insomnia or a
psychiatric disorder (Weissman, Greenwald, Niño-Murcia, & Dement,
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 1.08–3.60).
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 2.4–14.0). 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 sub-
strates 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 observa-
tions that states of fear (Uhde 2000) can take place during sleep and wakeful-
ness. Neither insomnia nor anxiety, therefore, necessarily reflect
disturbances in those neurobiological systems that mediate either wakeful-
ness 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 neuro-
anatomy of wakefulness-promotion and sleep-promotion in relation to those
neurotransmitter and neuropharmacological systems most commonly impli-
cated in anxiety and insomnia.
1. Wakefulness-Promotion versus Sleep-Promotion
Wakefulness is mediated in part by midbrain and pontine-acetyl choli-
nergic, pontine locus ceruleus-noradrenergic, reticular formation system
(superior)-sertonergic, and posterior hypothalamus (tuberomammillary

nucleus)-histaminergic systems whereas sleep-promotion is linked to
anterior hypothalamus (ventrolateral preoptic nucleus) and reticular
formation (caudal)-GABAergic systems.
2. Anxiety and Insomnia
Many of the substrates implicated in sleep- or wakefulness-promotion
also have been implicated in either anxiety or insomnia or both. The
noradrenergic, GABAergic and serotonergic systems have been particu-
larly associated in the pathophysiology or treatment of both anxiety and
insomnia.
a) Noradrenergic:
Anatomy: The pontine nucleus locus ceruleus (LC) plays a key role in
arousal and vigilance in animals and disturbances in this nucleus or
its neuronal projections such as the amygdala and related limbic
substrates, and nucleus accumbens have been implicated in panic
disorder, GAD, PTSD and insomnia (Abelson, Khan, Liberzon, &
Young, 2007; Alttoa, Eller, Herm, Rinken, & Harro, 2007; Charney &
Redmond, 1983; Charney et al., 1990; DeViva, Zayfert, & Mellman,
2004; Sullivan, Coplan, Kent, & Gorman, 1999; Uhde & Singareddy,
2002). The locus ceruleus likely mediates its wakefulness-promoting
effects, and possibly insomnia, via a number of actions including direct
activation of the cortex and pedunculopontine tegmental nucleus and
inhibitory inputs to the ventral lateral preoptic nucleus (VLPO), a
galanin-related structure implicated in insomnia associated with
aging (Gaus, Strecker, Tate, Parker, & Saper, 2002).
Drug Action: Clonidine, an 2 adrenergic agonist, has short-term
but not long-term anti-anxiety actions (Uhde et al., 1989), which
theoretically parallels the inhibition and then tolerance to clonidine’s
direct application via iontophoresis onto the LC in animals. Likewise,
it is likely that the sedating and anti-anxiety effects of other 2 adre-
nergic agonists such as dexmedetomidine and lofexidine are mediated
via locus ceruleus inhibition. Similarly, the 1 adrenergic antagonist,
prasozin, has been recently reported to have beneficial effects in the
treatment of the hyper-arousal, anxiety, and sleep-related problems in
PTSD, including insomnia and nightmares (Raskind et al., 2003).
b) GABAergic:
Anatomy: The neurotransmitter pathway most widely implicated in
both anxiety and insomnia is the GABAergic-benzodiazepine-chloride
(GBC) system, with the ionotropic GABAA receptor that regulates
chloride channels being particularly relevant for the biological func-
tions of alarm, arousal and sedation.
The role of the GABAergic system in animal fear is well-established
(Zorumski & Isenberg, 1991). Alterations in GABAergic receptor
function also are linked to arousal states, involving the full-range of
sedation-drowsiness to alertness-hypervigilence and alarm states in

humans. However, there is no known specific or final common pathway
disturbance known to be associated with insomnia, anxiety or any
anxiety disorder.
Extrapolating from observations largely obtained in panic disorder
patients using flumazenil, a pure benzodiazepine-receptor antagonist,
there are few consistent data to support the idea that pathological
anxiety states are directly mediated by either an excess or deficiency,
respectively, of an endogenous benzodiazepine inverse agonist or pure
agonist (Coupland, Bell, Potokar, Dorkins, & Nutt, 2000; Nutt et al.,
1990). It remains possible, however, that disturbances in benzodiaze-
pine receptor distribution, location or sensitivity or secondary
GABAergic influences could play a role in the pathophysiology of
anxiety or insomnia (Kalueff & Nutt, 1997; Kaschka, Feistel, &
Ebert, 1995; Malizia et al., 1998; Mohler, Fritschy, & Rudolph, 2002;
Mohler, Fritschy, Vogt, Crestani, & Rudolph, 2005). Consistent with
this notion are prevalent decreases in flumazenil and iomazenil binding
throughout the brains of panic and generalized anxiety disorder
patients, respectively, as well as decreases in the fear-associated and
anxiety-linked orbitofrontal cortex, amygdala and hippocampus
regions (Malizia et al., 1998, Tiihonen et al., 1997).
Of interest, Buhr and coworkers (2002) recently reported a mutation
in the b3 subunit of the GABAA receptor in a person with chronic
insomnia from a family with sleep problems. Unfortunately, there was
no comprehensive information provided, or available, on the specific
qualities of insomnia or anxiety within the individual or family. None-
theless, these observations, combined with separate lines of evidence in
rodents and humans suggest that the GABAA receptors, perhaps
particularly 1, 2, 3, and b3 subunits, may play a partial role in
the pathophysiology and treatment of insomnia and co-morbid anxi-
ety symptoms (Laposky, Homanics, Baile, & Mendelson, 2001; Moh-
ler et al., 2002, 2005; Rowlett, Cook, Duke, & Platt, 2005; Rush, 1998).
It is theoretically possible that some co-morbid anxiety-insomnia syn-
dromes have particular relevance to a specific GABAA subunit(s),
although developing such a specific animal co-morbidity model will
be a major challenge.
Drug Action: Many drugs with direct or indirect actions at the
GABAergic-benzodiazepine-chloride (GBC) receptor complex
have short-term sedating, sleep-promoting and anti-anxiety profiles.
Barbiturates, alcohol, benzodiazepines, and anesthetic agents, which
act at different sites of the GBC receptor complex, have both sedating
and subjective anxiety-reducing effects in humans, although the beha-
vioral effects of barbiturates, alcohol, and anesthetic agents in patients
who meet contemporary DSM-IV diagnostic criteria for anxiety or
sleep disorders have not been thoroughly examined. Propofol, an
anesthetic agent with GABAA receptor actions, is often reported by

subjects undergoing colonoscopy to produce the equivalent of a ‘‘full-
night’s restful’’ and restorative sleep (author observations).
Traditional hypnotic benzodiazepine drugs such as flurazepam,
estazolam, temazepam, triazolam and quazepam, which have FDA
indications for the short-term treatment of insomnia, produce anxio-
lysis but are generally considered impractical for such off-label use due
to short half-life pharmacokinetics. Benzodiazepine hypnotics admi-
nistered to patients with insomnia as target symptoms have been
shown to improve insomnia as well as reduce co-morbid daytime
anxiety (Fontaine, Beaudry, Le Morvan, Beauclair, & Chouinard,
1990) and improve a sense of physical well-being (Roth, Walsh, Krys-
tal, Wessel, & Roehrs, 2005). It is widely appreciated among clinicians
that benzodiazepine compounds and so-called Z drugs reduce anxiety
and subjective insomnia. These observations are consistent with the
notion that anxiety and insomnia share overlapping neuroanatomical
substrates, at least in terms therapeutic response patterns to drugs that
act at the GBC receptor complex. These observations, however, con-
tribute to the possible misperception that a critical, or even requisite,
ingredient of drug-mediated anxiolysis and especially sleep-promotion
is the induction of drowsiness or sedation. Drug properties of drowsi-
ness and sedation may not only be unnecessary for the effective treat-
ment of anxiety or insomnia or co-morbid anxiety-insomnia
conditions, but, theoretically may actually reduce the overall effective-
ness of sedating drugs in the treatment of selective anxiety disorders,
which require vigilance to monitor threat during sleep (Singareddy,
Uhde, & Commissaris, 2006).
c) Serotonergic:
Anatomy: The reticular formation has long been associated with func-
tions of wakefulness. Moruzzi and Magoun (1949) conducted studies
demonstrating that the transection of the reticular formation above the
pons in the face of intact sensory inputs to higher brain regions are
associated with behavior and EEG patterns consistent with sleep,
whereas lesions of the reticular formation below the pons are asso-
ciated with a reduction in sleep. These classic studies and subsequent
research indicate that different neural networks within and impinging
onto the reticular formation mediate wakefulness and arousal func-
tions, including serotonergic projections and activation of 5HT2A
receptors at the level of the cerebral cortex and possibly hypothalamus.
The serotonergic receptor system is strongly implicated in fearful
animal behaviors and human anxiety disorders, particularly panic and
obsessive-compulsive disorders (for review, see Uhde & Singareddy,
2002). Knock-outs of 5-HT1A receptors are associated with increased
fear behaviors in animal models including, but not limited to, the elevated
plus maze and foot shock (Heisler et al., 1998), forced swim (Ramboz et
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 reup-
take 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 phy-
sicians. 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 conver-
gent and parallel improvements in anxiety symptoms and insomnia (or
sleep efficiency on polysomnography) when treated with SSRI’s;
moreover, responses to some SSRI’s 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 SSRI’s 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 insom-
niacs 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
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 indivi-
duals 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,
1988; Labbate et al., 1997), social phobia (SP) and generalized anxiety dis-
order (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 dis-
order. 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 with-
out 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/exogen-
ous 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 polysomno-
graphy 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 symp-
toms of ‘‘psychic distress’’, worry, difficulty concentrating, feelings of jitteri-
ness, 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
disorder assessed in a large general population study of individuals with insom-

nia 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 general-
ized anxiety disorder. The convergence of symptoms and their robust treatment
response to benzodiazepines are particularly compelling from a clinical per-
spective. If GAD and primary insomnia represent different phases of the same
disorder (Fig. 1) or different conditions whose neurobiology significantly con-
verge 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 interven-
tions. 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, Bélanger, 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) life-
charting as well as prospective methods. Prospective studies in patients whose
initial presentation is anxiety versus insomnia or, in well-defined at-risk popula-
tions, 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
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 insom-
nia, 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 meet-
ing 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 proble-
matic 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 beha-
vioral, physiological, and neuroimaging studies, which might be conducted to
best characterize the relationship between insomnia and anxiety. Clearly, neu-
roimaging 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 phy-
siological 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
specific origin, maintenance, and neuroanatomical impact of putative glucocor-

ticoid 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 else-
where (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
Physical Conditions and Anxiety Disorders
Anxiety Disorders and Physical Illness
Comorbidity: An Overview
Tanya Sala, Brian J. Cox, and Jitender Sareen
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 find-
ings, 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.
Ó Springer 2008
132 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 considera-
tion 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.
Possible Explanations for Observed Relationships
The cross-sectional design of the majority of existing studies of anxiety psycho-

pathology and physical illness precludes any firm conclusions about the exact
nature of the observed associations. However, if a true association exists, pos-
sible explanations can be understood within three basic types of relationships.
Although intriguing, it must be emphasized that these relationships remain
speculative and are not yet convincingly supported by empirical evidence.
1. Direct causal relationship – The presence of an anxiety disorder may directly
increase the risk of suffering from a physical illness. For example, it has been
postulated that chronically high levels of anxiety may produce changes in
physiological functioning, which may in turn increase risk for physical illness
(e.g. Kubzansky, Koenen, Spiro, Vokonas, & Sparrow, 2007). Conversely,
the presence of a physical illness may directly increase the risk of having an
anxiety disorder, a possibility explored in studies of asthma and anxiety
disorders, especially panic disorder (e.g. Goodwin, Jacobi, & Thefeld,
2003; Goodwin & Pine, 2002). An interesting related concept is the model
of mutual maintenance (Sharp & Harvey, 2001), which refers to the phenom-
enon of physical symptoms and anxiety symptoms each exacerbating and
perpetuating the other.
2. Indirect causal relationship – An anxiety disorder may indirectly increase the
risk of having a physical illness through some intermediate factor, such as
smoking, obesity, physical exercise, or substance abuse. Alternatively, hav-
ing a physical illness could indirectly increase the risk of suffering from an
anxiety disorder, such as when the use of a particular medication has an
adverse effect on anxiety symptoms. In individuals being treated for respira-
tory disease, use of bronchodilators has been suggested as a possible exacer-
bating factor for anxiety symptoms.
Anxiety Disorders and Physical Illness Comorbidity: An Overview 133
3. Shared risk factors – There may be no causal relationship between anxiety

disorders and physical illness. Rather, they may share risk factors, such as
genetic, environmental (e.g. poverty), or personality characteristics.
It is also possible, although unlikely, that the reported associations are not
true associations, but the result of another process. Some studies have found
anxiety disorders to be associated with high utilization of medical services (e.g.
Calhoun, Bosworth, Grambow, Dudley, & Beckham, 2002; Hoge, Terhakopian,
Castro, Messer, & Engel, 2007; Richardson, Elhai, & Pedlar, 2006). Increased
frequency of medical attention, and possibly increased somatic complaints, may
lead to increased detection of physical illness in individuals with anxiety dis-
orders. This explanation may be particularly important to exclude for those
physical illnesses that are typically asymptomatic in the early stages, such as
Type II diabetes and hypertension.
A possible link between anxiety disorders and health behaviors such as
obesity (Simon et al., 2006), physical exercise, and smoking remains under-
studied. Although some studies have adjusted for health behaviors such as
smoking (Sareen, Cox, Clara, & Asmundson, 2005), the majority of studies
have not adjusted for important health behaviors. Given the well-known impact
of lifestyle and health choices on risk for physical illness, this remains an issue
for interpretive caution. However, debate exists about the utility of adjusting
for relevant health behaviors. Some authors argue that if health behaviors are
intermediate factors along a causal pathway, rather than confounding vari-
ables, these adjustments could potentially obscure an indirect causal relation-
ship as described above.
Anxiety Symptoms in General
Sareen et al. (2005) examined the relationship between anxiety disorders and a
range of physical disorders in the US National Comorbidity Survey (NCS), a
large nationally representative dataset. This study found that among respon-
dents with one or more physical disorders, a comorbid anxiety disorder diag-
nosis was associated with an increased likelihood of disability even after
adjusting for severity of pain, comorbid mood, and substance use disorders.
Interestingly, adjusting for smoking did not affect these associations. Using
German Health Survey data, Sareen et al. (2006) again examined these associa-
tions. Advantages of this study included both a large sample size and the fact
that the presence of physical illness was based on physician assessment and not
individual self-report, thus increasing reliability. Unfortunately, this study did
not include PTSD. After adjusting for sociodemographic factors and other
common mental disorders, the presence of an anxiety disorder was significantly
associated with thyroid disease, respiratory disease, gastrointestinal disease,
arthritis, migraine headaches, and allergic conditions. The presence of a comor-
bid anxiety disorder with one or more physical disorders was significantly
134 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.
Posttraumatic Stress Disorder (PTSD)
Editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM)

prior to the DSM-IV explicitly excluded life-threatening illness as a stressor that
could be considered a traumatic precipitant of PTSD. With the publication of
DSM-IV, individuals could receive a diagnosis of PTSD as a direct result of
being traumatized by the experience of a life-threatening illness. This develop-
ment has contributed to interest in the association between PTSD and physical
illness.
Much of the early work examining the co-occurrence of PTSD with physical
disorders involved studies of war veterans. Higher scores on measures of post-
traumatic stress symptoms have been linked with increased medical care utiliza-
tion and lower ratings of general health (Calhoun et al., 2002; Hoge et al., 2007;
Richardson et al., 2006). Frayne et al. (2004) reported that female veterans with
PTSD had a greater number of physical illnesses and poorer physical health
functioning than female veterans with either depression alone or neither
diagnosis.
Within the general population of the United States, Sareen et al. (2005)
reported that, among DSM-IV anxiety disorders, PTSD had the greatest num-
ber of significant associations with chronic physical disorders, including neu-
rological, cardiovascular, gastrointestinal, metabolic/autoimmune, and bone
or joint conditions. A study of primary care patients found PTSD to be a
stronger predictor of a reported number of medical problems than trauma
history, physical injury, lifestyle factors, or comorbid depression (Weisberg
et al., 2002).
Studies have not been limited to adult populations. A descriptive epidemio-
logic case-control analysis of Medicaid service-use data in the United States
found PTSD to be associated with adverse health outcomes in female children
and adolescents (Seng, Graham-Bermann, Clark, McCarthy, & Ronis, 2005),
and significant associations with PTSD were found across a wide range of
disease categories. The importance of PTSD diagnosis as a predictor of having
a physical illness appeared to increase with age. Studies of different ethnic

groups have also identified PTSD as being significantly associated with cardi-
ovascular disease, even after controlling for major depression and traditional
cardiovascular risk factors including age, sex, education, diabetes, high blood
pressure, and smoking (Sawchuk et al., 2005).
Efforts to understand the biological pathways through which PTSD and
physical illness might be linked have included examination of the hypothala-
mic-pituitary-adrenal and sympathetic-adrenal-medullary axes. Findings of
lower cortisol, higher catecholamine levels, and increased circulating
T-lymphocytes in individuals with PTSD support the possibility of biological
underpinnings (e.g. Yehuda et al., 1995).
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 physi-
cian-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 con-
dition 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,
D’Andrea, and Figueira (2004) recently conducted a review of studies on the
136 T. Sala et al.
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 phenom-
enon, might be understood as a severe form of PTSD that includes prominent
dissociative features. There is currently too little information to warrant con-
clusions 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 asso-
ciation between self-reported diabetes and PTSD in a community sample of
adults. In this study, self-reported diabetes was found to be significantly asso-
ciated with an increased likelihood of PTSD, but not with an increased like-
lihood of any other mental disorder. This study not only provides evidence for
generalizability of previous findings to adults in the community, it also suggests

some specificity for the association with PTSD compared to other mental
disorders.
Cancer
The majority of studies assessing incidence or prevalence of PTSD in indivi-

duals 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 indivi-
duals with cancer, including increased emotional distress following diagnosis,
female gender, a history of negative life stressors, prior psychological distur-
bance, 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 litera-
ture, 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 chroni-
city 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
138 T. Sala et al.
treatment. PTSD also needs to be distinguished from reactive stress to ongoing

medical issues, or a grief reaction when the diagnosis is a terminal or signifi-
cantly disabling illness.
There is good evidence supporting cognitive-behavior therapy (CBT) for
treatment of PTSD. However, solid research supporting CBT for treatment of
PTSD co-occurring with physical illness is lacking. The relative benefits of
cognitive vs. behavioral components of CBT may also vary in this population.
Panic Disorder (PD)
Adding to the complexity of the relationship between panic disorder and

physical illness, both for individuals suffering from these disorders and for the
professionals who provide them with care, is the high degree of overlap between
symptoms of panic and certain physical illnesses, particularly cardiac and
respiratory 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 respon-
dents 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.
Kawachi et al. (1994) reported on a prospective study of phobic anxiety and

the risk of coronary artery disease (CAD) in a sample of 34,000 male health
professionals. Although not a DSM-IV disorder, phobic anxiety likely most
closely resembles panic symptoms, and these findings are therefore discussed
here. Subjects were initially free of cardiovascular disease at baseline. A sig-
nificant difference was found in the age-adjusted relative risk of fatal coronary
artery disease when groups with the highest and lowest anxiety scores were
compared. The excess risk was confined to sudden death. A more recent pro-
spective study examined the relationship between phobic anxiety and coronary
artery disease among women participating in the Nurses’ Health Study over
12 years of follow-up (Albert, Chae, Rexrode, Manson, & Kawachi, 2005). In
this sample of over 72,000 women with no history of cardiac disease at baseline,
a higher anxiety score was associated with an increased risk of sudden cardiac
death and fatal coronary artery disease, but not of nonfatal MI. After adjusting
for possible intermediaries (hypertension, diabetes, and elevated cholesterol),
only a trend toward increased risk persisted for sudden cardiac death.
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
140 T. Sala et al.
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 indivi-
duals 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 treat-
ments, abnormalities in routine physical exam or laboratory investigations, or
family history.
With respect to vestibular dysfunction, a two-year prospective study exam-
ining the role of cognitions in the development of panic disorder after the
experience of vestibular neuritis (Godemann, Schabowska, Naetebusch,
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 dys-
function 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 pre-
valence 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 vestibu-
lar dysfunction in general show increased levels of anxiety symptoms,
especially panic, no consistent pattern of association has yet been
described.
Gastrointestinal (GI) Disease
The majority of studies within this system of disease have focused on associa-
tions of anxiety disorders with ‘‘Functional’’ GI symptoms. Functional refers
to symptoms reported by an individual that do not correlate to any tissue
pathology detectable by medical testing. In a nationally representative survey
of over 13,000 individuals in the United States, Lydiard et al. (1994) found
that individuals with panic disorder had the highest rate of unexplained GI
symptoms (7.2%) compared with other diagnostic categories. Respondents
who reported two gastrointestinal symptoms had significantly higher lifetime
prevalence rates for panic disorder and agoraphobia than those who reported
no GI symptoms. In patients with severe irritable bowel syndrome (IBS),
panic disorder has been associated with impaired functioning (Creed et al.,
2005).
In a longitudinal study of a representative cohort of Swiss adults by
Hochstrasser and Angst (1996), subjects were assessed for functional GI
symptoms and anxiety and depressive disorders. Cross-sectionally, a signif-
icant relationship was found between functional GI complaints and panic
disorder, subthreshold panic disorder, agoraphobia, social phobia, simple
phobia, and GAD. However, those who reported functional GI complaints
at younger ages were not at increased risk for subsequent development of
an anxiety disorder. The authors concluded that functional gastrointestinal
complaints reflect a non-specific concomitant vegetative disturbance asso-
ciated with anxiety disorders, not a risk factor for the development of a
specific anxiety disorder. Data from a large-scale, nationally representative
sample of Japanese subjects was analyzed for comorbidity of IBS with
panic disorder and agoraphobia (Kumano et al., 2004). Significantly higher
rates of PD and agoraphobia were observed in subjects with IBS than in
142 T. Sala et al.
non-IBS subjects. Although IBS was more prevalent in females, comorbid-

ity 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). How-
ever, 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 distur-

bances in cancer patients (van’t 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 associa-
tion 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 symp-
toms could pose an even greater challenge for lay interviewers than clinicians.
Generalized Anxiety Disorder (GAD)
Barger and Sydeman (2005), using data from a large US community sample of
adults aged 25–74, found that independently of depression, subjects with GAD
were more likely to have coronary artery disease risk factors, as measured by
self-reported smoking status, body mass index, and recent medication use for
hypertension, hypercholesterolemia, and diabetes.
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 differ-
ences 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 socio-
demographic 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 fre-
quencies 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,
144 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.
Obsessive-Compulsive Disorder (OCD)
The bulk of the research exploring a link between obsessive-compulsive dis-

order and physical illness has focused on a possible etiologic link between
Group A b-Hemolytic Streptococcus (GABHS) and the onset and subsequent
exacerbations of OCD. Allen, Leonard, and Swedo (1995) published an early
description of cases in which the onset of obsessive-compulsive symptoms and
tics appeared to follow streptococcal infection. Based on the first 50 cases
described, Swedo et al. (1998) defined five inclusion criteria for this postulated
subgroup of OCD cases, referred to as PANDAS – pediatric autoimmune
neuropsychiatric disorders associated with streptococcus infection: (1) presence
of OCD and/or a tic disorder (meeting DSM-IV criteria); (2) pediatric symptom
onset (between 3 years and the beginning of puberty); (3) episodic course
characterized by abrupt onset of symptoms or dramatic symptom exacerba-
tions; (4) temporal relationship between GABHS infections and symptom
exacerbations; (5) neurological abnormalities (e.g. choreiform movements,
motoric hyperactivity, and/or tics) present during symptom exacerbations.
The postulated biological mechanism for PANDAS is referred to as mole-
cular mimicry, a process by which pathogens attempt to evade host immune
defenses designed to distinguish between host and foreign antigens. In the case
of PANDAS, the mimicry is thought to exist between surface antigens of the
streptococcus bacterium and neuronal antigens in the basal ganglia, resulting in
neuropsychiatric symptoms.
The majority of studies examining PANDAS are limited by small sample size,
and there is a strong bias in the literature towards samples from specialty clinics.
Although a robust association was reported in a large, population-based case-
control study (Mell, Davis, & Owens, 2005), another recent prospective study
found no association between OCD or tic symptom exacerbations and GABHS
infections beyond that expected based on chance alone (Luo et al., 2004).
The presence of anti-basal ganglia antibodies (ABGA) in the peripheral
blood of patients with tics and/or OCD may be an important clue to the
involvement of autoimmunity in these disorders (Dale, Heyman, Giovannoni,
& Church, 2005). However, it is important to note that the presence of ABGA
does not prove autoimmunity as a causal mechanism. Autoantibodies against a
variety of tissue antigens are present in healthy individuals, and therefore, the
presence of these antibodies does not by itself prove pathological significance.
In fact, a recent study did not detect differences in antineuronal antibody
profiles between children with Tourette’s syndrome, PANDAS, or age-matched

controls (Singer, Hong, Yoon, & Williams, 2005).
Efforts to elucidate a possible autoimmune mechanism have included a
number of treatment studies. A pilot study of antibiotic prophylaxis for pre-
vention of symptom exacerbations, analogous to penicillin prophylaxis in
rheumatic fever, revealed no difference in number of infections or obsessive-
compulsive or tic symptom severity between antibiotic and placebo groups
(Garvey et al., 1999). A study of 29 patients fulfilling proposed PANDAS
criteria reported sustained benefits after both intravenous immunoglobulin
and plasma exchange, compared to placebo (Perlmutter et al., 1999). However,
this small study had significant methodologic problems, and its findings have
not been convincingly replicated. Other authors have reported rapid diminu-
tion of OC symptoms in cases fulfilling PANDAS criteria following treatment
with antibiotics (Murphy & Pichichero, 2002), and positive correlations
between streptococcal titers and obsessive-compulsive severity rating changes
in subjects with large symptom changes (Murphy et al., 2004).
Despite a large body of literature in this area, the existence of a PANDAS
subgroup of OCD sufferers remains controversial. There is a clear need for long-
itudinal studies aimed at delineating the precise relationships between GABHS
infections, OC symptom exacerbations, and alterations in immune parameters. It
remains uncertain whether an association, if it truly exists, refers to a specific
subgroup of patients with OCD or tics (PANDAS), to tic disorders and OCD in
general, or to a broader range of diagnostic entities perhaps encompassing eating
disorders and impulse control disorders such as trichotillomania. Based on the
evidence so far, some argue for routine throat culture and antistreptolysin-O titres
in children with an abrupt onset or exacerbation of OCD or tic disorder, although
others dispute this recommendation. In summary, there is ample evidence to
warrant further research in this area, but insufficient data to definitively describe
the PANDAS subgroup or any treatments specific to such a group.
Social Anxiety Disorder
See the section on Panic Disorder and gastrointestinal disease for discussion of
a relevant study by Hochstrasser and Angst (1996).
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
146 T. Sala et al.
using larger community samples have generally supported a significant associa-

tion. 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.
Specific or Simple Phobia
Respiratory Disease
Goodwin, Jacobi, et al. (2003) reported a strong association between physician-

diagnosed severe asthma and specific phobia in a German community sample,
which included assessment by a physician rather than self-report by study
participants. This finding is consistent with analysis of NCS data by Sareen
et al. (2005), which found a significant association between specific phobia and
respiratory disease.
See the section on Panic Disorder and gastrointestinal disease for discussion of
a relevant study by Hochstrasser and Angst (1996).
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
strong, broad general health ramifications of this subtype of specific phobia.

However, individuals with diabetes and blood-injection-injury phobia had
higher than expected rates of macrovascular complications. This finding sup-
ports those from a previous study reporting that phobic symptoms are frequent
in patients with Type I diabetes, and that the intensity of blood and injury fears
negatively correlated with number of blood glucose measurements per day and
metabolic control (Berlin et al., 1997). These findings together suggest the
possibility that decreasing blood-injury fears could lead to improved metabolic
control.
Cancer
See the section on Panic Disorder and cancer for discussion of relevant studies
by van’t 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 unex-
plored. 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 anxi-
ety disorders and physical illness exist, but the precise nature of the relation-
ships 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.
148 T. Sala et al.
An essential caveat accompanying any discussion of associations between

mental and physical disorders is the necessity of ruling out a physical illness
masquerading as an anxiety disorder by virtue of overlapping symptomatology.
In order for this very real possibility to be reliably distinguished from comor-
bidity, a thorough history and physical exam is required in any patient present-
ing for the first time with symptoms of an anxiety disorder, in any patient with
markedly altered nature or severity of symptoms, and in any patient whose
symptoms are resistant to standard treatments. Only when any existing physical
illness is diagnosed and optimally treated can associations with mental disor-
ders be accurately and safely explored.
Limitations and Future Directions
Within the currently available literature, a number of methodological issues

limit our understanding of associations between anxiety disorders and physical
illness. The relative lack of large clinical or epidemiological studies, and relative
preponderance of smaller studies, is one of the primary limiting factors. In
addition, much of the available research still relies heavily on self-report in
assessment of physical illness. In a population of individuals shown to be
sensitized to perception of physical symptoms, reliance on self-report is parti-
cularly problematic.
The lack of understanding of the role of other health behaviors, such as
physical exercise and substance use, must also be highlighted as an issue for
interpretive caution. It remains to be discovered whether health behaviors play
a significant role in the observed associations between anxiety disorders and
physical illness, and if so, whether they represent confounding variables or inter-
mediate factors in an indirect causal pathway. The majority of studies in this area
are cross-sectional, precluding any causal inferences. The scarcity of longitudinal
data is a major limitation of existing research, and the need for more prospective,
longitudinal epidemiologic data with objective measures of both physical and
mental health status stands out as a clear mandate for future research efforts.
Despite the limitations in available studies, existing research is compelling and
argues convincingly that further attention to this area is warranted.
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The Relation Between Puberty and Adolescent
Anxiety: Theory and Evidence
Ellen W. Leen-Feldner, Laura E. Reardon, Chris Hayward, and Rose C. Smith
The Role of Puberty in Adolescent Anxiety: Theory and Evidence
Anxiety disorders are among the most prevalent forms of psychopathology

affecting youth, with recent estimates ranging from 3% to 18% for particular
disorders (Albano, Chorpita, & Barlow, 1996). These rates are alarming, in
light of the fact that anxiety psychopathology negatively impacts functioning
across multiple domains (e.g., McGee & Stanton, 1990), maintains a chronic
course for a significant proportion of youth affected (Orvaschel, Lewinsohn, &
Seeley, 1995), and increases the risk for other types of disorders (Cole, Peeke,
Martin, Truglio, & Seroczynski, 1998; Goodwin & Hamilton, 2002a, 2002b).
The period of adolescence appears to be a particularly ‘‘high-risk’’ epoch in
terms of the onset and intensification of anxiety problems; for instance, panic
attacks (Macaulay & Kleinknecht, 1989; Warren & Zgourides, 1988), social
phobia (Inderbitzen & Hope, 1995; Liebowitz, Gorman, Fyer, & Klein, 1985)
and obsessive-compulsive disorder (Rasmussen & Eisen, 1990) commonly
emerge during this developmental stage. Furthermore, traumatic event exposure
is common among youth, with estimates indicating 16%–47% of youth ages
12–17 years have been exposed to at least one traumatic event (Giaconia,
Reinherz, Silverman, & Stashwick, 1995; Perkonigg, Kessler, Storz, & Wittchen,
2000; Kilpatrick et al., 2000). Overall, adolescence represents a critical period
during which anxiety vulnerability may be transformed into psychopathology.
Efforts to develop sophisticated and comprehensive etiological models of
adolescent anxiety psychopathology must necessarily consider the role of pub-
erty, conceptualized as the most significant milestone of this period (Hayward &
Sanborn, 2002). In addition, a growing body of literature links various aspects of
puberty to clinical problems (Graber, Lewinsohn, Seeley, & Brooks-Gunn, 1997;
Graber, Seeley, Brooks-Gunn, & Lewinsohn, 2004), including depression
Ellen W. Leen-Feldner
University of Arkansas, Department of Psychology, 216 Memorial Hall, Fayetteville, AR
72701, Tel: 479-575-5329, Fax: 479-575-3219
eleenfe@uark.edu
Ó Springer 2008
156 E. W. Leen-Feldner et al.
(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.
Operationalizing and Assessing Puberty: Methodological

and Conceptual Issues
Puberty is a period of profound biopsychosocial development; in a relatively

short time-span (i.e., two to four years), youth experience extensive physical
development, including reaching skeletal maturity (i.e., growth spurt), devel-
oping primary and secondary sexual characteristics (e.g., breast and penis
growth), and attaining reproductive capability (Rogol, Roemmich, & Clark,
2002; Sheehy, Gasser, Molinari, & Largo, 1999). Although the experience can
be exciting and relatively positive for many youth, puberty also is characterized
by potentially undesirable bodily events, such as spontaneous erections,
nocturnal emissions, gynecomastia, as well as onset of menses and irregularity
of initial menstrual cycles (Kipke, 1999). Indeed, some youth report feeling
under-prepared for the events of puberty, potentially contributing to a sense of
‘‘unexpectedness’’ or dyscontrol around these somatic events (Forest, Strange,
Oakley, & The RIPPLE Study Team, 2004; Omar, McElderry, & Zakharia,
2003). In addition, puberty is associated with increased susceptibility to nega-
tive affectivity (Brooks-Gunn, Graber, & Paikoff, 1994; Susman, Dorn, &
Chrousos, 1991), sleep deprivation (Carskadon et al., 2002), conflict in
parent-child relationships (Paikoff & Brooks-Gunn, 1991), and enhanced
emotional lability (Buchanan, Eccles, & Becker, 1992; Spear, 2003).
Collectively, these data suggest puberty may be a difficult experience, at least
for some adolescents. Indeed, puberty may be associated with the onset or
exacerbation of clinically meaningful symptomatology among vulnerable
youth (Caspi, & Moffitt, 1991, 1993). As the field endeavors to construct
developmentally sensitive models of the etiology and maintenance of anxiety
psychopathology among youth, it has become apparent that puberty deserves
theoretical and empirical attention. However, operationalizing and assessing
the complex construct of puberty is a challenging task.
Puberty and Anxiety 157
Because puberty is a multifaceted and dynamic process, there is no

‘‘gold standard’’ for its assessment (Hayward, 2003). When considering the
mechanisms by which puberty may confer risk for psychopathology, research-
ers typically highlight three aspects of puberty: pubertal status, timing, and
hormones, all of which are conceptualized to be in dynamic relation with one
another and the larger social context (Graber, Brooks-Gunn, & Warren, 2006).
A brief overview of each, including assessment approaches, is provided in the
next section. For more comprehensive discussions of methodological
approaches to the study of puberty, the reader is referred to reviews by Graber,
Petersen, and Brooks-Gunn (1996) as well as Dorn, Dahl, Woodward, and Biro
(2006). Finally, it is important to note in this context that, despite a significant
correlation between the two variables, puberty is not redundant with chrono-
logical age. For example, age does not necessarily reflect pubertal status
because the age at which the events of puberty occur vary across individuals
(e.g., female breast development typically begins anywhere from ages 8 to 13;
Tanner, 1962). In addition, a number of studies have shown that during early
adolescence, puberty, and not age, is related to clinical problems such as eating
disorders (Killen et al., 1992) and depression (Angold et al., 1998). Therefore, it
is important to consider how age and puberty, both independently and in
concert, alter risk over time for the development of specific clinical outcomes
(Hayward, 2003).
Pubertal Status. Pubertal status refers to an adolescent’s current level of
morphologic development (Dubas, Graber, & Petersen, 1991) and can be
indexed by asking participants to self-report their development in terms of
specific physical indicators (e.g., height, pubic hair growth, skin changes;
Petersen, Crockett, Richards, & Boxer, 1988) or experience of particular
pubertal events such as spermarche (first emission of spermatozoa) or menarche
(first menstrual period or bleeding). One of the most commonly used indices of
pubertal status is the Tanner Staging System (Tanner, 1962; Morris & Udry,
1980), a five-stage classification system based on maturation of secondary
sexual characteristics (i.e., breasts and pubic hair for females; genitalia and
pubic hair for males) ranging from Tanner stage I (immature) to Tanner stage
V (mature). Tanner stage can be self- or parent-reported (by asking respondents
to select from a series of schematics), or directly evaluated by a practitioner. The
Tanner staging system is a standard assessment of pubertal status in the
literature; however, some limitations of the instrument include 1) inconsistent
reliability between self report and practitioner evaluation, 2) concerns about
the generalizability of the Tanner schematics across ethnic groups, and 3) the
degree to which perceptions of status may affect adolescents’ self ratings of
physical development (Dorn, Dahl et al., 2006).
Pubertal Timing. Pubertal timing refers to the timing of pubertal onset relative to
peers (i.e., early, on-time, or late). Timing can be objectively indexed by classifying
participants on the basis of established standards of physical development (e.g.,
Todd standards of skeletal maturity) or comparing participants’ status on concep-
tually-relevant indicators, such as breast/pubic hair development (Wilson et al.,
1994), menarche/spermarche (Kaltiala-Heino, Marttunen, Rantanen, & Rimpela,

2003), or age at peak height velocity (Dubas et al., 1991) with sample- or epide-
miologically-defined norms. The timing of puberty also can be indexed via sub-
jective self-report (e.g., ‘‘do you think your development is (was) any earlier or later
than most other boys/girls your age?’’ Petersen et al., 1988). Although such reports
evidence modest associations with objective measures (r’s range from 0.28 to 0.56;
Dubas et al., 1991), puberty researchers conceptualize adolescents’ interpretation of
pubertal development as reflecting meaningful variance in participants’ affective
response to pubertal events. In other words, tapping into adolescents’ sense of their
experience of puberty, irrespective of the degree to which it maps onto actual
development, is theoretically important, as it is indicative of the broader psycho-
social context in which the youth is developing. As an illustrative example, Michael
and Eccles (2003) found that objectively indexed early timing (i.e., self-report of
onset of menarche) was not associated with psychological distress (e.g., depressive
symptoms; anger problems) among a sample of 266 African American females ages
13–14 years. However, when perceptions of pubertal timing were evaluated,
females who viewed their maturation as early or late relative to on-time peers
evidenced elevated depressive, eating, anger, and problem behavior symptoms.
Maternal report corroborated these adolescent self report data. These findings
suggest that subjective indices tap conceptually-relevant processes that may be
important in terms of risk for psychopathology during puberty (cf., Silbereisen, &
Kracke, 1997). Indeed, assessing perceptions of timing is recommended in studies
where outcome variables are theorized to vary as a function of individual differ-
ences in the experience of puberty (e.g., perceptions of pubertal timing may be more
relevant if self-perception is related to the outcome variable [self-esteem; anxiety;
body image] whereas objective indices are indicated if research questions are
focused on the effect of actual physical development on a particular outcome
[aggression; muscle strength]; Dorn, Dahl et al., 2006).
Pubertal Hormones. The two primary hormonal processes that drive pub-
ertal development are adrenarche and gonadarche (Fechner, 2002). The first
phase of puberty, adrenarche, commences between ages five and nine years in
girls (approximately one year later in boys; Grumbach, & Styne, 2003).
Activation of the adrenal axis results in the release of the adrenal hormones
including cortisol, dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and
androstendione (4-A; Parker, 1999). The second phase of puberty,
gonadarche, commences around age 9–10 years in females and is characterized
by the release of leutinizing hormone (LH) and follicle stimululating hormone
(FSH) by gonadotropes in the anterior pituitary (Johnson & Everitt, 2000).
These hormones stimulate the enlargement of the gonads, which in turn release
testosterone (T) and estrogen (E)/estradiol (E2) that promote the development
of breasts and genitalia. Hormone concentrations typically are measured via
blood serum or salivary sample assay. Salivary samples are less invasive and
typically more cost effective, with professional assay services offered by
well-respected companies such as Salimetrics, Inc. Moreover, there is
evidence of adequate inter-correlations between the two assessment approaches
(e.g., r =0.91 [cortisol]; r = 0.86 [DHEAS]; Salimetrics, LLC). However,

salivary assay may not be sensitive enough to detect some hormones
(e.g., estradiol; Shirtcliff, Reavis, Overman, & Granger, 2001) and can be
affected by multiple variables, including contraceptive use, teeth brushing,
medication, as well as recent meals and exercise (e.g., Bhagwager, Hafizi, &
Cohen, 2002; Kirschbaum, Kudielka, Gaab, Schommer, & Hellhammer, 1999).
Therefore, blood serum assessments may be preferable, particularly if
researchers have access to the appropriate personnel and testing services
(e.g., affiliations with a medical school). Regardless of the approach however,
rigorous assessment (e.g., multiple assessments within- and across- days;
Goodyer, Park, & Herbert, 2001) is critical to ensure valid hormone indices
because hormones evidence significant fluctuation (e.g., ultradian; circadian;
monthly rhythms; Cauter, 2001).
Puberty as a ‘‘Risk Factor.’’ A necessary first step toward theoretical and
empirical integration of puberty into models of etiology and maintenance of
anxiety psychopathology is to clarify how the various aspects of puberty fit into
contemporary conceptualizations of risk. Specifically, Helena Kraemer and her
colleagues (Kazdin, Kraemer, Kessler, Kupfer, & Offord, 1997; Kraemer, Stice,
Kazdin, Offord, & Kupfer, 2001; Kraemer et al., 1997) have developed a
standardized nomenclature for operationalizing risk factor processes in which
a risk factor is defined as characteristic, experience, or event that indicates the
relative likelihood of a given outcome among individuals within a population
(e.g., if the entire population is exposed to the variable in question, it is not a risk
factor). The authors suggest that a characteristic can be classified as a risk factor
(i.e., a characteristic that temporally precedes, and is correlated with, an
outcome) or a causal risk factor (i.e., a characteristic that temporally precedes
and, when manipulated, produces systematic change in an outcome). Risk
factors can be further categorized according to whether they are malleable; if
the characteristic changes spontaneously (e.g., age) or can be manipulated
(e.g., skill set) is it classified as a variable risk factor, whereas if the characteristic
is non-modifiable (e.g., gender), it is referred to as a fixed marker.
According to the Kraemer model, puberty per se (i.e., an individual’s
pubertal status; hormonal changes characteristic of puberty) is not a risk
factor; all youth are exposed to puberty and as such it does not designate
sub-populations of youth more or less likely to evidence a given outcome.
A more accurate conceptualization of puberty generally is as a ‘‘critical period,’’
reflecting a high-risk phase for youth who are otherwise vulnerable. Indeed, the
unparalleled physical, cognitive, and psychosocial changes associated with
puberty can be stressful for some adolescents, making it an important time
for screening and intervention. Pubertal timing, on the other hand, is a facet of
puberty that reflects individual differences in an otherwise universal human
experience. Accordingly, pubertal timing more readily lends itself to classifica-
tion within the Kraemer model. Specifically, pubertal timing characterizes
specific sub-groups of youth at risk for a number of psychiatric outcomes
(e.g., early-maturing females evidence increased risk of substance use problems;
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.
Overview of Findings from the Empirical Literature –

Differentiating Pubertal Status and Timing Effects
The available empirical literature focused on the puberty-anxiety association is

briefly reviewed in this section, addressing anxiety in relation to each of the
aspects of puberty discussed above. In light of the marked gender differences in
the process and experience of puberty (Hayward, 2003), findings among males
and females are presented separately. Finally, in light of space limitations, more
detailed descriptions are presented for studies that, relative to others in the
literature, are characterized by greater methodological rigor (e.g., sample size;
prospective assessments) thereby allowing for more confidence in the observed
findings.
Pubertal Status and Anxiety. In terms of the main effects of pubertal status,
findings are mixed. Among females, for instance, a significant positive
relation was observed in two large samples of non-clinical youth conducted in
the United States (Hayward et al., 1992) and Australia (Patton et al., 1996).
Specifically, Hayward and colleagues found, after controlling for age, a
two-fold increase in the likelihood of having had a panic attack for each
one-point change in self-reported Tanner stage among 754 ethnically diverse
6th and 7th grade females. Interestingly, none of the females at Tanner stages
I or II reported having had a panic attack. Similarly, in a sample of more than
2,000 adolescents, Patton and colleagues reported a positive association
between psychiatric symptoms (including anxiety) and pubertal status

(self-reported age at menarche) after controlling for chronological age. Indeed,
females for whom menarche had occurred more than 36 months prior to the
study were more than twice as likely to evidence psychiatric morbidity.
Studies also have demonstrated an association between advancing pubertal
status and trait anxiety among females (Huerta & Brizuela-Gamino, 2002)
but others have found either a weak negative association or no relation at
all (Canals,Marti-Henneberg, Fernandez-Ballart, Cliville, & Domenech, 1992;
Laitinen-Krispijn, van der Ende, & Verhulst, 1999; Susman et al., 1991; Stone &
Barker, 1939).
Among males, Ge, Conger, and Elder (2001) reported a positive association
between ‘‘internalized distress’’ (i.e., summary measure of self-reported depres-
sive, anxious, somatization, and eight additional symptoms) and self-reported
pubertal status among 202 adolescent males between the ages of 12 and 14
assessed annually over a four year period. However, the association did not
persist, suggesting this effect may be short-term in nature. Specifically, pubertal
status indexed in grade 7 predicted internalized distress at grades 8 and 10, but
pubertal status assessed at grades 8, 9, and 10 was unrelated to internalized
distress at any other assessment point. Similarly, Susman and colleagues (1991)
found that physician assessed pubertal status related positively to interview-
assessed depressive and anxiety symptoms 12 months later among 56 males
aged 10 to 15 years (age was entered simultaneously into the model). However,
inconsistent with these two studies, other work has found no association
between pubertal status and anxious symptoms (Patton et al., 1996), a decrease
in anxious-depressed symptoms as a function of advancing pubertal stage
(Laitinen-Krispijn et al., 1999), or mixed findings (i.e., elevated state anxiety
at the beginning and end of puberty; Canals et al., 1992).
One reason that the literature is mixed may be that key constructs that
might influence or moderate the pubertal status-anxiety association have
received limited attention. This relative degree of neglect is unfortunate,
particularly because, as discussed above, puberty per se is a normative
developmental process (Rosenfeld & Nicodemus, 2003). Therefore, the char-
acteristic changes of puberty would only be expected to increase risk for
psychopathology under certain conditions (e.g., among psychologically vul-
nerable adolescents; Buchanan et al., 1992). This conceptualization is in line
with the idea that puberty in and of itself is a ‘‘critical period,’’ or a period of
high risk for youth who are otherwise vulnerable. Specifically, the accentua-
tion hypothesis (Caspi & Moffitt, 1991, 1993) postulates that the changes
associated with puberty amplify pre-existing vulnerability, thereby resulting
in psychopathology among at-risk youth. Consistent with this perspective,
panic-relevant (anxiety sensitivity; Leen-Feldner, Reardon, et al., 2006; Leen-
Feldner, Reardon, & Zvolensky, 2007) and biological (seratonergic dysfunc-
tion; Twitchell, Hanna, Cook, Fitzgerald, & Zucker, 2000), individual differ-
ence vulnerability variables have been found to moderate the association
between advancing pubertal status and anxiety outcomes. For instance,
among 123 psychologically healthy adolescents aged 12–17 years, Leen-Feld-

ner and colleagues (2006) found that more mature youth who also were high
in anxiety sensitivity [AS], a cognitive vulnerability factor reflecting a ten-
dency to fear the consequences of anxiety (Reiss & McNally, 1985), reported
the most fearful reactivity in response to a panic-relevant voluntary hyper-
ventilation 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 vulner-
ability during pubertal development, including behavioral inhibition (Hirsh-
feld 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 addi-
tional 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
11–17 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
decrease in testosterone across the course of the day evidenced elevated

symptomatology. No relation was observed among females. Nottelmann and
colleagues (1987) measured LH, FSH, DHEA, DHEAS, T, E2 4-A, and
internalizing-type symptoms among 108 youth aged 9 to 14 years. The only
associations observed were among males; a positive correlation between 4-A
and an index of obsessive-compulsive symptoms and a negative correlation
between ‘‘emotional tone’’ (combined sadness/anxiety ratings) and a T/E2 ratio.
Finally, in a one-year prospective study of more than 100 youth (ages–years),
Susman and colleagues (1991) measured cortisol in addition to the hormones
indexed in the Nottelmann et al. study. Among females, cortisol and T relate-
positively to concurrent anxious symptoms and emotional tone, respectively.
DHEAS related negatively to concurrent maternal report of internalizing
symptoms. Prospective analyses with females indicated LH (positive associa-
tion) and DHEAS (negative association) predict anxiety symptoms assessed
one year later. Among males, T and E2 (negative associations) as well as 4-A
(positive association) related concurrently to emotional tone. In addition, LH
and cortisol related negatively to maternal report of internalizing symptoms
12 months later; DHEA and 4-A also prospectively predicted anxious symp-
toms (positive associations).
As noted above, it seems premature to draw integrative conclusions about
the role of hormones in potentiating anxiety, although there is some evidence
that T and 4-A are related to anxious symptomatology among males; reliable
associations among females have not been observed across studies. There are
multiple empirical questions to address in this domain (please see the
Suggestions for Future Research section). From a conceptual perspective, it is
useful to highlight the fact that hormones represent a ‘‘piece of the puzzle’’ as
they exhibit reciprocal effects on other hormones, behavior, and pubertal
development (Nelson, 2000). Therefore, the role of pubertal hormones in
anxiety development will likely be understood only if studied within the context
of a larger, biopsychosocial model (Brooks-Gunn et al., 1994; Booth, Johnson,
Granger, Crouter, & McHale, 2003).
Pubertal Timing and Anxiety. Although the literature is not uniform, com-
pared to pubertal status and hormones, pubertal timing evidences the most
consistent and robust associations with anxiety psychopathology, particularly
among females. Specifically, early-maturing females report elevations in
anxious symptoms (Dorn, Hitt, & Rotenstein, 1999; Graber et al., 2006;
Kaltiala-Heino et al., 2003; Silbereisen & Kracke, 1997; Sonis et al., 1985),
psychological distress (including anxiety symptoms; Ge, Conger, & Elder, 1996;
Hayward et al., 1997), panic attacks (Hayward et al., 1997) and anxiety
disorders when prospectively assessed (Graber et al., 2004). As an illustrative
example, in one of the most comprehensive studies completed to date,
Graber and colleagues examined perceptions of pubertal timing in relation
to psychiatric symptoms and interview assessed diagnoses among an
epidemiologically-defined mixed gender sample of 1,709 adolescents aged
14–18 years. Concurrent analyses (adjusted for chronological age) indicated
early maturing females evidenced elevated depressive symptoms as well as

disruptive behavior, eating, and major depressive disorders (but not anxiety
disorders). These associations were significant (with the exception of eating
disorders) at the follow-up assessment (approximately 10 years after the initial
evaluation). In addition, there appeared to be a ‘‘sleeper effect’’ for anxiety;
compared to their on-time counterparts, early maturing females were almost
twice as likely to meet criteria for an anxiety disorder (lifetime). There is no
evidence that late maturation is associated with anxiety among females.
Among males, the pattern is somewhat less consistent; studies have found
early maturation is associated with increased anxiety symptoms (Ge, Brody,
Conger, & Simons, 2006), state anxiety (i.e., a single question on which parti-
cipants self-reported the ease with which they became anxious or distressed;
Kaltiala-Heino et al., 2003), observations of manifest anxiety (i.e., trained
interviewers’ ratings of participants’ anxiety (e.g., tendency to worry) based
on direct observation and interviews with family and teachers, taken yearly
between the ages of 5 and 16; Peskin, 1967), and ‘‘internalized distress’’ (i.e., a
self-report of depression, anxiety, somatization, and other complaints such as
poor appetite, trouble sleeping, and overeating, as measured on the SCL-90-R;
Ge et al., 2001). In contrast, other reports suggest late maturation relates
positively to self-reported internalizing-type symptoms (including anxiety;
Graber et al., 1997) and observer rated social anxiety (Jones & Bayley, 1971).
In the studies conducted by Graber and colleagues discussed above, the follow
up study indicated that the positive association between late maturation and
internalizing symptoms does not persist among males and, in contrast to
females, pubertal timing does not prospectively predict anxiety diagnoses
(although late maturation was associated with current substance use and
lifetime disruptive behavior diagnoses at the follow-up assessment).
There are a number of individual and contextual factors that appear to
influence the association between pubertal timing and anxiety. For instance,
significant interactions have been observed between early maturation and life
stress (Ge et al., 2001), as well as early maturation and pre-pubertal internaliz-
ing symptoms (Hayward et al., 1997) in the prediction of anxious symptoma-
tology. Specifically, early maturing youth who also reported elevated life stress
and internalizing symptoms, relative to all other variable combinations,
evidenced the most anxiety. In a more fine-grained analysis, Ge and colleagues
(2001) examined pubertal timing as indexed by age at menarche in a four-year
longitudinal study of 216 females (7th through 10th grade). These authors
found evidence for the idea that early maturation exacerbates vulnerability to
psychological distress and that this process is influenced by a number of
variables. Specifically, among early maturing females only (cf., on-time
and late developers), early psychological distress relates positively to later
psychological distress, suggesting early maturation increases susceptibility to
continued emotional problems. In addition, early maturing females were more
likely to associate with deviant peers, which in turn predicted later psychologi-
cal distress. Finally, peer group composition moderated the timing-distress
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 further-
more 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 associa-
tion 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 environ-
ment 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
divorce; alcoholism; Hulanika, 1999) and childhood sexual abuse (Herman-

Giddens, 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 methodolo-
gical 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
symptomatology. Finally, pubertal timing, particularly early maturation

among females, appears to be a fixed marker for anxiety (e.g., Graber, 2003);
there is less compelling evidence for the effects of early or late maturation on
anxiety among males. As with pubertal status, our understanding of the effects
of off-time maturation will be most comprehensive when other variables, such
as the role of concomitant life stress, are considered. In addition, there is at least
some evidence indicating that early-life anxiety predicts early maturation,
suggesting the association between anxiety and pubertal timing is complex
and likely bi-directional, at least for some youth. Despite the overarching
promise of the emerging literature in this domain, the direction, magnitude,
and nature of the puberty-anxiety association have yet to be fully explicated.
Building on the suggestions for future research proposed in previous sections,
the next section offers additional ideas within the context of the overarching
limitations of the extant work.
Moving this Literature Forward: Conceptually-Driven Suggestions

for Future Research
We have three specific suggestions for future research, aimed at increasing the
methodological and conceptual sophistication of the literature. First, there is a
general need for more comprehensive and integrated assessments of puberty.
For instance, it will be important to replicate and extend findings from the
hormone literature suggesting a main effect of specific hormones on anxious
symptomatology (Granger et al., 2003). Here, methodologically innovative
approaches that involve multiple assessments across the course of puberty
will be critical for addressing questions related to the short-term (e.g., rapidly
escalating hormones; Apter, 1980) and long-term effects of hormonal changes
during puberty. In addition, because hormones affect each other in complex
ways (Johnson & Everitt, 2000) it will be important for researchers to obtain
indices of several different hormones and examine their independent and com-
bined effects on anxiety. Although expansion of the hormone-anxiety literature
would fill an important empirical gap, perhaps a more pressing challenge is to
evaluate the combined (additive and interactive) effects of pubertal status,
timing, and hormones on anxiety, as well as the impact of childhood anxiety
on pubertal maturation. An integrated approach to pubertal assessment is
critical here, as these aspects of puberty are fundamentally inter-related
(Brooks-Gunn et al., 1994). As an illustrative example, consider breast devel-
opment among females. This process is driven by gonadal hormones, which
may have an independent effect on anxious reactivity (Susman et al., 1991).
However, personal and social (e.g., parents; peers) reactions to a female’s
status on this relatively visible pubertal event may also contribute to anxiety
(Brooks-Gunn, 1984), particularly if she is ‘‘off-time’’ with respect to her
contemporaries (Brooks-Gunn & Warren, 1985). Of course, some of the
greatest yield in terms of improving our conceptual understanding of the

puberty-anxiety association will come from prospective assessments of the
inter-relations between the two across the course of puberty, beginning, ideally,
as young as five or six years so that the early stages of puberty are studied
(e.g., awakening of the adrenal glands; Dorn, Dahl et al., 2006) and questions of
the temporal association can begin to be addressed. In addition, advanced
statistical techniques, aimed at delineating the associations among childhood
anxiety, early puberty, and subsequent anxiety, are needed. Overall,
multi-modal, integrated, and longitudinal assessments of puberty will be neces-
sary to cultivate a comprehensive understanding the puberty-anxiety
association.
Related to this first point, the literature would also benefit from more
fine-grained assessments of anxiety. For instance, with some important
exceptions (e.g., Graber et al., 1997, 2004; Hayward et al., 1992, 1997), the
majority of available studies focus on associations among pubertal indices and
non-specific anxiety-relevant outcomes (e.g., anxiety as a part of a larger
internalizing construct). Although this approach yields useful information in
terms of the role of puberty in terms of general risk trajectories (e.g., internaliz-
ing versus externalizing), it does not speak to the aspects of puberty that may
potentiate fearful reactivity to distinct classes of stimuli (e.g., social; bodily;
mental; Craske, 2003) or the development of specific types of anxiety
psychopathology (e.g., social anxiety disorder; post-traumatic stress disorder).
In addition to the conceptual utility of such tests, data pertinent to the role of
puberty in the development of specific anxiety disorders would be useful for the
development of tailored preventative interventions (e.g., Mrazek & Haggerty,
1994; Zvolensky, Schmidt, Bernstein, & Keough, 2006). To this end, investiga-
tors could explore pubertal processes in the context of specific anxiety
outcomes, including symptom checklists that correspond to specific anxiety
disorders (e.g., generalized anxiety disorder subscale of the Screener for Child
Anxiety and Related Disorders; Birmaher et al., 1997) and diagnostic status
across the anxiety disorders as indexed via structured clinical interview. These
data would be extraordinarily useful in clarifying the nature and magnitude of
the puberty-anxiety association and would furthermore position researchers to
examine whether and how pubertal processes affect anxious symptomatology
across disorders (e.g., is puberty more likely to potentiate social anxiety as
compared to obsessive compulsive disorder?). As a complement to this
approach, there may be significant merit in integrating laboratory-based assess-
ments of anxiety processes (e.g., are aspects of puberty related to changes in
social anxiety as indexed via distress elicited by a laboratory-based social
evaluative task?; Ferrell, Beidel, & Turner, 2004). Laboratory-based methodol-
ogy has the advantage of allowing for the evaluation of ‘‘real-time’’ emotional
responding, thereby delimiting recall biases other types of reporting errors
common to affective processing (Zvolensky, Lejuez, Stuart, & Curtin, 2001).
Finally, the extant literature can be described as largely descriptive in nature,
focusing on whether a relation exists between puberty and anxiety. Building on
this foundation will require systematic testing of the putative ‘‘mechanisms of

action’’ underlying the link between puberty and anxiety. The broad-based
questions that need to be addressed include 1) precisely how does puberty
contribute to anxiety psychopathology (and vice versa)? 2) what individual
difference and social-contextual variables increase the explanatory power of
puberty-anxiety models? and 3) what types of ‘‘process variables’’ mediate the
puberty-anxiety association? Given the multi-faceted nature of both puberty
and anxiety, there are multiple systematic research programs that will converge
to address these questions. Consistent with our suggestion to develop the
literature on the role of puberty in the development and maintenance of specific
anxiety-relevant outcomes, we will utilize panic disorder (PD) as the outcome
of interest to exemplify this issue. However, because pubertal timing is a
non-specific fixed marker, it is our hope that investigators with expertise in
other types of anxiety psychopathology (e.g., post-traumatic stress disorder;
social anxiety disorder) will extrapolate ideas relevant to their own programs of
research from the current discussion.
Panic disorder is a common, severe, and chronic condition associated with
substance use disorders, poor physical health outcomes, social/occupational
disability, and high rates of healthcare utilization (APA, 2000; Greenberg et al.,
1999). Importantly, adolescence is a critical developmental period during which
panic problems first manifest, making it an important stage to study in terms of
panic-related problems (e.g., Ollendick, Mattis, & King, 1994; Von Korff,
Eaton, & Keyl, 1985). The hallmark characteristic of PD is fearful reactivity
to bodily sensations, which is posited to result, at least in part, from interocep-
tive learning (Craske, 2003). Specifically, the repeated pairing of somatic cues
and personal threat/anxiety results in bodily arousal becoming a phobic
stimulus (Bouton, Mineka, & Barlow, 2001). Puberty may be a ‘‘critical period’’
for such interoceptive learning. Specifically, puberty is replete with bodily
oriented changes, some of which, as discussed earlier, may be conceptualized
as unpredictable, uncontrollable, and undesirable bodily events (e.g., sponta-
neous erection; Omar et al., 2003). Importantly, an array of studies using
diverse methodological procedures have demonstrated that uncontrollable
and unpredictable aversive events are associated with heightened anxiety states
and bodily arousal (Maier & Seligman, 1976; Mineka & Kihlstrom, 1978;
Sanderson, Rapee, & Barlow, 1989; Sapolsky, 1990; Sapolsky, Alberts, &
Altman, 1997; Zvolensky, Eifert, & Lejuez, 2001). As youth traverse puberty,
they are increasingly exposed to somatic events that may result in
panic-relevant interoceptive learning. This hypothesis predicts that puberty,
reflective of adolescents’ relative degree of exposure to such learning trials,
will be associated with elevated panic symptomatology. However, because
puberty per se is not a malleable risk factor (all youth experience puberty, but
not all youth develop clinical problems [Graber, 2003]), investigators are tasked
with identifying other variables that may explain the puberty-panic association.
To identify risk factors that are malleable and therefore subject to interven-
tion it is necessary to identify the specific mediators and moderators of the
puberty panic association. Specifically, identification of mediators/moderators

will 1) elucidate the causal chain that links pubertal effects to panic outcomes,
2) point researchers toward modifiable factors that will aid in the prevention of
panic, and 3) increase model specificity (e.g., anxiety-relevant mediators and
moderators such as fear of negative evaluation may improve the prediction of
anxiety problems, whereas depression-relevant mediators/moderators such as
dysfunctional attitudes will likely aid in the prediction of depressive outcomes).
Discussions of some candidate mediators and moderators of the puberty-panic
association are provided below.
Mediators temporally follow and are correlated with a risk characteristic (in
this case, pubertal effects), and attenuate the association between the risk
characteristic and the outcome (i.e., anxiety; Kraemer et al., 2001). One poten-
tial mediator may be the fear-relevant somatic learning that occurs during the
course of puberty (see Fig. 1).This hypothesis requires an assessment of the
posited mediating process. To this end, it would be helpful to design a
psychometrically sound self-report index of fear-relevant experiences with
puberty-related bodily sensations (e.g., ‘‘I was scared when I first started having
menstrual cramps’’). With a valid and reliable index, researchers would be well
positioned to address questions such as whether fear-relevant learning changes
across the course of puberty and whether such learning accounts for observed
associations between puberty and panic. Another class of conceptually inter-
esting mediators, given their effects on neurotransmitter systems hypothesized
to be involved in mood regulation (McEwen, 1991), are the gonadal steroids
associated with puberty. For instance, estrogen modulates the serotonin
neurotransmitter system in a number of ways, including effects on serotonin
synthesis and receptor density (Biegon et al., 1990). Animal research suggests
puberty ushers in changes in the serotonin system reaction to stress, particularly
among females. For instance, following separation, post-pubertal female rhesus
monkeys, compared to males, evidence higher levels of 5-Hydroxyindoleacetic
acid (5-HIAA), a primary metabolite of serotonin and an index of the
organism’s level of serotonin (Higley, Suomi, & Linnoila, 1990). This difference
is not apparent prior to puberty, suggesting gonadal steroids may potentiate the
stress response among pubertal females (Sanborn & Hayward, 2003).
Time
Puberty Panic-Related Problems
Mediators
(e.g., fear-relevant
learning; gonadal
steroids)
Fig. 1 Mediators of the puberty-panic association

It also is important to identify potential moderators of the puberty- panic

association. These variables precede and are uncorrelated with aspects of
puberty (Kraemer et al., 2001). An important potential individual-difference
factor that could moderate the puberty panic association is anxiety sensitivity
(AS), or the fear of anxiety and anxiety-related sensations (Reiss & McNally,
1985), which has been theoretically (Barlow, 2002) and empirically (Hayward,
Killen, Kraemer, & Taylor, 2000) supported as a key cognitive vulnerability
factor involved in the development of anxious responding to bodily sensations –
a hallmark characteristic of panic attacks. From a conceptual perspective, AS
might be expected to amplify the panic-relevant learning that occurs during
puberty. That is, compared to low AS youth, adolescents with elevated AS may
perceive the bodily events that occur during puberty (e.g., early breast
development; menstrual discomfort/accidents; autonomic arousal secondary
to hormonal shifts) as more threatening. Across the course of puberty,
vulnerable youth (i.e., high AS youth) may more readily learn that physical
sensations are aversive and anxiety-relevant, possibly resulting in a panic
attack. In contrast, adolescents low in AS may be less susceptible to
panic-relevant interoceptive learning during puberty because they are less
fearful of bodily sensations (see Fig. 2).
In addition to individual-difference characteristics, there are a number of
panic-relevant social/contextual moderators that would be theoretically
interesting to investigate. For instance, there is emerging evidence for the role
of parenting behavior in increasing the ‘‘threat value’’ of bodily sensations via
direct (e.g., informational transmission), or indirect (e.g., modeling) reinforce-
ment of fearful responding to somatic cues (Craske & Rowe, 1997; Ehlers, 1993;
Muris, Merckelbach, & Meesters, 2001; Watt & Stewart, 2000). Thus, a parent
Time
Moderator
(e. g., youth HIGH in
anxiety sensitivity)
Presence of Panic-
Puberty Related Problems
Absence of Panic-
Related Problems
Moderator
(e. g., youth LOW in
Fig. 2 Moderators of the puberty-panic association

who communicates fear in the context of bodily arousal (e.g., dizziness

secondary to a childhood fever) may inadvertently facilitate the child’s pairing
of fear and interoceptive experiences. Subsequently, the bodily perturbation
characteristic of puberty (particularly when such experiences are off-time com-
pared to peers) may be experienced as panic-relevant. In this example, the
moderating effect of specific parenting behaviors would be expected to increase
the likelihood of panic-relevant learning during puberty. Another conceptually-
relevant social-contextual moderator is pre-pubertal traumatic event exposure,
such as childhood sexual abuse. A number of studies suggest a link between
significant stress and changes (e.g., hypersecretion of corticotropin-releasing
hormone) to the hypothalamic-pituitary-adrenal (HPA) axis (e.g., Miller,
Chen, & Zhou, 2007). Such changes are thought to directly increase
vulnerability to psychopathology; this outcome may be more likely among
females because of the role estrogen plays in enhancing the HPA stress
response. When this vulnerability is combined with the normative HPA axis
changes that occur during puberty, Sanborn and Hayward (2003) suggest that
impairments in HPA functioning may reach a threshold, thereby putting
trauma-exposed, pubertal females at particular risk for anxiety psychopathol-
ogy (including panic).
Together, although the discussion was focused on panic-related problems,
the third general suggestion is for researchers to complement the available
descriptive research and work toward identifying key mediators and
moderators of the puberty-anxiety association. Understanding the processes
that influence the association between puberty and anxiety will be critical from
a public health perspective. For instance, if research bears out the prediction
that panic-relevant learning mediates the association between puberty and
panic, high risk youth (e.g., early maturing females) could be identified in a
primary care setting and presented with a brief intervention focused on reducing
fear of bodily sensations and encouraging interoceptive exposure to attenuate
the effects of subsequent panic-relevant leaning trials (e.g., latent inhibition;
Bouton et al., 2001). However, at this stage of research development, the key
tasks relate to clarifying the nature of the puberty-anxiety association. To this
end, the role of individual-difference and social-contextual factors, as well
as variables that may mediate the puberty-anxiety relation need to be
systematically and comprehensively addressed, irrespective of what type of
anxiety serves as the outcome variable.
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),
the process of puberty appears to enhance anxiety-related symptoms, although

there are a number of important gaps in the research base on which researchers
could focus their investigative efforts, including improved methodological
approaches and more sophisticated and comprehensive conceptual models.
Nonetheless, this is a promising area of research; we hope the suggestions
presented here will stimulate what we conceptualize as important future work
aimed at clarifying the association between puberty and anxiety among youth.
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Anxiety, Anxiety Disorders,
and the Menstrual Cycle
Sandra T. Sigmon and Janell G. Schartel
Fluctuations in mood, bodily sensations, and behavior have long been

associated with the premenstrual phase of the menstrual cycle. Research has
found that women with psychological disorders often experience symptom
exacerbation and psychiatric admission rates are increased during the
premenstrual phase (e.g., Hendrick, Altshuler, & Burt, 1996). There are a few
studies focusing on the follicular or intermenstrual phase of the menstrual cycle
but the majority has focused on the premenstrual phase. This chapter covers the
empirical research on the relationship between anxiety, anxiety disorders and
the premenstrual phase of the menstrual cycle; however it is not an exhaustive
review of the literature on menstrual cycle effects. There is a significant
premenstrual literature on depression and other mood states; however this
chapter focuses on anxiety.
The complex relationship between anxiety and menstruation is presented by
(1) identifying the continuum of experience of premenstrual anxiety, (2) addres-
sing issues in assessment and treatment, (3) reviewing the literature on the
premenstrual experience of normal and clinical samples of women, (4) discussing
current models used to explain this relationship, and (5) briefly reviewing how
health behaviors are influenced by the menstrual cycle. Anxiety is discussed both
as a common symptom of menstrual distress and as clinical disorders that are
influenced by the menstrual cycle. Limitations of the current literature and
suggestions for future research are also presented.
The Menstrual Cycle
Phases of the normal menstrual cycle are typically based on a 28-day timeline
that corresponds to changing hormone levels in a woman’s body (e.g., Hillard &
Deitch, 2005). The normal range of women’s cycles varies from 24–35 days. The
Sandra T. Sigmon
University of Maine, 5742 Little Hall, Orono, ME 04469-5742, Tel: 207-581-2049,
Fax: 207-581-6128
sandra.sigmon@umit.maine.edu
Ó Springer 2008
182 S. T. Sigmon, J. G. Schartel
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 1–13),
ovulation (days 13–14), and luteal (days 15–28). Days 1–7 represent menses and
days 21–28 are generally considered the premenstrual or late luteal phase of the
cycle.
Premenstrual Symptoms and Disorders
Premenstrual Symptoms. Menstrual cycle fluctuations in mood and behavior

have been addressed for over 2500 years (e.g., Hippocrates [600 B.C.]
described premenstrual complaints) in Western and non-Western cultures
(e.g., Chrisler & Caplan, 2002; Hylan, Sundell, & Judge, 1999). Epidemiolo-
gical surveys suggest approximately 75% of menstruating women experience
premenstrual symptoms each month (APA, 2000). Approximately 40% of
women experience premenstrual and menstrual symptoms of a mild nature
with only 2–10% reporting severe symptoms (e.g., Logue & Moos, 1986).
Over 150 symptoms have been identified with the premenstrual phase of the
menstrual cycle, the most common domains being affective (e.g., depression,
anxiety, irritability, mood lability), somatic (e.g., bloating, breast tenderness),
and behavioral (e.g., difficulty concentrating, overeating). Symptoms of
anxiety include physiological sensations, emotional and cognitive symptoms,
as well as behavioral symptoms. Typical anxiety symptoms associated with
the premenstrual phase include muscle tension, stomach pain, feeling restless
or irritable, difficulty concentrating, and avoidance behaviors.
Premenstrual Syndrome. There are no universal or uniform definitions for
premenstrual syndrome [PMS] (e.g., Johnson, 2004), but the defining factor is
typically presence of symptoms exclusively during the late luteal phase. To
assist researchers and foster more uniformity in PMS research, the American
College of Obstetricians and Gynecologists (ACOG, 2000) proposed the
following criteria: symptoms must only occur five days prior to menses onset,
remit by day 4 of menses and symptoms must be absent during the follicular
phase (or symptom free for at least one week). These criteria also require
prospective reporting for 2 consecutive cycles to document the pattern. There
are two consistent aspects of PMS examined in the literature; (1) the timing of
the symptoms, and (2) the symptoms must be distressing and interfere with
normal functioning.
Premenstrual Dysphoric Disorder. A controversial debate ensued when Late
Luteal Phase Dysphoric Disorder (LLPDD) was included in the DSM-III-R in
1987 and continued with the inclusion of Premenstrual Dysphoric Disorder
(PMDD) in DSM-IV (APA, 1994). Women with LLPDD reported greater
affective symptoms during the premenstrum than controls; however anxiety
symptoms do not reach the level of severity reported by women diagnosed with
Anxiety and the Menstrual Cycle 183
anxiety disorders such as panic disorder (Veeninga, de Rutter, & Kraaimaat,

1994). Although the estimates for women experiencing PMS symptoms are some-
what high, research indicates that only 3–8% of women may meet diagnostic
criteria for PMDD (e.g., APA, 1994; Halbreich, Borenstein, Pearlstein, & Kahn,
2003). However, subsyndromal levels that may also result in severe impairment are
estimated to occur in 13–18% of women.
Currently, PMDD is diagnosed under ‘‘Depressive Disorder Not Otherwise
Specified’’ and appears under ‘‘Criteria Sets and Axes Provided for Further
Study’’ (APA, 2000). There are four major criteria for a diagnosis of PMDD to
be assigned. First, at least 5 of 11 identified symptoms must meet the same criteria
used for PMS. There are four core affective symptoms (depressed mood, anxiety,
affective lability, and persistent irritability or anger), at least one of which must be
present for diagnosis. This symptom pattern must occur in most menstrual cycles
for at least one year. The second criterion for PMDD requires that the symptoms
cause marked interference with work, school, social activities or relationships.
Third, the symptoms cannot be an exacerbation of another diagnosable disorder.
For example, a diagnosis of PMDD would exclude the many women with panic
disorder who experience an exacerbation of their panic symptoms premenstrually.
And finally, the symptom pattern must be verified by at least two consecutive
cycles of prospective daily symptom ratings for two symptomatic cycles.
Issues and Methods of Assessment
Retrospective versus Prospective Reporting. The research that exists on

pmenstrual cycle effects in general has yielded inconsistent results. One
reason may be that early research on menstrual cycle effects relied almost
exclusively on women’s retrospective self-reports. Women often overestimate
the exacerbation of their anxiety symptoms when asked to recall their symp-
toms retrospectively (e.g., Endicott & Halbreich, 1982; Rubinow, 1985).
Indeed, many of the retrospective studies on anxiety and the menstrual
cycle have found strong cyclic effects in that anxiety symptoms worsen
during the premenstrum (Breier, Charney, & Heninger, 1986; Cameron,
Kuttesch, McPhee, & Curtis, 1988; Williams & Koran, 1997). Retrospective
accounts of the premenstrual experience have been hypothesized to reflect a
reliance on stereotypical and cultural biases regarding the menstrual cycle
(e.g., McFarland, Ross, & DeCourville, 1989; Ruble, 1977).
Prospective assessment of menstrual symptoms has addressed some of the
concerns stemming from retrospective measures, yet has simultaneously
presenting challenges to retrospective results, often finding no significant
fluctuations premenstrually (e.g., Stein, Schmidt, Rubinow, & Uhde, 1989).
Prospective studies that have shown menstrual fluctuations in anxiety disorder
symptomatology suggest much smaller fluctuations than have been found in
retrospective studies (Cameron et al., 1988; Cook et al., 1990). In the discussion
of anxiety that follows, research will be discussed in terms of retrospective

versus prospective methodologies.
Assessment Measures. The gold standard for assessing any symptom across
the menstrual cycle is prospective monitoring. Thus, fluctuations in anxiety
across the cycle can be tracked by having women repeatedly complete any state-
dependent measure of anxiety or visual analogue scales focused for specific
symptoms (e.g., frequency of panic attacks or obsessive-compulsive rituals).
As one of the core symptoms of PMS and PMDD, anxiety and anxiety
fluctuations across the menstrual cycle are often assessed within that context.
There are several empirically supported measures for PMS and PMDD, all of
which include items assessing anxiety (see Table 1). Readers are encouraged to see
Haywood, Slade, and King (2002) for a review of retrospective and prospective
measures of symptoms across the menstrual cycle. On retrospective measures,
women are asked to consider either several recent menstrual cycles or to report on
their typical experience across the menstrual cycle. Prospective measures typically
take the form of a ‘‘daily diary,’’ asking women to indicate if a symptom did or did
not occur or rate on a Likert scale the severity of individual symptoms each day.
Some measures, such as the Premenstrual Tension Rating Scale (Steiner, Haskett,
& Carroll, 1980) include both a self and observer rating form. Researchers and
clinicians need to be aware of the format and the intended purpose of the
assessment, as not all assessment measures are diagnostic in nature.
A major difficulty with requiring prospective analysis over two months is
time and effort to complete the measures. Many women are unable to complete
daily ratings over several months’ time and many of the rating forms are
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 Diagnostic and Treatment Both
and observer forms (Steiner et al., 1980) Response – PMS
Daily Rating Form (Endicott et al., 1986) Assess Symptoms – PMS P
Premenstrual Symptom Diary Diagnostic – PMS P
(Thys-Jacobs et al., 1995)
Calendar of Premenstrual Experiences Diagnostic – PMS P
(Mortola et al., 1990)
Menstrual Distress Questionnaire (Moos, Assess Symptoms – Both R
1968)
Menstrual Distress Diagnostic – PMS; P
Questionnaire – Today version (Blake et al., Treatment response
1998)
Premenstrual Assessment Form (Halbreich Assess Symptoms – Both R
et al., 1982)
Daily Record of Severity of Problems Diagnostic – PMDD P
(Endicott et al., 2006)
Daily Symptom Rating Scale (Taylor, 1979) Assess Symptoms – Both P
lengthy. Researchers have made efforts to validate short forms of empirically

supported measures with limited success (Haywood et al., 2002). As such, it is
common clinical practice for these forms to be adapted or for clinicians to create
unique versions of these forms to suit the needs of their individual clients.
However, clinicians should take several things into consideration when refor-
matting assessment measures. First, because of validity issues noted above, it is
recommended to rate symptoms on a severity scale rather than in yes/no format
(Freeman, 2003). Symptoms most relevant or most distressing to the client
should be the focus of monitoring. Consolidating information into as few
pages as possible increases compliance, reduces errors and minimizes data.
One common way to do this is to have a monthly page, much like a calendar,
rather than daily pages to record information (Freeman, 2003). Most impor-
tantly, women must make note of the first day of bleeding so that ‘‘menstrual
time’’ can be established and accurate comparisons made between the follicular
and luteal phases.
Co-morbidity versus Premenstrual Exacerbation. With regard to assessment
of menstrual-related symptoms, three options need to be considered: (1) is
anxiety manifesting as a primary symptom of a menstrual problem, (2) are
symptoms of an anxiety disorder worsening premenstrually, or (3) are
symptoms consistent with a comorbid menstrual problem and anxiety disorder.
Differentiating between comorbidity and premenstrual exacerbation (PME)
may be one of the most difficult challenges facing researchers and clinicians.
Anxiety disorders and menstrual difficulties are highly comorbid (see below).
Specifically, Kim and colleagues (2004) found that panic disorder occurs in
25% of PMDD samples, social phobia in 19–23%, OCD 11–13% and GAD in
4–38% across studies. Moreover, many women with anxiety disorders report
premenstrual exacerbation (PME) of their symptoms. Previous research has
found that women with Generalized Anxiety Disorder (GAD), Panic Disorder
(PD), and simple phobia (SP) report premenstrual worsening of their anxiety
symptoms (e.g., Busch, Costa, Whitehead, & Heller, 1988). Moreover, 45–50%
of psychiatric admissions for women occur during the premenstrual phase (e.g.,
Targum, Caputo, & Ball, 1991).
Distinguishing PME from comorbidity presents challenges for women with
PMS. Stout and colleagues (1986) found that in a sample of 223 women seeking
treatment for PMS, 81% of the women had at least one psychiatric diagnosis
lifetime with 65% meeting criteria for phobia and 16% meeting criteria for
OCD. Hsiao, Hsiao, and Liu (2004) examined the prevalence of PMS and
premenstrual exacerbation (PME) in 200 Chinese women and found that
78% of the women with GAD and 68 % of the women with PD met criteria
for PMS. In addition, 52% of the women with GAD and 36% of the women
with PD reported PME of their anxiety symptoms.
The distinction between comorbidity and PME might stem from controversy
surrounding the diagnostic validity of PMS and PMDD. Some researchers
argue that PMDD is a distinct disorder with irritability and mood lability as
defining features (e.g., Landén & Eriksson, 2003) rather than a subtype of
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 women’s
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 symp-
toms 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 indivi-
dual women’s 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 nonconse-
cutive days. Thus, the literature suggests that in well-defined PMS samples,
symptoms persist across time and can cause significant impairment in women’s
lives even if two consecutive symptomatic cycles are not established during the
diagnostic period.
Research on Premenstrual Anxiety
Normal Samples. Normal samples of women have been studied extensively to

ascertain the level of distress associated with the premenstrual phase. It should
be noted that although most studies indicate a normal sample, typically no
assessment has been made of pre-existing levels of trait anxiety or anxiety
disorders. Studies utilizing retrospective methodology have demonstrated
increases in negative affect (depressed mood and anxiety in particular) and
increases in severity of physical symptoms during the premenstrual phase
compared to the intermenstrual phase of the cycle (e.g., Boyle & Grant,
1992). Some prospective studies of menstrual cycle fluctuations in affective
and somatic symptoms in normal populations have shown premenstrual effects
(e.g., Gallant, Hamilton, Popiel, Morokoff, & Chakraborty, 1991) whereas
others have failed to find increased symptoms during the premenstrual phase
(e.g., Slade, 1984). When normal women report more anxiety during the
premenstrual phase, the level of anxiety appeared to be more comparable to
women who are mildly stressed, not to a clinical sample (Golub, 1976). This
equivocal pattern was not clarified whether or not participants were informed
of the true purpose of the study (e.g., Gallant et al., 1991).
Although the majority of individuals who seek treatment for PMS are
typically in their mid 20’s to mid 30’s, Hillard and Deitch (2005) found that
75% of older adolescents who visited a health care provider perceived a
problem with menstruation. However, Golub and Harrington (1981) found
no significant differences between premenstrual and menstrual physical or
mood symptoms in 158 15–16 year old females. Moreover, they did not
significantly differ from comparisons to same-age males during the same time
period. In a prospective study (Layton, 1989), adolescent females reported
elevated rates of state anxiety during the premenstrual phase compared to the
menstrual phase. Although the findings for premenstrual worsening of mood
symptoms vary in adolescent samples, it appears that premenstrual complaints
are common across different age samples.
Large community surveys have also been conducted to determine if women
experience greater distress during the premenstrual phase of the menstrual cycle
(e.g., Strine, Chapman, & Ahluwalia, 2005). As part of the 2002 National
Health Survey, over 11,000 women from ages 18–55 completed a computer-
assisted personal interview. Approximately 19% of the sample indicated men-
strual difficulties over the past year with white non-Hispanic women reporting
more difficulties than Hispanic women and 16% reported interference from
menstrual problems. In addition, women who reported menstrual problems
were more likely to report psychological distress including anxiety, sleep
difficulties, and negative health behaviors (e.g., smoking, drinking, obesity).

Unfortunately, no associations between distress and cycle phase were assessed.
A growing area of research on menstrual cycle effects examines physiological
differences in normal women during phases of the menstrual cycle. Researchers
have found phase differences in hypothalamic pituitary axis (HPA) functioning,
specifically related to cortisol and DHEA (i.e., dehydroepiandrosterone) levels
(Symonds, Gallagher, Thompson, & Young, 2004). Cortical activity has also
been found to fluctuate across menstrual cycle phase in samples of normal
women (Asso & Braier, 1982; Protopopescu et al., 2005). It has been suggested
that varied levels of estrogen and progesterone across the menstrual cycle may
affect neuronal circuitry (Protopopescu et al., 2005). Asso and Braier (1982)
found increased skin conductance during the premenstrual phase compared to
the intermenstrual phase in a normal sample of women. It is clear that more
research needs to be conducted regarding normal menstrual cycle psychophy-
siology in order to inform how such processes may be impaired in women with
anxiety disorders.
Premenstrual Anxiety in PMS Samples. Similar to the findings in normal
samples, there are mixed results in women self-reporting PMS with retrospec-
tive and prospective methods. Women with PMS retrospectively report higher
levels of state (e.g., Haskett, Steiner, & Carroll, 1984; Mira, Vizzard, &
Abraham, 1985) and trait anxiety (e.g., Giannini, Price, Loiselle, & Giannini,
1985; Watts et al., 1980) during the premenstrum. However, prospective
self-reports of premenstrual changes have yielded inconsistent results (e.g.,
Sampson & Jenner, 1977; Taylor, 1979). In a sample of 69 undergraduate and
community women, Kessel (2000) found women who experienced significant
premenstrual changes (>30%) reported higher levels of anxiety compared to
women who did not report severe changes. Christensen and Oei (1989) found
that women with PMS prospectively reported more anxiety, depression, and
automatic negative thoughts than controls during the premenstrual phase.
Magos, Brincat and Studd (1986) found that retrospective and prospective
reports of women seeking treatment for PMS were similar, with 61–85%
reporting symptoms consistent with PMS. In contrast, Hardie (1997) found
that none of the retrospective reports of PMS from their sample of 101 women
were confirmed by 2 prospectively monitored cycles. Fluctuations in mood were
better predicted by interpersonal relationship quality and stress level than cycle
phase. Thus, anxiety fluctuations across the menstrual cycle in PMS popula-
tions are just as inconclusive as those in normal samples.
Other research has focused on assessing attributions for PMS symptoms (e.g.,
Veeninga & Kraaimaat, 1995). For example, women with PMS were more likely
than controls to attribute symptoms to their cycle when in the premenstrual
phase than when they were in the intermenstrual phase. Women with PMS also
reported more menstrual symptoms both premenstrually and during the inter-
menstrual phase (Veeninga & Kraaimaat, 1995). However, a large number of the
women with PMS also met criteria for an anxiety disorder and thus this study
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 woman’s reproduc-
tive 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).
Menstrual Cycle Effects on Anxiety and Anxiety Disorders
Anxiety Sensitivity. Anxiety sensitivity (AS; i.e., fear of symptoms of anxiety

and its consequences; Reiss & McNally 1985) has been well-studied as a
vulnerability to anxiety disorders, panic disorder in particular (e.g., Schmidt,
Lerew, & Trakowski, 1997; Weems, Hayward, Killen, & Taylor, 2002) and
gender differences in anxiety sensitivity may account for some of the gender
differential in anxiety disorder prevalence rates. In a series of studies, Sigmon
and colleagues have investigated the relationship between AS, self-reports of
menstrual symptoms, gender roles, somatic beliefs, and psychophysiological
reactions to anxiety stimuli across the menstrual cycle (Sigmon, Dorhofer,
Rohan, & Boulard, 2000; Sigmon, Fink, Rohan, & Hotovy, 1996; Sigmon,
Rohan, Boulard, Dorhofer, & Whitcomb, 2000).
In the first study (Sigmon et al., 1996), women high or low in anxiety sensi-
tivity were assessed during either the intermenstrual or premenstrual phase.
Results indicated that women high in AS reported more severe premenstrual
symptoms, more state and trait anxiety, and exhibited greater skin conductance
responses to auditory anxiety-provoking stimuli than women low in AS, regard-
less of current cycle phase. Researchers proposed that women high in anxiety
sensitivity are more likely to focus on internal stimuli, have a higher nonspecific
arousal level, and negatively interpret normal bodily sensations. In addition to
confirming greater premenstrual distress reported by women high in AS, two

subsequent studies (Sigmon, Rohan et al., 2000; Sigmon, Dorhofer, et al., 2000)
suggested that women high in AS may demonstrate more gender specificity
(endorsing more feminine and less masculine characteristics), illness attitudes,
and may be more vigilant to bodily sensations than women low in AS.
The above results led Sigmon and colleagues to propose the menstrual reac-
tivity hypothesis (Sigmon, Dorhofer, et al., 2000) which states that certain women
(e.g., high in AS, women with asthma) are more likely to report greater menstrual
distress due to accurate reports of symptoms, expectations about the meanings of
symptoms, hypervigilance to bodily sensations, and increased psychophysiologi-
cal responding in response to anxiety stimuli. The menstrual cycle may represent a
cyclical stressor that provides increased opportunities for self-focus, symptom
attribution and interpretation. The authors suggest that researchers should rou-
tinely assess for AS and for gender-related variables that could add to a more
complete account of the relationship between the menstrual cycle and anxiety.
Although existing research on menstrual effects and anxiety sensitivity has
focused on AS as a continuous variable, recent research has found support for a
latent structure that is taxonic (i.e., categorical in nature; e.g., Schmidt, Kotov,
Lerew, Joiner, & Ialongo, 2005; Bernstein et al., 2005). In general, the taxon
accounts for more variance than variables such as body sensations and body
vigilance and possesses incremental validity in predicting future panic attacks.
Bernstein and colleagues (2005) suggest that taxon criteria may differ across
gender and population, pointing to the need for more research to determine if
AS has a latent taxonic structure for women experiencing PME of an anxiety
disorder and women for whom anxiety is the core symptom of a menstrual
disorder. It is possible that taxon identification may be useful in identifying
women who are vulnerable to menstrual cycle influences on anxiety and
formulating successful treatment strategies.
Premenstrual Symptoms and Anxiety Disorders
Anxiety represents a prominent premenstrual symptom for some women and

comorbidity between premenstrual and anxiety disorders is high (e.g., Fava
et al., 1992), however the course of specific anxiety disorders across the
menstrual cycle is less clear. Few studies have investigated if and how specific
anxiety disorders are affected by the menstrual cycle and that which does exist
is complicated by issues surrounding retrospective and prospective recording.
Panic Disorder. Although evidence suggests that panic disorder symptoms can
be exacerbated premenstrually (e.g., Klein, 1993; Cameron et al., 1988), retro-
spective and prospective self-reports of menstrual symptoms are inconsistent.
Given the similarity between certain premenstrual symptoms (e.g., muscle tension,
hot flashes, increases in breathing rates, anxiety) and symptoms of panic, the
ability to distinguish between the exacerbation of panic symptoms or the
experience of premenstrual symptoms is complicated, regardless of the methodol-

ogy 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 experi-
ence 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 women’s 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 women’s 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,
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 women’s experi-
ence 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 women’s experience of anxiety is warranted.
Models of Anxiety-Premenstrual Cycle Phase Interaction
Feminist Views. Chrisler and Caplan (2002) provide an excellent overview of

the evolution of scientific thought regarding PMS. The authors discuss the
implications surrounding the medicalization of the menstrual cycle and
the promulgation of ‘‘the belief that the (menstrual) cycle itself is a problem to
be solved’’ (p. 283). Ussher (2003) also discusses hegemonic truths that
need to be carefully scrutinized: ‘‘PMDD as a thing that can be objectively
defined and measured; PMDD is pathology to be eradicated; PMDD is caused
and treated by one factor; PMDD as a bodily phenomenon, and PMDD causes
women’s symptoms’’ (p. 131). In a similar vein, Clare (1983) argues that it may
be unrealistic to assume that women would be symptom free during any given
menstrual cycle given that the symptoms that are most reported are ubiquitous
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 Mellédo &
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; Hammarbäck, Damber, &
Bäckström, 1989). Thus, researchers have proposed that there may be differ-
ences 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 60–70% of women with panic disorder and with LLPDD experi-
ence 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 responsive-
ness to alprazolam in women with PMS (e.g., Facchinetti et al., 1998). Although
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 diag-
nosed 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 incor-
porating social and psychological processes are surfacing as it has become clear
that biological explanations alone cannot suffice (e.g., Anson, 1999). A woman’s
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., Marván & Cortés-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.
Treatment Approaches for Premenstrual Anxiety
There are several treatment options available for women who experience
significant levels of anxiety either as a result of PME or as a core symptom of
PMS or PMDD. Efficacious treatments include lifestyle changes, medications,
hormone supplements, and psychotherapy. Researchers have suggested that

when there are questions of comorbidity, patients should be treated first for the
primary anxiety disorder, as many premenstrual symptoms will resolve with its
effective treatment and additional treatment for residual premenstrual
symptoms can then be provided (e.g., Steiner & Born, 2000).
Lifestyle changes, stress management and/or dietary supplements (e.g.,
Clayton, 2003; Steiner & Born, 2000) are often recommended as the first
step in treatment. Establishing and maintaining a regular sleep-wake cycle
(Clayton, 2003) and regular exercise may reduce the severity and impact of
both physical symptoms and anxiety during the premenstrum (e.g., Kirkby &
Linder, 1998; Hightower, 1997). Studies have found particular positive effects
of exercise on anxiety disorders such as OCD (Lancer, 2005) and PTSD
(Manger, 2005).
Various forms of psychotherapy have been found to be helpful in
alleviating menstrual difficulties and may have implications for anxiety symp-
toms. Although random controlled trials on psychotherapeutic interventions
for menstrual-related problems are few, the existing research is promising.
Relaxation training has been shown to be superior to a distracting activity
such as leisure reading and to symptom monitoring (Goodale, Domar, &
Benson, 1990) and coping skills groups have demonstrated superior efficacy
to relaxation and hormone therapy (Morse, 1999). Cognitive-behavior
therapy for PMS has demonstrated effectiveness in both group and individual
format (Morse, 1999; Slade, 1984) when compared to placebo treatments
(Kirkby, 1994) and wait list control (Blake, Salkovskis, Gath, Day, & Garrod,
1998). Educational groups have demonstrated effectiveness when compared to
CBT groups (Christensen & Oei, 1995).
As with most forms of CBT, it is critical that a strong, collaborative
therapeutic alliance between patient and therapist be established. Most
women who experience menstrual-related problems typically adhere to medical
explanations for their problems (Hunter, Ussher, Cariss, Browne, Jelley, &
Katz, 2002). Thus, it is important for therapists to explain the biopsychosocial
model (presented in next section) as an alternative, more complete framework
from which women can understand their symptoms and their impact on their
lives (Blake et al., 1998). When presented with a biopsychosocial model, most
women find it an acceptable alternative to traditional medical explanations and
subsequently report more active cognitive and behavioral coping strategies
(Hunter et al., 2002). Specific components of CBT for PMS typically consist
of teaching coping skills, identifying symptom triggers and maintaining factors,
identifying and challenging cognitive distortions, and implementing behavior
change strategies (Blake et al., 1998). Other therapies include cognitive restruc-
turing and assertiveness training (Christensen & Oei, 1995).
Women receiving CBT for PMS have shown greater reductions in symptoms
and irrational thinking compared to placebo control therapy through 9-month
follow up (Kirkby, 1994) and reductions in impairment, depressive symptoms,
and prospective ratings of both physical and mood symptoms when compared to
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, & O’Brien, 2000). Clearly, more research is needed
on what components of psychological and biological treatments are effective
for anxiety symptoms across the menstrual cycle.
Health Behaviors and the Menstrual Cycle
Health behaviors seem to be significantly impacted by anxiety and menstrual

distress. It is well-established that anxiety problems are associated with negative
health behaviors such as drug and alcohol use (e.g., Strine, Chapman, Kobau,
& Balluz, 2005). Unfortunately, very little research has been done with specific
regard to anxiety across the menstrual cycle and health behavior, thus this brief
section is intended to provide an overview of how general symptoms associated
with menstrual distress influence women’s behavior.
Results of the National Health Interview Survey indicated that women
reporting menstrual problems were more likely to report frequent anxiety,
nervousness, restlessness and were also more likely to engage in health risk
behaviors (e.g., smoking, drinking, overeating) than women reporting no
menstrual problems (Strine, Chapman, & Ahluwalia, 2005). Both physical
and affective menstrual symptoms have been positively associated with
smoking (e.g., Sloss & Frerichs, 1983), alcohol use (e.g., Tobin, Schmidt, &
Rubinow, 1994), and caffeine intake (e.g., MacKay, 1985). Affective symp-
toms may be more strongly associated with negative health behaviors (Woods
et al., 1992).
There is some evidence to suggest that negative health behaviors may

increase during the premenstrum. Smoking in particular may be likely to
increase during the premenstrual phase both for women without menstrual
disorders (Kritz-Silverstein, Wingard, & Garland, 1999) and for women with
PMDD (Pomerleau, 1996). In addition, women may experience more cravings
or have a more difficult time quitting during the premenstrum (see Carpenter,
Upadhyaya, LaRowe, Saladin, & Brady, 2006 for a review). However, women
may be more likely to relapse during menses (Frye, Ward, Bliss, & Garvey, 1992
as cited in Carpenter, Upadhyaya, LaRowe, Saladin, & Brady, 2006). Some
research has found that women who quit during the luteal phase rated with-
drawal symptoms worse than those who quit during the follicular phase and
shown positive correlations between withdrawal distress and menstrual distress
(O’hara, Portser, & Anderson, 1989).
Alcohol consumption has been shown to increase premenstrually by both
retrospective (e.g., Harvey & Beckman, 1985) and prospective (e.g., Epstein,
Rhines, Cook, Zdep-Mattocks, Jensen, & McCrady, 2006) reports. However
such increases might only be related to those suffering from severe premenstrual
distress (Griffin, Mello, Mendelson, & Lex, 1987), as results have not been
consistent (e.g., Abraham & Mira, 1989). In contrast, Tobin and colleagues
(1994) found that women with PMS prospectively reported more alcohol use
than controls over the course of the menstrual cycle, not just the premenstrum.
Physical activity is a positive health behavior that is supported as a protective
factor both for physical and mental health problems including anxiety (e.g.,
Petruzello, Landers, Hatfield, Kubitz, & Salazar, 1991). Kirkby and Lindner
(1998) found that increases in trait anxiety from mid-cycle to premenstrum were
common in sedentary women with a history of PMS; however there were no
changes in self-reported anxiety among women who exercised. Adolescent girls
who reported severe menstrual symptoms also reported the least amount of
physical activity (Teperi & Rimpela, 1989).
Menstrual distress and health behaviors are thus closely associated; however
it has been difficult for researchers to determine causation. One reason may be
that women are attempting to self-medicate through the use of substances or
through decreasing the amount of physical activity in which they engage.
Conversely, negative health behaviors may make women more vulnerable to a
wide array of health conditions including menstrual distress (Teperi & Rimpela,
1989). In addition, research in this area to needs to distinguish between the
impact of the physical and affective symptoms of menstrual distress.
Summary of Research on Anxiety and the Menstrual Cycle
Inconsistencies abound in the literature on anxiety and the menstrual cycle.

Different definitions and different methodologies used by researchers contribute
to equivocal results. In general, it may be safe to conclude that a significant
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.
Limitations in Existing Research
In this review, several issues have been delineated that make the literature on
anxiety, its disorders and menstrual cycle phases difficult to summarize.
Retrospective and prospective methods of reporting anxiety symptoms across
the menstrual cycle reveal many inconsistent findings. Researchers are often
unclear about whether they are discussing anxiety as a symptom caused by the
premenstrual phase of the menstrual cycle or the exacerbation of a
pre-existing anxiety disorder. The menstrual literature is replete with differing
definitions of premenstrual complaints, menstrual cycle timing, and
premenstrual exacerbation of existing pathologies. Conceptually, researchers
need to reach consensus on diagnostic criteria for premenstrual difficulties
and premenstrual exacerbation of psychological disorders. In addition,
researchers need to be more consistent in definitions and lengths of menstrual
cycle phases. It may be time for researchers to conduct more translational
research in which both camps agree on these matters.
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 sensi-
tivity 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
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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Pain and Anxiety Disorders
Gordon J. G. Asmundson, Murray P. Abrams, and Kelsey C. Collimore
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
Ó Springer 2008
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 psycho-
logical (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 auto-
somal 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, some-
times 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 popula-
tion 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 well-
being.
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 clini-
cally significant pain and anxiety disorders in both community and treatment-
seeking samples. It is noteworthy that chronic musculoskeletal pain has
Pain and Anxiety 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 popula-
tion 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 popula-
tion (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
Table 1 Prevalence of anxiety disorders among persons with pain (community samples)
210
Study Participants Data set Diagnostic criteria % Meeting criteria for an anxiety disorder
McWilliams et Nationally National DSM-III-R Chronic pain (arthritis; n = 382) General population (n = 5495)
al. (2003) representative Comorbidity Any anxiety disorder 35.1 Any anxiety disorder 18.1
sample of the Survey Part II PD 6.5 PD 1.9
U. S. (NCS) AWHPD 8.4 AWHPD 3.3
population (n SP 11.8 SP 7.8
= 5877)
SiP 15.7 SiP 8.3
PTSD 10.7 PTSD 3.3
GAD 7.3 GAD 2.6
McWilliams et Nationally Midlife DSM-III-R Arthritis (n = 588) No arthritis
al. (2004) representative Development in Panic attacks 11.2 Panic attacks 5.8
sample of the the United States GAD 5.6 GAD 2.7
U. S. Survey (MIDUS) Migraine (n = 340) No migraine
population (n Panic attacks 17.4 Panic attacks 5.5
= 3032)
GAD 9.1 GAD 2.5
Back pain (n = 614) No back pain
Panic attacks 13.0 Panic attacks 5.3
GAD 6.2 GAD 2.5
Von Korff et al. Nationally National DSM-IV Chronic spinal pain (n = 2397) -
(2005) representative Comorbidity Any anxiety disorder 26.5
sample of the Survey PD 4.8
U. S. Replication AWHPD 1.3
population (n (NCS-R) SP 8.3
= 5692)
SiP 12.5
PTSD 7.3
GAD 6.4
Note: PD = Panic Disorder; AWHPD = Agoraphobia Without History of Panic Disorder; SP = Social Phobia (also called social anxiety disorder);
SiP = Simple Phobia; PTSD = Posttraumatic Stress Disorder; GAD = Generalized Anxiety Disorder; Not all studies evaluated all anxiety disorders;
G. J. G. Asmundson et al.
All studies based on 12-month prevalence.

Table 2 Prevalence of anxiety disorders among pain patients (clinical samples)
Diagnostic
Study Participants Criteria Lifetime prevalence (%) Current prevalence (%)
Pain and Anxiety
Reich et al. (1983) Mixed chronic pain patients (n = 43) DSM-III - Any anxiety disorder 7.0
(PTSD only)
Katon et al. (1985) Mixed chronic pain patients (n = 37) DSM-III - Any anxiety disorder 16.2
(PD only)
Large (1986) Mixed chronic pain patients (n = 50) DSM-III - Any anxiety disorder 8.0
GAD 4.0
PD 2.0
PTSD 2.0
Fishbain et al. Mixed chronic pain patients (n = 283) DSM-III - Any anxiety disorder 19.4
(1986)
Atkinson et al. Chronic low back pain patients (n = 97) DSM-III Any anxiety 37.9 Any anxiety disorder 28.8
(1991) disorder
Generalized 22.7 Generalized disorder 13.4
disorder
PD 8.2 PD 7.2
OCD 13.4 OCD 8.2
Kinney et al. (1993) Chronic back pain patients (n = 90) DSM-III-R Any anxiety 29.0 Any anxiety disorder 25.0
disorder
PD 3.0 PD 3.0
Phobic disorders 17.0 Phobic disorders 13.0
OCD 3.0 OCD 3.0
PTSD 2.0 PTSD 2.0
GAD 4.0 GAD 4.0
211
212
Table 2 (continued)
Diagnostic
Study Participants Criteria Lifetime prevalence (%) Current prevalence (%)
Polatin et al. (1993) Chronic low back pain patients (n = DSM-III-R Any anxiety 19.0 Any anxiety disorder 17.0
200) disorder
PD 3.0 PD 3.0
Phobic disorders 11.0 Phobic disorders 9.0
OCD 2.0 OCD 2.0
PTSD 1.0 PTSD 1.0
GAD 2.0 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.
G. J. G. Asmundson et al.
remarkable nor elevated relative to the general population. This may be a

product of the nature of structured assessments employed in these studies;
specifically, the PTSD module may have been skipped if the participant did
not respond affirmatively to introductory questions regarding exposure to
traumatic experiences, examples of which do not often include accidental or
painful injury. Contrary to these unremarkable findings, several comprehensive
reviews of the literature indicate that 10% to 50% of patients receiving rehabi-
litation services for chronic musculoskeletal pain and related conditions have
PTSD (Asmundson, Coons, Taylor, & Katz, 2002; Otis, Keane, & Kerns, 2003).
Moreover, the available data indicate that up to 45% of patients with pain
subsequent to burn-related injury exhibit significant posttraumatic stress symp-
toms (Saxe et al., 2001).
Overall, it appears that there is a high prevalence of some anxiety disorders in
people with conditions characterized by chronic musculoskeletal pain. The
most common appear to be PTSD, SAD, GAD, and possibly PD. However,
there are notable limitations in the scope of inquiry to date. Additional inves-
tigation in samples seeking treatment for various chronic pain conditions, using
structured and comprehensive assessment of current and lifetime occurrence
of each anxiety disorder, is warranted.
Prevalence of Pain in Anxiety Disorder Samples
A growing number of studies have assessed the prevalence of clinically signifi-

cant pain conditions in people with anxiety disorders. Two of these studies have
focused on pain reports in patients with PD. Kuch, Cox, Woszczyna, Swinson,
and Shulman (1991) reported that nearly 40% (54 of 141) of their sample of
consecutively referred patients with PD reported chronic pain, most commonly
in the head, shoulders, and lower back. Almost 10% of those in the sample were
using analgesic medications on a daily basis. Similarly, in a study of 71 patients
with PD, Schmidt and Telch (1997) identified a variety of comorbid physical
conditions, including chronic back problems (46%), arthritis (22%), irritable
bowel syndrome (17%), heart conditions (13%), and other conditions such as
migraine, cancer, and diabetes (24%). A substantial number (35%) had seen a
physician in the last month, and most (89%) in the last year; however, only 6%
had been hospitalized in the past six months. These studies provide preliminary
evidence that chronic pain, particularly that of the musculoskeletal system, is
prevalent in patients seeking treatment for PD.
Acute and chronic pain are reported with striking frequency in people with
PTSD (for review, see Asmundson et al., 2002). Upwards of 20% to 30% of
those with PTSD seeking outpatient treatment from community and mental
health clinics report chronic pain (e.g., Hubbard, Realmuto, Northwood, &
Masten, 1995). Prevalence estimates of current chronic pain have, in most cases,
been even higher in military veterans and volunteer firefighters with PTSD,
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 accom-
panied 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 asso-
ciations 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 meta-
bolic 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 treat-
ment-seeking samples, using comprehensive pain assessment batteries, is
warranted.
Course
Few studies have systematically investigated the extent to which anxiety dis-
orders 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
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 deline-
ate 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 expli-
cate 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 relation-
ship between the anxiety disorders and chronic pain. For the most part, they
have been developed in the context of efforts to understand mechanisms under-
lying 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.
Mutual Maintenance Model
The mutual maintenance model (Sharp & Harvey, 2001) holds that certain
components of PTSD (e.g., physiological arousal, absence of positive emotions,
avoidance of trauma stimuli) maintain or exacerbate symptoms of pain
and, similarly, that certain components of chronic musculoskeletal pain
(e.g., physiological arousal, catastrophizing about pain, avoidance of physical
exertion) maintain or exacerbate symptoms of PTSD. The model predicts, for
example, that pain sensations experienced by a person with chronic musculos-

keletal 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-perpetuat-
ing distress and functional disability.
Shared Vulnerability (Diathesis)/Stress Models
We (Asmundson et al., 2002; Asmundson, & Taylor, 2006) and others (Otis
et al. 2003; Turk, 2002) have extended the idea of mutual maintenance, suggest-
ing that some maintenance factors may actually denote a shared vulnerability,
or diathesis, for developing both conditions. The shared vulnerability model
(see Fig. 1) holds that there are individual difference factors, possibly geneti-
cally influenced, that predispose people to develop PTSD and chronic muscu-
loskeletal pain when exposed to certain environmental conditions. Specifically,
the model suggests that the interaction of individual difference characteristics –
a psychological vulnerability for feelings of loss of control (and anxiety), and a
lowered physiological threshold for alarm reactions (i.e., activation of physio-
logical processes that prepare one to fight or flee) to stressors – and instigating
Psychological
Vulnerability
(e.g., high injury
sensitivity, high
Autonomic Nervous
System and Muscular
Responsivity
Emotional Disabling
Life Event Avoidance
Response Condition
(e.g. traumatic of situations or activities
(e.g. fear, anxiety, (specific or
incident, injury) perceived as negative
worry, agitation) co-occurring)
Hypervigilance and
Cognitive Biases
Low Threshold for

Alarm
(e.g., sympathetic
disregulation,
hyperalgesia)
Fig. 1 Shared vulnerability model

stressful events (e.g., traumatic incident, injury) explain the development of

PTSD, chronic musculoskeletal pain, and their co-occurrence. To illustrate,
PTSD is likely to occur in trauma-exposed people who are predisposed to react
to traumatic stressors with alarm and feelings that the situation, and their
emotional response to it, are beyond their control. Similarly, chronic muscu-
loskeletal pain is most likely to develop in injured people who believe that the
pain they are experiencing, and their emotional responses (e.g., anxiety, worry,
fear, agitation) to it, are uncontrollable.
The shared vulnerability model further predicts that co-occurring PTSD and
chronic musculoskeletal pain are most likely to develop in cases where vulner-
able people are exposed to an event that is both traumatic and painful, and that
both reminders of the trauma and sensations of pain can serve as triggers for
further alarm reactions. The latter is consistent with postulates of the mutual
maintenance model and further illustrates how predisposing factors can con-
tribute to maintenance of these conditions.
Our understanding of co-occurring PTSD and chronic pain might apply to
other anxiety disorders that frequently co-occur with chronic pain. Symptoms
of physiological arousal and lack of positive emotions – both general character-
istics of the anxiety disorders – may maintain or exacerbate symptoms of pain.
Likewise, one or more aspects of the pain experience (e.g., physiological arou-
sal, pain-related catastrophizing, avoidance of physical exertion) may maintain
or exacerbate clinically significant symptoms of anxiety. For example, avoid-
ance of physical exertion in persons experiencing persistent pain may result
in avoidance of specific social environments (e.g., fitness center, sporting com-
plex) which may, in turn, contribute to the maintenance of symptoms of social
anxiety through rewards (i.e., anxiety reduction) derived from behavioral
avoidance. Likewise, physiological arousal in these social environments
may promote muscle tension, avoidance of pain-related activities, physical
deconditioning, and an associated increase in muscle pain. As with PTSD,
persons with other anxiety disorders may become trapped in a cycle wherein
symptoms of anxiety and pain interact to promote clinically significant distress
or impairment.
Summary
It is plausible that postulates of the mutual maintenance and shared vulner-

ability 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.
Overview of Empirical Support
Evidence supporting the postulates of the mutual maintenance and shared

vulnerability models has been culled in the context of pain that accompanies
PTSD (or vice versa). Below we review this literature, with specific focus on
symptom overlap, anxiety sensitivity (AS), selective attention for threat, and
lowered threshold for alarm. These models have not heretofore been applied in
the context of understanding the co-occurrence of chronic musculoskeletal pain
and the other anxiety disorders. While it is likely that the models will prove
useful in this regard, direct empirical evaluation of the model postulates in these
contexts remain a direction for future consideration.
Symptom Overlap
There is considerable symptom overlap between PTSD and chronic musculos-

keletal 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 conse-
quences) 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). Conse-
quently, it has been postulated that AS is responsible for the extreme emotional
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.
Selective Attention to Threat
Cognitive models suggest that people with various forms of psychopathology

or general medical conditions tend to selectively attend to threat-related stimuli
that are representative of the core concerns of their specific disorder; that is,
they direct attention towards objects or situations that they fear. This increases
state anxiety and, according to some, makes one vulnerable for emotional
disorders (e.g., Mathews & MacLeod, 2002). Evidence for syndrome-specific
attentional biases is, with few exceptions, robust across various anxiety disor-
ders (see Williams, Mathews, & MacLeod, 1996). This has been consistently
demonstrated in patients with PTSD using emotional Stroop colour-naming
and fear-potentiated startle tasks (e.g., Paunovic, Lundh, & Öst, 2002) but not
with the dot-probe task (e.g., Elsesser, Sartory, & Tackenberg, 2005). The
findings from chronic musculoskeletal pain patients have been mixed and
there is no clear consensus amongst modified Stroop and dot-probe investiga-
tions as to whether patients with chronic musculoskeletal pain do or do not
selectively attend to pain-related stimuli.
A recent meta-analysis of five modified Stroop investigations suggests that
chronic pain patients, compared to healthy participants, have an attentional bias
to both sensory and affect pain words (Roelofs, Peters, Zeegers, & Vlaeyen,
2002); however, scrutiny of the findings from the individual investigations used in
the meta-analysis as well as findings from controlled investigations (Andersson &
Haldrup, 2003) fail to provide convincing evidence for this conclusion. The
results of dot-probe investigations, with some exceptions, also fail to provide
clear evidence that chronic pain is associated with a pain-specific bias in
attentional processing (Asmundson, Carleton, & Ekong, 2005; Asmundson,
Kuperus, & Norton, 1997, Asmundson, Wright, & Hadjistavropoulos, 2005;
Roelofs, Peters, Fassaert, & Vlaeyen, 2005). Most recently, fear-potentiated
startle has been employed as a means of potentially resolving the mixed findings
yielded using other cognitive tasks. Some of these studies have indicated
increased startle to pain-related stimuli (Flor, Knost, & Birbaumer, 1997) while
others have not (Carleton, Asmundson, Collimore, & Ellwanger, 2006;
Kronshage, Kroener-Herwig, & Pfingsten, 2001); however, strong associations

between startle responses to pain-related stimuli and fear-based individual dif-
ference constructs (e.g., AS, fear of pain) were noted in both studies that assessed
the latter (Carleton et al., 2006; Kronshage et al., 2001).
The assumption underlying this area of research is that patients with chronic
musculoskeletal pain are generally fearful of pain and, thus, will selectively
attend to pain-related stimuli; however, it is plausible that investigators have
not identified the specific objects or situations that are feared by these indivi-
duals (for detailed discussion of objects of fear in pain conditions, see Morley &
Eccleston, 2004). That is, pain-related stimuli may not be the object of fear for
the majority of patients with chronic musculoskeletal pain. There is evidence to
suggest that trauma-related stimuli may be the most relevant object of fear for
many patients with chronic musculoskeletal pain. Specifically, we (Asmundson,
Bonin, Frombach, & Norton, 2000) and others (Beck, Gudmundsdottir, &
Shipherd, 2003) have demonstrated that when the heterogeneous nature of
chronic musculoskeletal pain is considered, those patients classified as dysfunc-
tional are far more likely to have co-occurring PTSD (70%) than those
classified as interpersonally distressed (35%) or as adaptive copers (20%).
The empirically-derived system for making these classifications – the Multiaxial
Assessment of Pain (MAP; Turk & Rudy, 1987) – is described in detail in the
Assessment section below. There is also preliminary evidence that patients with
co-occurring PTSD and pain show attentional biases (on a modified Stroop
task) for both pain and accident words (e.g., crash), whereas those with pain
and no PTSD are biased only toward pain words (e.g., throbbing; Beck,
Freeman, Shipherd, Hamblen, & Lackner, 2001). While the latter findings
await replication, they suggest that the object of fear in some chronic pain
patients (i.e., those classified as dysfunctional) may be associated with prior
traumatic and painful injury. Confirmation of these findings may explain the
lack of robustness observed in efforts to identify attentional biases in patients
with chronic musculoskeletal pain and may shed light on cognitive mechanisms
underlying the co-occurrence of these conditions.
Lower Threshold for Alarm
Pain and anxiety are both associated with physiological arousal (e.g., acceler-
ated heart rate, elevated blood pressure, increased respiration, decreased gas-
trointestinal activity, increased muscular tension, increased blood flow to
skeletal muscles; Hoehn-Saric & McLeod, 1993). The bodily changes stemming
from arousal serve a protective function, promoting escape and withdrawal, but
can have detrimental effects if prolonged. Physical injury and traumatic experi-
ences also initiate other complex neural and hormonal processes (e.g., release
of cytokines, b-endorphin, 5-HT-moduline) that, while designed to promote
tissue healing and reinstate homeostasis, can be destructive to muscle, bone,
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 uncontrol-
lable) 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 asso-
ciated 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 measur-
able, bi-directional ANS responses. Preliminary analyses indicate no between-
group 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 character-
ized 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
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, Grüsser, & 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 media-
tion 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 stimulus-
response 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 partici-
pants. This, combined with evidence that the serotonergic system – an aminer-
gic 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., David-
son & Connor, 2001), provides clues as to the peripheral and central physiolo-
gical 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
and chronic musculoskeletal pain. However, given that empirical scrutiny of

these models is in its infancy, we remain at a stage where there are more
questions than answers. With regard to the applicability of these models to
understanding, explaining, and guiding treatment for those with other anxiety
disorders that are accompanied by clinically significant pain, even less is known.
Notwithstanding, these models provide a foundation on which to make recom-
mendations for assessment and treatment planning for these potentially com-
plicated cases.
Assessment and Treatment
As noted above, clinically significant pain often goes unnoticed when assessing
and planning treatment for a patient with an anxiety disorder. When over-
looked, pain can make treatment of the anxiety symptoms complicated at best,
and frustrating and ineffective at worst. There is little information available on
assessment and treatment planning for anxiety disorder patients who present
with co-occurring pain symptoms. In order to facilitate clinical and research
efforts, we provide a brief overview of tactics for assessment and treatment in
this context.
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 meth-
ods 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 iden-
tifiable physical factors that might account for the patient’s presenting pain
symptoms.
Assessment methods include reviewing hospital medical records (in order
to chart the course of the patient’s 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
accompanied by select self-report measures as an easy and time efficient means

of getting essential information. Use of semi-structured interviews can provide
a wealth of information regarding pain origins, its impact on current beliefs
and assumptions, its impact on behavior, as well as associated complications
(e.g., marital conflict, depression, substance abuse). Therapist guided inquiries
may facilitate identification of the patient’s conceptualization of his or her
problem. Specific questions (e.g., What makes your pain worse?) can provide
valuable information regarding pain triggers, patterns of avoidance, and the
patient’s treatment goals. Where self-report measures are administered in
advance of interviews, the direction of interviews can be guided to some extent
by information gained from these measures; conversely, information gained
from interviews may guide the choice of instruments.
We recommend that assessment batteries provide maximal information with
minimal overlap. The following measures meet this criterion (also see Mikail,
DeBreuil, & d’Eon, 1993).
Multidimensional Pain Inventory (MPI; Kerns, Turk, & Rudy, 1985). The
MPI assesses physical, psychological, and social factors related to the pain
experience. It is comprised of 52 items and is a reliable, valid self-report
measure. To classify pain patient subgroups, responses on the MPI can be
submitted to the MAP (Turk & Rudy, 1987), an empirically-based and compu-
terized application. Patients can be classified as dysfunctional (i.e., higher than
average pain severity, interference, and distress, and lower levels of self-efficacy
and activity), interpersonally distressed (i.e. lower levels of perceived social
support), or minimizers/adaptive copers (i.e., lower than average pain severity,
interference, and distress, and higher levels of self-efficacy and activity).
Asmundson, Bonin, et al., (2000) found that a substantial proportion of dys-
functional and interpersonally distressed patients were classified as having
PTSD (71.4 and 42.9%, respectively) when compared to minimizers/adaptive
copers (21.3%). These findings suggest that MAP subgroups differ with regard
to their likelihood of having PTSD. Additional research is needed to determine
if they differ with regard to other anxiety disorders.
Short Form McGill Pain Questionnaire (SF-MPQ; Melzack, 1987). The
SF-MPQ is used to measure dimensions of the pain experience. It comprises
15 adjectives describing sensory (e.g. throbbing) and affective (e.g., sickening)
dimensions of pain, a visual analogue scale (VAS) and present pain index [PPI;
based on a scale of 0 (no pain) to 5 (excruciating)]. The SF-MPQ has been widely
used to measure pain experiences in many different types of patients (e.g., low
back pain, fibromyalgia, rheumatoid arthritis), and as a measure of treatment
efficacy (e.g., Frost et al., 2000). A more comprehensive assessment of the pain
experience can be achieved by using the full length MPQ (MPQ; Melzack,
1975).
Pain Anxiety Symptoms Scale (PASS; McCracken, Zayfert, & Gross, 1992).
For assessing pain-related anxiety, the 40-item PASS, and a shorter 20-item
version (PASS-20; McCracken & Dhingra, 2002) are commonly used. The
PASS and the PASS-20 both assess four theoretically distinct components of
pain-related anxiety, including cognitive anxiety (e.g., I find it hard to concen-

trate 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 compre-
hensive 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 sig-
nificant 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 dis-
orders 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 diver-
sion 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.
Relaxation Training. We recommend a modified version of the method

described by Taylor and Asmundson (2004). This includes systematic education
about and practice doing release-only relaxation, rapid relaxation, and dia-
phragmatic breathing. Implementation of these strategies may help the patient
to control muscle tension and associated pain, and provide general skills that
can be used in everyday living to become more relaxed. In patients with chronic
musculoskeletal pain or headache we typically omit tense-release relaxation as
the process of repeatedly tensing and releasing certain muscle groups can, rather
than providing relief, increase muscle tension or cramping.
Cognitive Strategies. Cognitive strategies may further enhance pain manage-
ment. Cognitive restructuring strategies involve identification of catastrophic
cognitions about pain (e.g., Hurt equals harm) followed by teaching the patient
strategies to challenge and change their catastrophic thoughts (e.g., My pain is
not harmful, and I can function despite it). Attention diversion strategies may
include focusing attention on external stimuli (e.g., pictures of landscapes),
focusing on neutral (e.g., an instructor attending a lecture) or pleasant (e.g.,
sitting comfortably in a chair) imagery, dramatized reconstruction of the context
in which pain occurs (e.g., imagining pain due to an injury in a sports game),
repetitive or systematized cognitive strategies (e.g., counting backwards from
100 by 3), and pain acknowledging (e.g., reappraisal of pain in terms of objective
sensations). A meta-analysis of 61 studies showed that these strategies enhanced
pain tolerance and reduced pain ratings more than 85% of the time relative to no
treatment (Fernadez & Turk, 1989). Imagery strategies were most effective.
Graded Activity. The purpose of graded activity is to counter the effects of pain-
promoting deconditioning that might occur due to inactivity and pain-related
behavioral avoidance. When applied in the context of patients with an anxiety
disorder and co-occurring chronic pain we recommend a variant of graded
activity that specifically targets exercise and fitness training. The premise is similar
to that of graded activity – exercise and fitness training may serve to promote
activity pacing, recommencement of previous activity levels, and physical recon-
ditioning in patients with a variety of chronic pain conditions (for review, see
Wright & Sluka, 2001). Because exercise can also serve to ameliorate anxiety
symptoms, particularly panic-related symptoms (Smits, Powers, Berry, & Otto, in
press; Stathopoulou, Powers, Berry, Smits, & Otto, 2006), it is an attractive
consideration for the patient with both anxiety and chronic pain symptoms.
Exposure. Many patients with chronic musculoskeletal pain avoid situations
or activities based on the fear that these will provoke further pain or re-injury.
Accordingly, clinicians have used various forms of exposure therapy to reduce
fear of pain and increase involvement in leisure and work activity. Exposure is
conducted within treatment sessions and as homework assignments. Recent
data from studies using replicated single-case experimental (e.g., de Jong et al.,
2005; Vlaeyen, de Jong, Leeuw, & Crombez, 2004) and randomized controlled
(Woods & Asmundson, in press) designs indicate that graded in vivo exposure –
exposure to specific pain-related activities that are feared or avoided – is more
effective than graded activity in reducing fear of pain, avoidance behaviors, and
reports of pain severity. In vivo exposure is explained in detail elsewhere

(Vlaeyen et al., 2004). In vivo exposure may be an effective strategy to incorpo-
rate when a patient with an anxiety disorders reports significant fear and
avoidance of pain-related situations or activities; however, this may require
substantial time (e.g., two weekly session of 45 mins for approximately 8 weeks)
and divergence from standard treatment. Interoceptive exposure (i.e., exposure
to anxiety provoking bodily sensations) is an interesting alternative to in vivo
exposure; it is an empirically-supported intervention often included as part of
CBT for anxiety disorders (e.g., Taylor, 1999) and, more recently, has been
shown effective in reducing both PTSD symptoms (Wald & Taylor, in press)
and fear of pain (Watt, Stewart, Lefaivre, and Uman, 2006).
Other Treatment Considerations. While we have emphasized CBT in our dis-
cussion of treatment options for co-occurring chronic musculoskeletal pain and
anxiety disorders, there are other promising approaches. Pharmacotherapy can be
effective in alleviating pain associated with various conditions (e.g., Portenoy,
2000); thus, combining analgesics with CBT may prove particularly effective in
cases where an anxiety disorder and clinically significant pain co-occur. Combined
pharmacotherapy and CBT is, in fact, recommended in current expert consensus
guidelines for comorbid PTSD and chronic pain (Foa, Davidson, & Frances,
1999). Moreover, recent developments in pharmacotherapy suggest that some
pharmacologic agents may be particularly effective for alleviating co-occurring
PTSD and pain. Specifically, results from two small, randomized trials indicate
that propranolol, a beta-blocker with analgesic effects, reduces PTSD symptoms
(Pitman et al., 2002; Pitman & Delahanty, 2005). Speculations of effectiveness
of combination treatments across the anxiety disorders do, however, await
systematic empirical scrutiny. Acceptance and mindfulness-based interventions
(e.g., Kabat-Zinn, 1990; Hayes, Wilson, & Strosahl, 1999) have also been found to
be effective for a range of medical and psychological problems that include pain
syndromes and anxiety disorders (for reviews, see Baer, 2003; Bishop, 2002;
Melbourne Academic Mindfulness Interest Group, 2006). It is plausible that
these interventions may prove effective, either on their own or as adjuncts to
CBT, for the treatment of anxiety disorders that co-occur with chronic pain. On
the other hand, while standard physical treatments of chronic musculoskeletal
pain (e.g., electrotherapy, muscle manipulation) are potentially therapeutic, there
is a lack of substantive empirical evidence supporting their effectiveness (Wright &
Sluka, 2001); thus, we do not recommend their use in treating a patient with
co-occurring anxiety disorder and chronic musculoskeletal pain.
Outstanding Issues and Conclusion
Generally speaking, relatively little is known about the mechanisms that

underlie the co-occurrence of the anxiety disorders and conditions character-
ized by clinically significant pain. The majority of evidence comes from
investigations of the co-occurrence of PTSD and chronic musculoskeletal pain.

Examination in the context of the other anxiety disorders may serve to identify
mechanisms of co-occurrence (e.g., mutual maintenance, shared vulnerability)
that are common to each. Systematic inquiry may also allow further develop-
ment, refinement, and empirical validation of treatments geared specifically
toward those patients who have both an anxiety disorder and chronic pain. As
noted at the outset of this chapter, the co-occurrence of an anxiety disorder and
chronic pain does not bode well for assessment or treatment outcome. It
remains undetermined whether co-occurrence negatively influences health com-
promising behaviors and, if so, how this will affect treatment. However, given
that the anxiety disorders and chronic pain syndromes present with a strikingly
similar cluster of health compromising behaviors (e.g., heavy smoking,
increased alcohol and substance consumption, poor sleep, increased depression
and suicidal ideation, avoidance of leisure activities and exercise), it seems
reasonable to speculate that co-occurrence will, at minimum, be associated
with reduced likelihood that such patients will present with a well developed
arsenal of adaptive health behaviors. This, in turn, may complicate or, at
minimum, prolong treatment.
Below we highlight a number of specific research directions that await
investigation. For those investigators who pursue one or more of these
directions, we urge careful attention to the heterogeneous nature of chronic
pain (e.g., as illustrated by the MAP categories of minimizers/adaptive copers,
interpersonally distressed, dysfunctional; Turk & Rudy, 1987), as failure to do
so may significantly reduce power to detect mechanisms at play. We also urge
that efforts are made to evaluate aspects of both mental and physical health.
First, further elaboration of current and lifetime prevalence of various pain
conditions in each of the anxiety disorders, in community and treatment-
seeking samples, using comprehensive pain assessment batteries is warranted.
Second, and of particular importance, investigation of the temporal sequence of
co-occurring anxiety disorders and chronic pain are required to determine
whether one condition is more likely to precede the other, and whether sequen-
cing of onset is consistent across the anxiety disorders. Third, further empirical
exploration of the mechanisms of co-occurrence, as posited in the mutual
maintenance and shared vulnerability models, for various chronic pain condi-
tions and each of the anxiety disorders will improve our understanding of co-
occurrence. Further empirical scrutiny may also serve to guide treatment for
those with anxiety disorders accompanied by clinically significant pain. The
preliminary research regarding the application of each of propanolol and
interoceptive exposure in this context is promising. Finally, there are a number
of specific studies related to shared vulnerability factors that will advance the
field, including (a) longitudinal studies to examine whether elevated AS
precedes the development of anxiety disorders and chronic musculoskeletal
pain, or whether it becomes elevated as a consequence of these conditions, (b)
additional study of other potential vulnerability factors (e.g., trait negative
affectivity, illness/injury sensitivity, fear of pain) in understanding the
association between anxiety disorders and chronic musculoskeletal pain, (c)

further examination of the object of fear in chronic musculoskeletal pain
patients with and without a co-occurring anxiety disorder (e.g., whether they
are associated with prior traumatic and painful injury), and (d) examination of
the possible interactive roles of ANS dysregulation and the endogenous opioid
system in reducing threshold for alarm in PTSD (and other anxiety disorders)
and chronic musculoskeletal pain.
The aforementioned research directions are neither exhaustive nor presented
in order of importance. There are, instead, ideas that may stimulate research in
this emerging but currently underdeveloped area. Ultimately, the outcomes of
studies targeting theses avenues of inquiry may serve to inform assessment and
treatment that, in turn, will increase the probability that clinicians can posi-
tively impact the mental and physical health of their patients who present with
an anxiety disorder accompanied by clinically significant pain.
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Asthma in Anxiety and Its Disorders: Overview
and Synthesis
Lisa S. Elwood and Bunmi O. Olatunji
Asthma is a respiratory disease with symptoms including reversible airway obstruc-

tion, 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 symp-
toms 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 dis-
orders. 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
Ó Springer 2008
238 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 individual’s 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 classi-
fying 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 individual’s pul-
monary 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, night-
time 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
20–30% variability. Criteria for moderate persistent asthma include daily day-
time symptoms, nighttime symptoms more than once a week, and FEV1 or PEF
greater than 60–80% 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 conceptua-
lized as a syndrome, with many etiologies that may result in different presenta-
tions 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 fre-
quent wheezing in infancy is associated with an increased likelihood of chronic
Asthma and Anxiety 239
asthma symptoms; infants with infrequent wheezing typically do not continue

to display asthma symptoms as they mature. Allergic asthma commonly devel-
ops during the second decade of life when individuals become exposed to
allergens they did not have contact with as children. Allergic asthma is typically
not severe and does not progress over time. Intrinsic asthma appears to develop
frequently in middle-aged and older adults, but can begin at any age. Intrinsic
asthma tends to be persistent, is likely to increase in severity over time, and may
become irreversible.
Non-psychological Risk Factors for Asthma
Research examining risk factors for asthma have identified sex, race, weight,
timing of birth, smoking, environmental factors, and atopy (i.e., allergic
responses) as potential risk factors for the development of asthma. The relation-
ship between sex and asthma appears to fluctuate over time. Studies have found
that asthma appears to be more prevalent in males in childhood (van Merode,
Maas, Twellar, Kester, & van Schayck, 2007), but in females in adulthood
(Apter, 2007; Wenzel & Busse, 2007). Members of ethnic minority groups,
with the exception of Mexican Americans, appear to be at an increased risk
for asthma when compared to Caucasians (Apter, 2007, McCoy et al., 2006).
Specifically, within the US, asthma appears to be most prevalent in Puerto
Rican Americans, followed by Native Americans, African Americans, and then
by Caucasians. In addition, members of minority groups and individuals with
low socioeconomic status (SES) appear to be at an increased risk for not
receiving appropriate medical care for asthma, resulting in higher rates of
medical visits and death related to asthma (Apter, 2007; Joseph, Williams,
Ownby, Saltzgaber, & Johnson, 2006). However, one study found support for
chronic stress as a mediator between low SES and decreased immune processes
and asthma symptoms (Chen, Hanson et al., 2006). A meta-analysis examining
the relation between weight and asthma indicated that both high weight at
birth and at middle childhood appear to be related to increased risk for future
asthma (Flaherman & Rutherford, 2006). The article suggests that diet, gastro-
esophageal reflux, mechanical effects of obesity, atopy, and hormonal influ-
ences may serve as links between body weight and asthma symptoms. The link
between overweight status and asthma has also been supported in adolescents
(OR 1.4, 95% confidence interval (CI) 1.1–1.6; Jones, Merkle, Fulton, Wheeler,
& Mannino, 2006). Research suggests that obesity in adulthood is associated
with the presence of asthma symptoms in females, but not males (McLachlan
et al., 2007). A separate meta-analysis revealed that premature birth may also
serve as a risk factor for asthma (Jaakkola et al., 2006). However, the strength
of the association varied across studies, with cross-sectional design, broad
outcome criteria, small sample size, young sample, and more recent publication
displaying the strongest associations between pre-term birth and asthma
symptoms.
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 co-
existing 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 1.00–1.77) and among ex-smokers with an adjusted
OR 1.49 (CI 1.12–1.97) 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 1.30–3.00; 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.
Asthma and Mental Health
Many studies have outlined how immunological and physiological factors mod-
erate asthma outcomes (e.g., Grupp-Phelan, Lozano, & Fishman, 2001; Watson,
Becker, & Simons, 1993). However, the potential influence of psychological
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 symp-
toms (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 psycho-
logical distress in the conceptualization of the etiology, maintenance, and treat-
ment 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).
The Intersection of Anxiety and Asthma
Prevalence and Impact of Anxiety Disorders
Anxiety disorders have the highest overall prevalence rate among psychiatric
disorders, with a 12-month rate of 18.1% and a lifetime rate of 28.8% (Kessler,
Berglund, Demler, Jin, Merikangas, & Walters, 2005; Kessler, Chiu, Demler, &
Walters, 2005). The estimated costs associated with anxiety disorders has been
reported to be over $45 billion, accounting for over 30% of total expenditures in
mental health (DuPont et al., 1996). Anxiety disorders also have a substantial
negative impact on quality of life (Mendlowicz & Stein, 2000; Olatunji, Cisler, &
Tolin, 2007).
Anxiety in Children and Adolescents with Asthma
Asthma is the most common medical disorder among adolescents and is asso-
ciated with increased functional impairment and lost days at school (Weitzman,
Gortmaker, Sobol, & Perrin,1992). There is also evidence that the presence of
asthma increases the risk for the development of an anxiety disorder. As outlined
in Table 1, the presence of asthma in children and adolescents has been linked with
anxious disorders and symptoms in clinical (Butz & Alexander, 1993; Gupta,
Mitchell, Giuffre, & Crawford, 2001; Vila, Nollet-Clemencon, de Blic, Mouren-
Simeoni, & Scheinmann, 2000) and non-clinical samples (Goodwin, Pine, &
Hoven, 2003; Goodwin, Fergusson, & Horwood, 2004; Ortega et al., 2003; Ortega,
Table 1 Findings of studies examining the relation between asthma and anxiety in children and adolescents
242
Comparison
Study Sample Asthma Measurement Anxiety Measurement group Main Findings
Butz and Children 7–12, Recruited Self-reported number and State-Trait Inventory for None 65% reported feeling
Alexander from pediatric ER, type of symptoms, Children, reported ‘‘panic’’ at the
(1993) Diagnosis of acute number of hospital and emotion at the beginning of an asthma
asthma ER visits, limitation of beginning of an asthma attack, feeling panic at
activity, medication attack the beginning of an
attack significantly
predicted trait, but not
state, anxiety
Goodwin Data drawn from an Parents report of child DISC; Child global Asthma to no Asthma was associated
et al. (2003) epidemiology study asthma symptoms and assessment scale asthma with an increased
hospitalization for likelihood of panic
asthma attacks; severe asthma
was associated with an
increased likelihood of
panic attacks and
disorder; Number of
panic symptoms was
associated with an
increased likelihood of
asthma and severe
asthma
Goodwin, Data collected during the Classified as presence of Items from CIDI; asked None Asthma was related to
Fergusson, course of a longitudinal absence of asthma for the previous two anxiety prior to
& study of an unselected during age 16–18 and years; Assessed GAD, (OR=1.6 (CI
Horwood birth cohort; at ages 18 18–21. Presence was social phobia, specific 1.2–2.2)), but not after
(2004) and 21 participants determined by reported phobia, and controlling for adverse
were asked about diagnosis and agoraphobia; assessed childhood experiences
asthma symptoms during the panic attacks and (e.g., SES, abuse,
L. S. Elwood, B. O. Olatunji
Table 1 (Continued)
Comparison
time period; also symptoms but not parental conflict) OR
obtained self-report of disorder = 1.2 (CI .5–2.9);
number of asthma suggested a third
Asthma and Anxiety
related medical common factor

consultations in past
year, number of
asthma attacks in past
year, frequency of
medication, and
current frequency of
symptoms
Gupta et al. Children recruited from Diagnosis, needed change Children: Fear Survey Compared to Both groups scored sig
(2001) an asthma clinic, a of 15% in FEV, Schedule-Revised; cardiology higher on medical
cardiology clinic severity determined by RCMAS; Parents: patients fears, fear of injury and
number of CBCL, STAI small animals than
breakthrough attacks norms; both groups
scored sig higher than
norms on the
internalizing T score on
the CBCL and on the
anxiety/depression
factor of the CBCL;
both groups scored
higher on the
physiological anxiety
subscale of the
RCMAS than norms
243
Table 1 (Continued)
244
Comparison
Ortega et al. Community sample, Parent report of asthma DISC, used diagnostic Asthma to no After controlling for
(2003) sample based on symptoms, diagnosis, categories of anxiety, asthma maternal mental
island-wide probability or asthma related affective, and health, income, and
household sample of hospitalization disruptive disorders; education asthma
children diagnoses of separation diagnosis was
anxiety, social phobia, associated with having
major depression, any psychiatric
conduct disorder, disorder, any affective
oppositional defiant disorder, having more
disorder, and ADHD than one disorder, and
ADHD; Asthma
attack associated with
most disorders, but not
social phobia or
conduct disorder;
hospitalization was
associated with
separation anxiety
disorder.
Ortega et al. Community sample, Parental reports of an DISC; anxiety disorders Children with Children with a history of
(2004) sample based on asthma diagnosis and included: panic and without asthma attacks had
island-wide probability parental reports of the disorder, separation reported higher prevalence of
household sample of child ever having an anxiety disorder, social histories of any anxiety disorder;
children asthma attack phobia, PTSD, and asthma however, separation
GAD anxiety disorder was
the only individual
anxiety disorder that
was significantly
different between
groups
Table 1 (Continued)
Comparison
Rietveld Adolescents with and Severity of asthma STAI With asthma to No sig differences in state
(2000) without asthma; with classified from one to healthy or trait anxiety
asthma recruited from five; class 1 (if needed controls
Asthma and Anxiety
general and lung bronchodilator) to

physicians class 5 (oral
corticosteroids)
Rietveld et al. Adolescents with mild to Severity of asthma was STAI Compared Average threshold for
(2000) severe stable asthma classified based on asthmatics breath holding did not
and healthy prescribed medicine: to healthy differ between groups;
participants without severe, moderate- controls state anxiety of
asthma severe, moderate, participants with
moderate-mild, mild asthma was sig higher
than those without; No
sig differences in trait
anxiety
Vila et al. Outpatients from Moderate to severe Revised Schedule for Asthmatic 35% of the asthmatic
(2000) pediatric allergology persistent asthma Affective Disorders children to children had at least
and pneumology and Schizophrenia for controls one DSM-IV anxiety
department compared School-aged children; disorders (29% GAD,
to healthy community CBCL; Anxiety and 16% separation
participants recruited Fears Behavioral Scale anxiety disorder, 10%
from schools social phobia, 1%
panic); children with
asthma reported
significantly higher
levels of anxiety than
controls
245
246
Table 1 (Continued)
Comparison
Wamboldt Children aged 7–19 were Severity was determined RCMAS; CBCL (parent None Neither child-reported
et al. (1998) recruited from asthma by a pediatric report) anxiety nor parent-
related summer camps pulmonologist and reported internalizing
and an inpatient unit; allergist/immunologist symptoms were
both children and a by reviewing medical significantly elevated
parent participated 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.
Note. ADHD = Attention Deficit Hyperactivity Disorder, CBCL= Child Behavior Checklist, CIDI = Composite International Diagnostic Inter-
view, DISC = Diagnostic Interview Schedule for Children; GAD = Generalized Anxiety Disorder PTSD = Posttraumatic Stress Disorder, RCMAS
= Revised Children’s Manifest Anxiety Scale, STAI = State-Trait Anxiety Interview, Sig. = p < 0.05.
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 collea-
gues (1998) found that child and parent ratings of the child’s psychological
symptoms displayed inconsistent patterns. While the child’s reported level of
anxiety failed to be significantly related to asthma severity, asthma severity was
significantly related to parent’s ratings of the child’s internalizing symptoms. In
addition, parental ratings of the child’s internalizing symptoms were signifi-
cantly related to the parent’s personal level of physical symptoms, suggesting
that parental reports of child symptoms may be biased by their own distress
(Wamboldt et al., 1998).
Anxiety in Adults with Asthma
Although asthma is commonly observed during childhood, the majority of the

research examining the relations between anxiety and asthma has been conducted
using adult samples. As outlined in Table 2, studies examining the relations
between asthma and anxiety disorders in adults have linked asthma with diagnoses
of panic disorder (Afari et al., 2001; Goodwin, Jacobi, & Thefeld, 2003; Brown,
Khan, & Mahadi, 2000; Goodwin & Eaton, 2003; Goodwin, Olfson, et al., 2003;
Goodwin & Pine, 2002; Lavoie et al., 2005; Nascimento et al., 2002; Perna Bertani,
Politi, Colombo, & Bellodi, 1997; Pollack et al., 1996; Shavitt, Gentil, & Mandetta,
1992; Yellowlees, Alpers, Bowden, Bryant, & Ruffin, 1987), social phobia (Afari et
al., 2001; Brown et al., 2000; Goodwin, Jacobi, et al., 2003; Nascimento et al.,
2002; Perna et al., 1997), generalized anxiety disorder (Goodwin, Jacobi et al.,
2003; Goodwin, Olfson et al., 2003; Goodwin & Pine, 2002; Heaney, Conway,
248
Table 2 Findings of studies examining the relation between asthma and anxiety in adults
Comparison
Study Sample Asthma Measurement Anxiety Measurement group Findings
Afari et al. Adult patients with Completed a DIS-III-R Compared to Participants endorsed PD,
(2001) diagnosis of mild to methacholine prevalence agoraphobia, and social
moderate asthma inhalation challenge rates phobia at higher rates than
recruited from an test to confirm general population
asthma clinic airway reactivity; prevalence rates
FEV1/ FVC
Brown et al. Recruited participants FEV1 SCID-IV None 59% met criteria for at least
(2000) using medication one anxiety disorder; 28%
regularly scheduled to specific phobia, 19%
receive prednisone at an PTSD, 15% PD, 13%
asthma clinic, social phobia
Davis et al. Evidence of asthma, ‘‘objective evidence of ASI, Sheehan Patient None 37% received an anxiety
(2002) recruited from an asthma based on the Rated Anxiety Scale disorder; 11% PD, 6%
asthma clinic Canadian Consensus (SPRAS), ADIS PTSD, 16% GAD, 3%
Guidelines’’ social phobia, 2% specific
phobia
Di Marco COPD patients were diagnosis of COPD; Italian version of the COPD a greater percentage of
et al. (2006) recruited from a FEV1 values; Italian STAI patients asthma participants
respiratory unit and versions of the compared endorsed high levels of
controls were recruited modified Medical to healthy anxiety (28%) than the
from annual check-ups Resource Council controls control participants (6%).
dyspnea scale and the
St. George’s
Respiratory
Questionnaire
Table 2 (Continued)
Comparison
Erhabor & Respiratory unit clinic Diagnosis of asthma, General Health Orthopedic Asthma patients reported a
Mosaku Questionnaire, and healthy significantly higher level of
(2004) STAI 1 and 2 controls state anxiety than
Asthma and Anxiety
orthopedic and healthy

participants; No sig
differences in trait anxiety;
Asthmatic patients scored
significantly higher on the
General Health
Questionnaires (indicating
higher psychiatric
symptoms)
Goodwin & Data was collected as part Self-report of asthma DIS, assessed panic Individuals Individuals with asthma were
Eaton of the Epidemiologic and treatment of attacks with sig more likely to report
(2003) Study asthma asthma PAs at baseline, OR= .75
compared (CI 1.08–2.84), and continued
to those PAs at time 2, but not
without incident PAs at
time 2. Reported treated
asthma was associated with
higher number of
symptoms during PA
Goodwin, Adult participants of an Self-report of current German National Community Current severe asthma was
Jacobi, epidemiological study and past asthma Health Interview individuals associated with any anxiety
et al. (2003) diagnosis, method of and Examination without disorder, specific phobia,
assessment by Survey-Mental asthma PD, and PAs. Lifetime
physician, type of Health Supplement severe asthma was
asthma, treatment associated with any anxiety
249
Table 2 (Continued)
250
Comparison
sought, and severity followed by Munich disorder, PD, PAs, social

of attacks. Rated as CIDI phobia, specific phobia,
current if present in GAD, bipolar, and any
the last 4 weeks. severe mental disorder.
Categorized as severe Current nonsevere asthma
or nonsevere was associated with any
affective disorder, any
severe mental disorder.
Lifetime nonsevere asthma
was associated with any
anxiety disorder, anxiety
NOS, any somatoform
disorder, and any severe
mental disorder.
Goodwin & Adult community sample Self-report. Assessed CIDI short form Community PAs, OR = 2.2 (CI 1.7–3.0)
Pine (2002) both respiratory individuals and GAD, OR = 1.5 (CI
disease (asthma, without .6–2.2) were associated with
chronic bronchitis, respiratory respiratory disease, lung
and emphysema) and & lung disease, and comorbid
lung disease (other disease respiratory and lung
lung disease). disease. When comorbid
mental disorders and
physical problems were
controlled for, only PAs
were associated with
respiratory disease and lung
disease.
Table 2 (Continued)
Comparison
Goodwin, Adult primary care Asthma diagnoses PRIME-MD; Patient Compared Participants with asthma were
Olfson, et al. patients at an internal obtained from billing Health patients sig more likely to report PA
(2003) medicine clinic encounter data Questionnaire; with and and GAD than those
Asthma and Anxiety
panic attack and without without; PA remained sig

panic disorder were diagnoses after controlling for
collapsed into one of asthma sociodemographic
group characteristics the
association PAs remained
sig.,
OR = 1.8 (CI 1.2–2.7), but
GAD did not,
OR = 1.4(CI = .9–2.2)
Halser et al. Adult participants of an Self-report of asthma SCL-90-R, Structured Cross-sectional results: 21%
(2005) epidemiological study, symptoms and self- Psychopathological of individuals with asthma
data collected over 20 yrs report of physician Interview and met criteria for PD, 33%
diagnosis Rating of the Social met criteria for any panic
Consequences for symptoms; 20% of
Epidemiology; individuals with PD met
assessed for the criteria for asthma, 12% of
presence of panic individuals with any panic
disorder, any panic, met criteria for asthma;
and childhood asthma was more strongly
anxiety associated with PD than
any panic;
Longitudinal results: asthma
and panic were not
associated at baseline;
asthma was predictive of
251
Table 2 (Continued)
252
Comparison
subsequent PD and any

panic, although when
demographic data was
included the only held up
for women and smokers;
PD, but not any panic, was
a significant predictor of
later asthma; childhood
anxiety also predicted
subsequent asthma
Heaney Participants were recruited Examined difficult to HADS; psychiatric Compared GAD was the most common
et al. (2005) if they had 1) persisting control asthma; interview offered to treatment anxiety disorder (16%),
refractory symptoms Asthma defined on participants (for also found PTSD, acute
prompting referral, the basis of symptom asthma) stress reaction, and specific
2) minimal maintenance with documented responders phobia (no mention of PD,
therapy of long acting b2 reversible airflow to Anxiety did not sig decrease
agonists, and inhaled obstruction (FEV1 of treatment across treatment and was
steroids 3) at least 1 > 12%), skin prick non not sig different between
course of systematic testing to 12 inhalant responders treatment responders and
steroids in preceding 12 allergens, chest x-ray, treatment nonresponders
months and spirometric
testing; Asthma
related quality of life
assessed using the
Juniper scale
Jonas et al. Self-report of doctor General Well Being None For non-smokers, increasing
(1999) diagnosed asthma Schedule, relaxed asthma incidence rates were
Table 2 (Continued)
Comparison
Adults 25 to 74 at baseline Spirometry was versus anxious found for increasing

and received a medical measured as 65% scale. anxiety. When split
examination. between presence and
Asthma and Anxiety
FEV1, 65%, or no
best trial. absence of early asthma
Respiratory symptoms, similar pattern
symptoms were for no early symptom non-
coded as present or smokers.
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 þ
during the past 3
years,
6) shortness of
breath, and 7)
wheezy or whistling
sounds in chest
Lavoie et al. Adult patients presenting Primary diagnosis of PRIME-MD Compared 25% met criteria for one or
(2005) to asthma clinic asthma; Asthma asthma more anxiety disorder, PD
Control patients most common (12%); 36%
Questionnaire and with and reported a lifetime history
Asthma Quality of without of PAs
253
Table 2 (Continued)
254
Comparison
Life Questionnaire anxiety

asthma diagnoses disorders
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
Meuret et al. Outpatients presenting to Self report ADIS-IV-L 13% of the sample reported
(2005) an anxiety disorders current asthma, which was
specialty clinic, met stated as being higher than
criteria for a principal in the general population;
diagnosis of PD with or patients with a current
without agoraphobia diagnosis of asthma
reported significantly
higher levels of the cardio-
respiratory symptom group
but no difference in the
other symptom groups
Table 2 (Continued)
Comparison
Nascimento Outpatients from an asthma defined by MINI None 52% met criteria for at least
et al. (2002) asthma unit (age range recurrent episodes of one current anxiety
13–80, mean 50.2) dyspnea with diffuse disorder; PD 14%,
Asthma and Anxiety
wheezing and either a agoraphobia without PD

20% improvement in 27%, social anxiety 9%,
FEV1 following a and GAD 24%; concluded
nebulized b2 agonist the prevalence of PD, social
bronchodilator or a anxiety, and GAD were
20% decrease in higher than found in the
FEV1 after the general population
metacoline
bronchoprovocation
test
Perna et al. Outpatients recruited from Age and onset of use of DIS-R. Asked to rate None 19.6% prevalence of PD,
(1997) Allergology Clinic; beta-agonists by the similarity 9.8% prevalence of social
diagnosis of asthma inhalation obtained between an asthma phobia, 45% experienced at
from medical files. attack and a panic least one unexpected
severity of asthma attack. Family sporadic PAs. 96%
scored as mild, history of anxiety described their PAs as
moderate, or severe disorders obtained ‘‘completely different’’ than
based on criteria using a modified their asthma attacks. 54%
defined by National Family History indicated that asthma
Asthma Education Method for occurred before panic,
Program. Research compared to 23% that
Diagnostic Criteria indicated panic before
asthma. Participants with
PD had higher rates of
family history of PD.
255
Table 2 (Continued)
256
Comparison
Pollack et al. Patients presenting for Used a computerized SCID None 41% reported PAs and 11%
(1996) pulmonary function grading system reported PD. 67% of
testing developed by the participants with COPD
hospital met criteria for PD.
Participants with PAs or
disorder were significantly
more likely to complain of
dyspnea at rest and irritable
bowel syndrome. No sig.
differences in pulmonary
functioning abnormalities
or severity
Shavitt et al. Recruited from asthma Screening None 13% indicated agoraphobia
(1992) outpatient clinic (age questionnaire without panic, 6.5%
range from 14–58, mean asking about the indicated PD; 6% simple
26.8) presence of panic/ phobias, 5% social phobia;
anxiety symptoms concluded found greater
in association with than expected prevalence
troubled breathing rates of agoraphobia and
or subjective panic when compared to
anxiety, previous general population
experience of panic,
agoraphobic fears,
and a question
about whether or
not they considered
themselves to be
anxious; SCID
Table 2 (Continued)
Comparison
Sreedhar Adult patients recruited Diagnosis at clinic Manifest Anxiety General Females experienced higher
(1989) from an asthma out- Scale hospital levels of anxiety than males,
patient clinic, a hospital, out- but the sexes demonstrated
Asthma and Anxiety
psychiatrists, and a patients, similar patterns of findings.

department store ‘‘neurotic’’ Asthma patients endorsed
psychiatry significantly higher levels of
patients, anxiety than general out-
and patients and controls, but
controls were not significantly
(no different than ‘‘neurotic’’
physical or psychiatry patients
mental
disorder)
van Beek et al. Relatives of individuals Lifetime prevalence of MINI Relatives of Family members of
(2005) receiving treatment at an respiratory disorder individuals individuals with PD were
anxiety clinic was assessed using a diagnosed sig more likely to report
questionnaire that with panic lifetime prevalence of a
distinguishes disorder COPD and of asthma
between asthma, were specifically than family
bronchitis, compared members of individuals
emphysema, and to relatives diagnosed with other
other respiratory of anxiety disorders
disorders; each was individuals
rated as past and diagnosed
present with other
anxiety
disorders
257
Table 2 (Continued)
258
Comparison
van Peski- Adult patients recruited to Physician diagnosis ADIS-R, STAI, Participants In individuals with asthma,
Oosterbaan a lung function based on chart Agoraphobic given 9% met criteria for current
et al. (1996) laboratory for a review; International Cognitions Scale, diagnosis PD and 12.8% in past year,
histamine challenge test Union Against Body Sensations of asthma In non-asthma
for clinical diagnosis Tuberculosis and Questionnaire, compared participants, 9% current
Lung Disease Panic Attack to those and 11% in past 12 mos. No
Questionnaire; Borg Questionnaire not given sig. differences in PD. Also
scale to assess diagnosis no sig. differences in
breathlessness; of asthma pulmonary functioning.
spirometry; FEV1
Yellowlees Adult patients recruited Pulmonary function Interview assessing None 36% met criteria for an
et al. (1987) from a respiratory unit, tests- FEV1, PaO2, DSM-III criteria anxiety disorder; 24% PD,
patients were required to PaCO2 10% GAD, 2% PTSD
have chronic airflow
obstruction from due to
bronchitis, emphysema,
or asthma
Note: ASI = ADIS = Anxiety Disorders Interview Schedule, Anxiety Sensitivity Inventory, COPD = Chronic Obstructive Pulmonary Disorder, DIS-
R = 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.
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 psychologi-
cal 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 1.3–1.8 (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 1.4–1.7, 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). How-
ever, another study found significant differences in state, but not trait, anxiety
(Erhabor & Mosaku, 2004). One study differentiating between airway obstruc-
tion 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 1.03–12.1; Neuman et al., 2006).
Specificity of Panic Disorder in Asthma
Panic disorder has been suggested to be the anxiety disorder that most fre-
quently co-occurs with asthma and has been more frequently studied in relation
to asthma than other anxiety disorders. Indeed, studies have consistently shown
that individuals with asthma report higher levels of both panic attacks and
panic disorder than found in the general population (Goodwin & Eaton, 2003;
Goodwin, Jacobi et al., 2003; Perna et al., 1997; Pollack et al., 1996). Butz and
Alexander (1993) reported that 65% of their sample of children diagnosed with
acute asthma reported feeling ‘‘panic’’ at the beginning of an asthma attack, and
the presence of panic feelings accompanying asthma attacks significantly pre-
dicted trait anxiety. The relation between asthma and anxiety is supported when
individuals with anxiety are examined as well. Meuret and colleagues (2005)
found that 13% of participants seeking treatment for panic disorder reported
current asthma. Those with co-occurring asthma and panic also reported higher
cardio-respiratory symptoms than participants with panic alone but did not
differ in severity on other types of panic symptoms (i.e., autonomic/somatic and
cognitive symptoms; Meuret et al., 2005). In an attempt to examine the associa-
tion between asthma and anxiety in families, van Beek, Schruers, and Griez
(2005) recruited family members of individuals receiving treatment for an
anxiety disorder and obtained information about their pulmonary health.
Results revealed that family members of individuals with panic disorder were
significantly more likely to report a lifetime prevalence of asthma than family
members of individuals diagnosed with other anxiety disorders.
Panic attacks and asthma attacks have similar symptom presentations includ-
ing sensations of being smothered, choking, and hyperventilation (Feldman,
Giardino, & Lehrer, 2000; Perna et al., 1997). However, studies have shown that
asthma and panic can be differentiated by specific processes. For example,
Schmaling and Bell (1997) recruited participants suffering from either panic
disorder or asthma who completed the Asthma Symptom Checklist (ASC;
Kinsman, Luparello, O’Banion, & Spector, 1973) for a relevant attack. The
findings showed that the panic fear, OR = 0.5, and hyperventilation/hypercap-
nia, OR = 0.70, subscales of the ASC significantly predicted panic disorder,
while the airway obstruction scales, OR =1.73 (dyspnea and congestion) pre-
dicted asthma. There is also some evidence suggesting that individuals suffering
from asthma and panic are able to differentiate between the two. Indeed, one
study found that 96% of participants, outpatients receiving treatment for allergy
at a specialized clinic, described their panic attacks as ‘‘completely different’’
than their asthma attacks (Perna et al., 1997). When the temporal nature of the
two conditions is examined, participants typically report experiencing asthma
attacks before panic attacks (Feldman, Lehrer, Borson, Hallstrand, & Siddique,
2005; Perna et al., 1997).
Studies that have compared patients with asthma and panic to those with
asthma alone suggest that individuals with co-occurring asthma and panic
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 find-
ings 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 1.1–20.1), and panic disorder served as a significant predictor of
future asthma, OR = 6.3 (CI 2.8–14.0). 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 1.1–8.6), and smokers,
OR = 3.5 (CI 1.0–13.4), but not for men, OR = 1.9 (CI .2–19.6), and
nonsmokers, OR = 2.1 (CI .5–8.5). Family history of allergy, OR = 1.8 (CI
1.1–2.9), smoking, OR = 1.6 (CI 1.0–2.5), and childhood anxiety, OR = 0.6
(CI .3–1.3), 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).
Anxiety and Asthma Symptom Severity
One explanation of the relation between asthma and anxiety is that individuals
experience anxiety in response to their asthma symptoms (Katon et al., 2004). In
support of this notion, two studies (Hommel, Chaney, Wagner, & McLaughlin,
2002; Hommel, Chaney, Wagner, White, Hoff, & Mullins, 2003) have reported
significant correlations between objective asthma illness severity (peak flow
rates) and self-reported anxiety (using the Beck Anxiety Symptom Inventory;
BAI). However, several studies have also failed to find significant relations
between asthma severity and/or pulmonary functioning and levels of anxiety
(Di Marco et al., 2006; Feldman et al., 2005; Kinsman, Dirks, & Jones, 1980;
Lavoie et al., 2005; Pollack et al., 1996; Rimington, Davies, Lowe, & Pearson,
2001; Rushford, Tiller, & Pain, 1998; Sández, Vázquez, Romero-Frais, Blanco-
Aparicio, Otero, & Verea, 2005). Furthermore, no significant relationship has
been observed between self-reported (both questionnaire and diagnostic inter-
view) baseline anxiety and respiratory symptom severity perception during
histamine induced bronchoconstriction in patients with asthma (Spinhoven
et al., 1997). Individuals with life-threatening asthma also do not appear to
endorse significantly higher levels of anxiety disorders, based on responses to
diagnostic interviews, than those with less severe asthma (Yellowlees, Haynes,
Potts, & Ruffin, 1988). In a study that compared asthmatics with and without
panic disorder, results of a histamine challenge test indicated that patients
did not differ in overall pulmonary functioning as measured by FEV1 (van
Peski-Oosterbaan et al., 1996). However, asthmatic patients with panic dis-
order reported higher levels of perceived breathlessness after completing
the histamine challenge test than asthmatic patients without panic disorder
(van Peski-Oosterbaan et al., 1996).
Although the findings are equivocal, there does not appear to be a strong
relation between asthma severity and anxiety symptoms. An alternative expla-
nation for the relation between anxiety and asthma is that the presence of
anxiety could potentially influence the individual’s interpretation of and reac-
tion to his or her asthma symptoms. In a recent study by Chen and collogues
(Chen, Hermann, Rodgers, Oliver-Welker, & Strunk, 2006), eighty-six children
with mild or moderate asthma had symptom perception and pulmonary func-
tion measured throughout methacholine challenge (to induce bronchoconstric-
tion). Higher trait anxiety was associated with heightened symptom perception
and greater asthma severity was associated with blunted symptom perception
and with a slower rate of increase in symptom perception across the methacho-
line challenge. These results suggest that anxiety may only play a role when
symptoms are mild, whereas medical variables, such as asthma severity, play a
role in perception of changes in asthma symptoms as bronchoconstriction
worsens. Past studies have failed to find a significant relation between anxiety
and subjective severity of symptoms, suggesting that the interpretation of the
symptoms themselves may not be different between those with and without
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 self-
efficacy which may reduce the individual’s quality of life.
The Effects of Anxiety on Asthma Related Quality of Life
There is evidence suggesting that increased levels of anxiety are associated

with poorer quality of life in individuals with asthma (Di Marco et al., 2006;
Feldman et al., 2005; Hommel et al., 2002; Lavoie et al., 2005; Rimington
et al., 2001). The co-occurrence of anxiety and asthma may also be related to
worse asthma medication usage (Lavoie et al., 2005). For example, indivi-
duals with asthma and comorbid psychiatric disorders (as diagnosed through
a structured interview) have reported greater use of bronchodilators than
individuals with asthma alone (Lavoie et al., 2005). High scores on the
Minnesota Multiphasic Personality Inventory (MMPI) scale Pt, indicative
of general anxiety, have been associated with arbitrary use of bronchodilators
(Mawhinney, Spector, Heitjan, Kinsman, Dirks, & Pines, 1993). An associa-
tion has also been found between high levels of self-reported anxious symp-
toms and low inhaled steroids treatment adherence (Cluley & Cochrane,
2001).
However, the demonstrated negative impact of anxiety on asthma-related
quality of life has not been a consistent finding in the literature. For example,
some studies have failed to find a significant relation between anxiety and
asthma control. One study failed to find a significant association between the
presence of an anxiety disorder in adults being treated for asthma, as indi-
cated by a structured interview, and overall physical, role, and social func-
tioning (Afari et al., 2001). A second study found that self-reported levels of
anxious symptoms were not related to overall functional morbidity, including
number of days missed from school, number of hospitalizations, number of
days hospitalized, and number of emergency visits for asthma in children
(Wamboldt et al., 1998). Studies have also failed to find significant relations
between self-reported anxiety and treatment compliance with inhaled corti-
costeroids and beta-agonists (Bosley, Fosbury, & Cochrane, 1995), overall
health care use (i.e., primary care visits, hospital visits, and oral steroids;
Kullowatz, Kanniess, Dahme, Magnussen, & Ritz, 2007) and emergency
room visits (Nouwen, Freeston, Labbé, & Boulet, 1999; Wamboldt et al.,
1998). These findings suggest that anxiety in individuals with asthma may
influence some domains of quality of life more than others. In addition, there
may be moderating variables that predict when anxiety results in poorer
quality of life in patients with asthma.
Anxiety Vulnerabilities in Asthma
Anxiety and asthma share common symptoms and are often comorbid, perhaps
reflecting a shared pathophysiological vulnerability (Smoller & Otto, 1998).
The construct of ‘‘panic-fear’’ (P-F) has been proposed as a potential vulner-
ability that may account for the occurrence of excessive anxiety in patients with
asthma (Kinsman et al., 1973). P-F refers to subjective panic and anxious
feelings associated with asthma episodes and the perception of bronchocon-
striction. Individuals high in P-F react to asthma symptoms by emphasizing
their distress in an anxious, dependent, and ineffective way (Kinsman et al.,
1980). P-F was originally assessed as a subscale of the Asthma Symptom
Checklist (Kinsman et al., 1973), however Dirks and colleagues later developed
a 15-item MMPI subscale to assess the construct (Dirks, Jones, & Kinsman,
1977). The MMPI scale uses original MMPI questions and was created by
selecting items that significantly differentiated between individuals that scored
low, moderate, and high on the ASC’s P-F scale. One study found that while the
ASC P-F scale significantly predicted the diagnosis of panic disorder in parti-
cipants with asthma, the MMPI P-F scale did not (Carr, Lehrer, & Hochron,
1995). This suggests that items that assess physical symptoms specifically (i.e.,
the ASC) may be more strongly related to panic disorder. High levels of P-F
have been linked with poorer asthma-related quality of life (Vázquez, 2000),
particularly in the physical (e.g., limitations in self-care, physical and social role
activities, bodily pain, and poor physical health) domain (Sández et al., 2005).
Individuals with high P-F have also been found to be more pessimistic about
their ability to cope with and master their asthma, feel more stigmatized and
psychologically different from others, feel more anxiety about their asthma
attacks, and feel more frequent irritation, worry, isolation, and hyperventila-
tion (Kinsman et al., 1980). Finally, levels of P-F have differentiated between
individuals with asthma that frequently visit the emergency room and those
without emergency room visits (Nouwen et al., 1999).
Anxiety sensitivity (AS) has also been examined as a potential vulnerability
that may account for the link between asthma and anxiety. AS is the fear of
anxiety and anxiety related sensations based on the belief that the symptoms
have harmful consequences (Reiss, 1991). AS is a stable, trait-like characteristic
that functions as a vulnerability to the development and maintenance of
anxious symptoms, particularly panic disorder (Taylor, Koch, & McNally,
1992). AS also has been found to significantly predict levels of panic fear
among individuals with asthma (Carr et al., 1995). Carr, Lehrer, Rausch, and
Hochron (1994) conducted a study examining the role of AS in individuals with
asthma and found that endorsement of panic symptoms was significantly
related to level of AS. Thirty-six percent of participants that endorsed high
levels of AS met criteria for panic disorder, while none of the individuals that
endorsed low levels of AS met criteria for panic disorder. In addition, the mean
AS scores of the participants with asthma and panic disorder were higher than
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).
Smoking and Anxiety Vulnerability in Asthma
There is also evidence that smoking is a risk factor for, and may serve to
maintain, some anxiety conditions, particularly; panic attacks and panic dis-
order (see Zvolenksy & Bernstein, 2005). However, few studies have examined
how smoking and anxiety interact in the context of asthma. In a population-
based cohort study of 5,231 participants (Jonas et al., 1999), non-asthmatic
persons aged 25 to 74 were followed for 13 years. For nonsmokers and persons
without respiratory symptoms, a high level of anxiety was a predictor of
increased asthma incidence rates. For the smokers, the relative risks for high
anxiety were not significantly elevated and there was no clear pattern between
anxiety symptoms and risk for the development of asthma. Although research
has also shown a robust association between anxiety and asthma, preliminary
findings highlight the possibility that the presence of smoking may suppress the
effects of anxiety symptoms on the subsequent development of asthma.
Specificity of the Anxiety-Asthma Relation
Although the extant research literature suggests that individuals with asthma
are at an increased risk of developing anxiety disorders, and panic disorder in
particular, when compared to healthy controls (Goodwin, Jacobi, et al., 2003;
Goodwin & Eaton, 2003; Goodwin & Pine, 2002), comparing individuals with
asthma to healthy controls does not provide information about the specificity
of the relation between asthma and anxiety. Consequently, some studies have
taken the approach of including an additional non-asthmatic medical group as
a comparison condition. Such studies are particularly helpful in determining if
increased anxiety is related to the presence of a medical condition or a reflection
of an effect that is unique to asthma. In an early study, Sreedhar (1989)
compared participants with asthma to general hospital outpatients, ‘‘neurotic’’
psychiatry patients, and controls (with no physical or mental disorder). Results
revealed that participants with asthma endorsed significantly higher levels of
anxiety than the general outpatients and controls, but were not significantly
different on anxiety than the psychiatric participants (Sreedhar, 1989). Simi-
larly, 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.
Towards a Cognitive-Behavioral Model of the Co-occurrence

of Anxiety and Asthma
Asthma and symptoms of anxiety share many similar symptoms and often co-
occur, suggesting that perhaps both conditions share a common underlying
vulnerability. It has been suggested that respiratory distress may be the com-
mon pathophysiology between asthma and anxiety symptoms, particularly the
experience of panic and panic disorder (Smoller, Pollack, Otto, Rosenbaum, &
Kradin, 1996). Respiratory distress as a common pathophysiology may also be
observed as exaggerated increases in respiratory drive. There is research evi-
dence that increases in respiratory drive (typically assessed by introducing
occlusion of breathing during inhalation through a tube) can be easily induced
in asthmatics (Kelsen, Fleeger, & Altose, 1979). Respiratory distress may lead
to episodes of hyperventilation, particularly in the absence of increases of a
physiological need for ventilation (Lehrer, 1998). The physical sensations asso-
ciated with episodes of hyperventilation may give rise to panic and anxiety.
Feldman and colleagues (2000) have suggested that the experience of respira-
tory distress (e.g., dyspnea) in asthma and anxiety-related conditions may also
be mediated by CO2 hypersensitivity. As a consequence of bronchoconstriction
in asthma, medullary chemoreceptors and/or the locus coeruleaus may be
stimulated. Repeated stimulation of the chemoreceptors may result in a low
‘‘suffocation alarm’’ threshold (Klein, 1993). This process may serve as the
developmental context for a vulnerability for anxiety/panic vulnerability in
patients with asthma. Although biological models based on CO2 hypersensitiv-
ity and a low ‘‘suffocation alarm’’ threshold are consistent with the clinical
description of anxiety/panic symptoms observed in patients with asthma, the
underlying processes articulated by these modes have not consistently been

supported in basic laboratory research (see Smoller et al., 1996 for review).
A cognitive-behavioral approach that emphasizes dysfunctional beliefs
about bodily symptoms may also have utility in better understanding how the
experience of anxiety is reinforced and subsequently maintained in the context
of asthma (Smoller et al., 1996). AS, the fear of bodily sensations derived from
beliefs that such sensations have harmful consequences, had been shown to be a
risk factor for the development of anxiety-related conditions, especially panic
disorder. AS is proposed to arise from the combination of genetic predisposi-
tions (Stein, Jang, & Livesley, 1999) and learning experiences that result in the
acquisition of beliefs about potential harmful effects of autonomic arousal
(e.g., Stewart et al., 2001). Previous longitudinal research has shown that
asthma occurs first thus possibly serving as a risk factor for the development
of anxiety-related problems (Goodwin & Eaton, 2003; Perna et al., 1997). A risk
factor is a variable that is related to, and temporally precedes, an undesirable
outcome. At some level, asthma may be regarded as non-malleable in that it is
chronic and when a risk factor is non-malleable (cannot be changed); it may be
classified as a fixed marker (see Zvolensky, Schmidt, Bernstein, & Keough, 2006
for review). However, negative attributions and beliefs that derive from asthma
can be classified as variable risk factors for anxiety in that they can be changed.
Although the identification of asthma may prove to be important for identify-
ing individuals who may be at risk for the development of anxiety conditions,
negative attributions and beliefs that derive from asthma will ultimately be the
target of preventative interventions.
Asthma and associated beliefs may serve as a context in which vulnerable
individuals learn to fear bodily sensations because such sensations could poten-
tially have harmful consequences (i.e., AS). Fig. 1 graphically depicts a cogni-
tive-behavioral model that may be used as a heuristic for conceptualizing
excessive anxiety that may be experienced in patients with asthma. This model
is adapted from available models that stress the importance of the misinterpre-
tation of physical symptoms in the etiology and maintenance of anxiety-related
conditions (Abramowitz, Deacon, & Valentiner, in press). The perceived sever-
ity of past asthma attacks may increase the perceived severity and consequences
of future attacks (Ten Thoren & Petermann, 2000). According to this cognitive-
behavioral model, mistaken beliefs about the likelihood and severity of having
an asthma attack among those predisposed towards being fearful of bodily
sensations may be the foundation for the development of anxiety pathology.
Such beliefs also include the assumption that the experience of respiratory
symptoms always indicate that something is seriously wrong (i.e., hurt equals
harm). Given that asthma episodes are often unpredictable and may be per-
ceived as uncontrollable, asthma-related dysfunctional beliefs may be mobi-
lized to deal with the uncertainty. However, chronic perceptions of
unpredictability and uncontrollability have a strong negative impact on func-
tioning and have been implicated in the development of anxiety-related disor-
ders (Mineka & Zinbarg, 1996).
Asthma-related dysfunctional beliefs among those fearful of bodily sensa-

tions may then motivate vigilance for respiratory cues. For example, it has been
shown that asthma patients with panic disorder tend to perceive more symp-
toms 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 uncer-
tainty 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 asso-
ciated 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.
Cognitive-Behavioral Treatment of Anxiety in Asthma
Although asthma may be a fixed marker, specific interventions derived from the
cognitive behavioral model may have clinical utility for the treatment and
prevention of anxiety among patients with asthma (Smoller et al., 1996). Such
interventions directly target catastrophic cognitions and the preoccupation and
fear of bodily sensations that may have specific links with anxiety, as such
symptoms appear to differentiate asthma patients who develop an anxiety
disorder, particularly panic, from asthma patients that do not develop an
anxiety disorder (Carr et al., 1994). However, it should be noted that the
experience of anxiety among patients with asthma is not necessarily
Dysfunctional Beliefs
Overestimating the likelihood/severity of having an
asthma attack
prevents acquisition of selective attention

disconfirmatory evidence to signs of asthma
Respiratory Vigilance
Safety-Seeking Behaviors
motivation to avoid sensations increase likelihood of noticing

and perceived harm benign respiratory sensations
Perception of
Uncertainty/Anxiety/Panic Airway Symptoms
misinterpretation of
activate respiratory fear
ambiguous symptoms
Catastrophic Cognitions
About Symptoms
Fig. 1 Cognitive-behavioral model of excessive anxiety in patients with asthma
problematic. Thus, the across-the-board application of cognitive behavioral

treatment for anxiety reduction in asthma is not indicated (Kinsman, Dirks,
Jones, & Dahlem, 1980). Among some patients, the experience of anxiety may
improve self-care by motivating patients with asthma to seek treatment. In fact,
there is evidence that the experience of low generalized anxiety and panic is
associated with a lower risk of rehospitalization among patients with asthma
(Jones, Kinsman, Dirks, & Dahlem, 1979).
Although some degree of anxiety regarding asthma is adaptive in motivating
self care, there is evidence that morbidity tends to be higher among asthmatic
patients who experience symptoms of panic disorder (Baron et al., 1986).
Cognitive behavioral interventions aimed at anxiety management may be useful
adjunctive treatments for asthma patients who are particularly fearful of bodily
sensations. Feldman and colleagues (2000) have outlined a cognitive behavioral
treatment of panic that has been adapted for patients with asthma. This inter-
vention highlights specific treatment components including: 1) Treatment
Rationale and Education (Sessions 1–2); 2) Asthma Self-Management (Sessions
3–4); 3) Panic Attack Management (Sessions 5–6); 4) Asthma and Panic Differ-
entiation (Sessions 7–8); and 5) Imagery Exposure, Problem Solving, and
Relapse Prevention. An important component of this treatment is teaching
patients to discriminate asthma and panic symptoms in order to correctly
address excessive fear of bodily sensations. Patients are also introduced to
interoceptive exposures as a method of confronting feared bodily sensations.
The patient is encouraged to practice the exposures (without engaging in safety
behaviors) that produces his or her most feared bodily sensations with the goal
of habituating to these sensations. Respiratory-related exposure is limited to

pursed lips breathing in this treatment, pending further evaluation, because of
possible iatrogenic effects in patients with asthma. Interoceptive exposure
exercises for panic control (e.g., spinning) may be applied if nonrespiratory
symptoms (e.g., dizziness) are present. Physical exercises designed to increase
heart rate and induce shortness of breath may be integrated into treatment for
anxiety among patients with asthma. However, integration of interoceptive
exposures that my cause respiratory distress should be done in consultation
with the patient’s internist or pulmonologist (Smoller et al., 1996).
Although there are well-validated treatments for anxiety-related disorders
based on empirically supported principles that may inform the development of
efficacious treatments for anxiety and panic in patients with asthma, very little
research on treatment development has been conducted along these lines. In a
recent review of the literature, Deshmukh and colleagues (Deshmukh, Toelle,
Usherwood, O’Grady, & Jenkins, 2007) concluded that the asthma research
literature is lacking in randomized controlled trials applying cognitive
behavioral techniques to patients with co-morbid asthma and clinical anxiety
manifestations. The available studies that have examined the efficacy of
psychological treatments, broadly defined, in individuals with asthma are also
characterized by relatively poor methodology with small sample sizes (Deshmukh,
Toelle, Usherwood, O’Grady, & Jenkins, 2007; Yorke, Fleming, & Shuldham,
2007). There is some preliminary evidence that cognitive-behavioral therapy leads
to improvements in quality of life among individuals with asthma (Yorke et al.,
2007). However, no conclusions could be reached regarding the effectiveness of
cognitive therapy in reducing anxiety symptoms. Overall, the paucity of research
highlights the need for additional studies examining the effectiveness of psycho-
logical interventions for excessive anxiety among individuals with asthma.
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 comor-
bid 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
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 inter-
pretations 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 conse-
quences (i.e., panic-fear, AS) may function as the underlying vulnerability for
the development of excessive anxiety among patients with asthma.
Limitations and Future Directions
Previous research has succeeded in identifying a link between asthma and the
experience of anxiety, both generally and with specific disorders. However,
much of the past research has focused on examining the frequency of the
comorbidity of asthma and anxiety, without providing information about the
nature or strength of the relation. Many non-psychological risk factors have
been identified for asthma, some of which (e.g., smoking habits) have also been
previously identified as risk factors for anxiety. Initial research suggests that the
relation between asthma and anxiety remains even when controlling for risk
factors, but that the relation may vary between individuals with and without
prominent risk factors (Halser et al., 2005). Future research should improve
assessment and consideration of non-psychological risk factors. Findings also
suggest that the prevalence of anxiety disorders and symptoms is higher in
individuals with asthma than in individuals with other medical conditions.
However, there is evidence to suggest that additional medical conditions with
similar presentations to anxiety symptoms (e.g., cardiac problems) may be also
be associated with anxiety. Continued use of medical control groups is needed
to determine if general factors related to illness are linked with anxiety, or if the
asthma-anxiety relation is unique.
Future research explicating the relation between asthma and anxiety may
benefit from appeal to a cognitive behavioral model. This model highlights the
importance of dysfunctional beliefs based on misinterpretations of benign
respiratory symptoms and excessive asthma-related safety-seeking. This
model offers components that are amenable to basic laboratory research and
identification of moderators (variables that alter the strength or direction of the
relation between asthma and anxiety) and mediators (mechanism that explains
the association between asthma and anxiety) of the cognitive behavioral model
inform effective treatment and prevention of excessive anxiety among patients
with asthma. Moderators in this context may consist of important individual
difference characteristics (i.e., high AS, chronic stress) that, in the presence of
asthma, increase the risk of the development of clinical anxiety. Research on

mediators or explanatory process linking asthma and anxiety symptoms would
benefit from the examination of the potential role of perceived uncontrollability
and unpredictability. Importantly, additional studies examining the efficacy of
cognitive behavioral treatments and other psychosocial treatment interventions
for asthma patients with excessive anxiety are clearly needed. Such treatments
have the potential of improving the quality of life of asthma patients as well as
potentially minimize unnecessary health care costs.
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Cardiovascular Disease and Anxiety
Kamila S. White
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 exhaus-
tion, 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
Ó Springer 2008
280 K. S. White
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.
Some Terminology and Background
The field of cardiac psychology or psychocardiology uses a number of impor-

tant medical terms to describe facets related to heart disease (Jordan, Barde, &
Zeiher, 2007). Although many terms are quite specific (e.g., myocardial
infarction [MI] or heart attack), other terms are more general. First, the terms
coronary artery disease (CAD) and CHD are often used synonymously, with
the understanding that CHD does not exist in the ICD-10 Classification of
Diseases (i.e., chronic ischemic heart disease) (World Health Organization,
2006). In this chapter, these terms are used interchangeably. Second,
nearly all indications of CHD including angina pectoris (i.e., CHD-related
chest pain), MI, and SCD are the product of atherosclerosis. The term athero-
sclerosis comes from the Greek words athero (meaning paste) and sclerosis
Cardiovascular Illness 281
(meaning hardness) and generally refers to the process of fatty substances

(i.e., cholesterol, cellular waste product, calcium, and fibrin) building up in
the inner lining of an artery (American Heart Association, 2006). This buildup
that results is termed plaque. Atherosclerosis then is the general term for the
thickening and hardening of the arteries. The precise nature of onset is not
known, however, theories posit that atherosclerosis is set in motion because the
innermost layer of the artery (the endothelium) becomes damaged. Three likely
causes of this damage are elevated cholesterol and triglyceride in the blood
(hypercholesterolemia), high blood pressure (hypertension), and cigarette
smoke. Cigarette smoke aggravates and hastens atherosclerosis in the coronary
arteries, the aorta, and the arteries of the legs. As a result of this damage and the
accumulation of substances deposited in the artery wall, the endothelium
thickens. If the artery wall is amply thickened, the diameter of the artery is
reduced resulting in less blood flow and decreased oxygen supply. If the oxygen
supply to the heart is reduced sufficiently, a heart attack can occur. Similarly,
reduced oxygen flow to the brain and legs may result in stroke and peripheral
vascular disease, respectively.
Atherosclerosis is thought to result from a number of risk factors. Extensive
research has documented the heritable (sex, age, race, family history) and
modifiable risk factors (tobacco use, obesity, hypertension, physical inactivity,
diabetes mellitus) associated with an increased risk for CHD (American Heart
Association, 2006). Each or a combination of these risk factors may combine
synergistically to contribute to CHD. Traditional risk factors are thought to
account for roughly 40% of CHD incidence (Marmot & Winkelstein, 1975),
and CHD has a genetic component independent of these risk factors (Shiffman,
Rowland, Sninsky, & Devlin, 2006). Incidence and severity of some of these
established risk factors are affected by behavioral factors – and, in fact, each of
the major modifiable risk factors has a behavioral component. In addition,
psychosocial risk appears to influence CHD including: Social support/social
isolation, job strain, vital exhaustion, depression, stress, hostility, and anxiety.
This chapter critically explores the current knowledge concerning anxiety in
CHD. Research has accumulated over the years establishing anxiety as a
possible risk factor in CHD development, progression, and outcome; however,
a number of important factors need to be considered in our contemporary
analysis of past studies.
Anxiety and Increased Risk for CHD: Prospective Evidence
Anxiety is a cognitive-affective process that is commonly exemplified by a

perceived inability to predict, control, or obtain desired results (Barlow,
2002). The emotion of anxiety is universally experienced and is seldom
pathological except when it becomes persistent. Anxiety disorders are among
the most prevalent psychiatric disorders in the general population afflicting
282 K. S. White
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.
Prospective Epidemiological Studies
Perhaps the most compelling support for a link between anxiety and CHD has
arisen from longitudinal studies conducted with initially healthy samples that
have controlled for the effects of known cardiovascular risk factors in the
prediction of subsequent disease. In the recent two decades, large-scale
community-based studies have established a significant relationship between
anxiety and subsequent death due to cardiac pathology in men (Haines,
Imeson, & Meade, 1987; Kawachi, Colditz et al., 1994; Kawachi, Sparrow,
Vokonas, & Weiss, 1994) and women (Eaker, Pinsky, & Castelli, 1992). Support
from these studies is bolstered because each study examined the anxiety-CHD
link in samples free of CHD at baseline, controlled for some known cardiovas-
cular risk factors, and predicted follow-up at time periods of up to 20 years.
First, one of the earliest prospective studies to systematically examine the
anxiety-CHD link was the Northwick Park Heart Study. The Northwick study
followed 1,457 initially healthy men across 10 years (Haines et al., 1987). After
controlling for a set of cardiovascular risk factors, elevated phobic anxiety, as
assessed by the Crown-Crisp Index (Crown & Crisp, 1966), was associated with
fatal CHD in this initially healthy sample of men. In a second study also
conducted exclusively with males, the Health Professionals Follow-up Study
(Kawachi, Colditz et al., 1994), Kawachi and colleagues followed a large sample
(N = 33,999) of health professionals free of CHD at baseline. Results revealed
that over the two-year follow-up period, the age-adjusted relative risk of fatal
CHD among men with the highest levels of phobic anxiety was three times that
compared to men in the lowest levels of anxiety. Risk for fatal CHD increased
with mounting phobic anxiety even after controlling for risks conferred by
other major cardiovascular risk factors (e.g., family history of heart disease,
smoking, blood pressure); notably, the excess risk conferred by phobic anxiety
was confined to SCD, defined as death within 1 hour of symptom onset, rather
than non-sudden CHD death. Nonfatal MI was not significantly associated

with phobic anxiety in this study.
Similar results were also found in the Veterans Administration Normative
Aging Study conducted with a sample of largely white males (Kawachi,
Sparrow et al., 1994). The Normative Aging study assessed anxiety symptoms
using a 5-item scale from the Cornell Medical Index. The association between
anxiety and CHD was only marginally significant after adjusting for other risk
factors. Likewise in another set of analyses using Normative Aging data, the
risk of disease was examined with regard to worry, a cognitive component of
anxiety (Kubzanksy et al., 1997). Study outcome showed that males with the
highest levels of worry were 2 ½ times more likely to suffer nonfatal MI; men
with moderately elevated worry were also at increased risk. At follow-up
(M follow-up = 10.9 years), Kubzansky and colleagues found that anxiety
and shared general distress were independently associated with the
development of CHD (Kubzansky, Cole, Kawachi, Vokonas, & Sparrow,
2006). In this case, the anxiety-CHD link was independent of shared general
distress, anger, and depression associations. Although anxiety was only weakly
associated with the development of angina, it was strongly associated with both
fatal and nonfatal MI. Another recent study again conducted with veterans
demonstrated a prospective association between post-traumatic stress disorder
(PTSD) symptoms and CHD. Researchers studied 1,946 male veterans of
World War II and Korea and found that veterans with symptoms of PTSD
are at greater risk of heart attacks as they age (Kubzansky, Karestan, Spiro,
Vokonas, & Sparrow, 2007). This association was significant even after
controlling for depressive symptoms. Although this study warrants replication,
results suggest that symptoms of post-traumatic stress increase CHD incidence
in older men. Importantly, each of these prospective cohort studies established
a dose-response gradient for the anxiety-CHD relation.
Although the prevalence of anxiety (Wittchen, Zhao, Kessler, & Eaton,
1994) and phobic disorders (Magee, Eaton, Wittchen, McGonagle, & Kessler,
1996) is known to be twice as high among women, less is currently known about
the relationship between anxiety and CHD among women. In one study
examining 20-year follow-up of women participating in the Framingham
Heart Study, multivariate analyses showed that symptoms of anxiety and
tension in 749 subjects were independent predictors of CHD after controlling
for a set of cardiovascular risk factors (Eaker et al., 1992). Significant associa-
tions were found for anxiety-MI and anxiety-coronary death among
homemakers, but not among employed women. Indeed, these researchers
found a 6 fold increase in CHD risk for women who self-reported any symptoms
of ‘‘tension’’ after controlling for known risk factors. In this case, anxiety was
assessed by self-ratings on a social strain scale developed for the study. In a
recently published 12-year prospective study conducted with women, the
Nurses’ Health Study, Albert and colleagues found that among women without
a history of cardiovascular disease, high levels of phobic anxiety were associated
with an increased risk of fatal CHD, particularly from SCD. Notably, some but
284 K. S. White
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.
Prospective Studies in Samples with Known CHD
In addition to studies conducted with initially healthy samples free of CHD at

baseline, important published reports have examined anxiety and subsequent
documented CHD and cardiac death in prognostic samples. To date, the
association between anxiety and cardiac death or documented CHD in samples
with known CHD at baseline has been examined in over 10 prospective studies
using independent patient samples (sample sizes ranging from 86 to over 5,000;
with follow-up periods from 6 months to 10 years). For a complete review see
(Suls & Bunde, 2005). Taken as a whole, the published research linking anxiety
and CHD in prognostic samples is mixed. Moreover, this research is compli-
cated by interpretation challenges and causal limitations. Although several
studies demonstrate a positive association between initial anxiety and later
cardiac morbidity and/or mortality (even after controlling for known risk
factors), still others have not found this relationship to be present in patients
with known CHD.
Based on data from several prognostic samples, anxiety appears to relate to
subsequent CHD, cardiac events, and cardiac death. Frasure-Smith and
colleagues followed 222 patients for 1 year post-MI and found that higher
scores on a self-report measure of state and trait anxiety were related to the
occurrence of new cardiac events (i.e., unstable angina admissions, recurrent
fatal and non-fatal MI) (Frasure-Smith, Lesperance, & Talajic, 1995).
Notably, the influence of anxiety was independent of other predictors
(i.e., depression, other cardiac risk factors), and it was the only variable
studied that was coupled with recurrent MI. Consistent findings were
reported in another study by this group conducted with 896 post-MI patients
(Frasure-Smith & Lesperance, 2003). In a study examining patients 48 hours
after acute MI, higher anxiety levels (assessed via brief, self-report symptom
checklist) conferred an almost 5 times increased likelihood of experiencing
in-hospital cardiac complications or death (i.e., 19.6% high-anxiety group

versus only 6% in lower anxiety), independent of cardiac risk factors
(Moser & Dracup, 1996). More than two thirds of patients suffered anxiety
levels considered above normal, and 26% reported levels of anxiety equivalent
to or above those reported by psychiatric inpatient samples. Other studies
have shown that over and above the effects of depression, anxiety appears to
have a negative influence on outcomes following ischemic coronary events. In
a study of 913 patients with unstable angina and MI, anxiety predicted
recurrent cardiac events at 6 months and one year follow-up (Grace, Abbey,
Irvine, Shnek, & Stewart, 2004). Anxiety was assessed using the self-rated
Crown-Crisp index and the Anxiety subscale of the PRIME-MD (Spitzer et
al., 1994). Hermann and colleagues studied CHD patients who were referred
for exercise testing and found that anxiety (measured by the Hospital Anxiety
and Depression Scale) was associated with cardiac mortality at 5-year
follow-up (Hermann, Brand-Driehorst, Buss, & Ruger, 2000). Finally, one
study that examined the relative contribution of both anxiety and depression
found that anxiety was an independent predictor of both cardiac events and
increased health care consumption. In this study, anxiety symptoms wholly
accounted for the depression-cardiac prognosis association (Strik, Denollet,
Lousberg, & Honig, 2003).
A related line of research shows that the tendency to suppress emotional
distress may be coupled with both cardiac and non-cardiac mortality, irrespec-
tive of disease severity and irrespective of disease biomedical risk factors of
mortality. In one study conducted with patients with established CHD, indivi-
duals who scored high on the trait scale of the Speilberger State-Trait Anxiety
Inventory and who endorsed high social inhibition (i.e., termed Type D person-
ality style) showed a four-fold increase in cardiac death as compared to those
who did not have this personality style at 6–10 years follow-up (Denollet et al.,
1996). In a more recent study by this same group, Denollet and colleagues found
that the Type D personality distinction was useful in predicting cardiac events
at 5-years follow-up even after controlling for concurrent symptoms and psy-
chological stress (Denollet, Pedersen, Vrints, & Conraads, 2006).
These prospective studies conducted with documented CHD patients
indicate that anxiety appears to have a negative impact on disease course and
outcome (i.e., disease severity, mortality, recurrent cardiac events), and this
influence appears to be independent of the effects of depression. However, it is
important to report that this conclusion is not without some contradictory
evidence. For instance, Ahern and colleagues examined anxiety in 502 patients
following MI and arrhythmia, and they concluded no relationship between
anxiety and cardiac arrest or death at 1 year follow-up after controlling for
known risk factors (Ahern et al., 1990). Similar null findings were reported by
others including Lane and colleagues (Lane, Carroll, Ring, Beevers, & Lip,
2001) and Mayou and colleagues who both examined anxiety in post-MI
patients (Mayou et al., 2000) at 1-year follow-up.
286 K. S. White
Studies in Psychiatric Samples
Although truly prospective studies of the anxiety-CHD association have not

been conducted with patients suffering anxiety disorders, a number of retro-
spective reports establish that anxiety (and panic disorder in particular) is a risk
factor for CHD. Specifically, psychiatric inpatients and outpatients with initial
diagnoses of anxiety conditions have shown a greater-than-expected mortality
rate. One early study suggested a link between anxiety disorders and CHD
mortality by examining psychiatric inpatients diagnosed with panic disorder
(PD) over the course of a 35-year follow-up. Coryell and colleagues found that
the risk of cardiovascular mortality was twice as high in this anxiety group
(i.e., anxiety neurosis, a panic-like form of anxiety that is similar to current
criteria for DSM-IV PD) as compared with the general population; this excess
risk was not found in patients with other psychiatric disorders (Coryell, Noyes,
& Clancy, 1982). A trend toward similar findings was reported for men but not
women in an age- and sex-matched sample of surgical control patients but these
findings did not quite reach traditional indications of statistical significance,
p < .07 (Coryell, Noyes, & House, 1986); as such, excess mortality due to CHD
in these studies was limited to males with PD, and CHD death rates among
females with anxiety were in the expected range. The authors concluded that the
increased mortality in general was largely ascribed to CHD and suicide. Still
other studies by Allgulander and Lavori found that ‘‘heart deaths’’ among men
with ‘‘pure’’ anxiety neurosis were higher than expected (Allgulander & Lavori,
1993) and predictive of fatal CHD at 14-year follow-up (Allgulander & Lavori,
1991); however, the extent of this association with suicide and CHD remains
unknown.
Although these studies have been often cited as prospective evidence that PD
is a CHD risk factor (Kubzansky, Kawachi, Weiss, & Sparrow, 1998; Suls &
Bunde, 2005), these results must be interpreted with vigilance. Unfortunately,
both of the above studies used suboptimal designs and were not truly prospec-
tive by comparison with age- and sex-matched controls. Moreover, in some
cases, the relatively small sample sizes lacked the statistical power to render
significance. Further, diagnoses were derived from chart review, and
cardiovascular ‘‘causes’’ of death were not definitive (e.g., ‘‘circulatory disease’’)
(Coryell et al., 1982). Because of these reasons, it is not possible to exclude other
biomedical, behavioral (i.e., smoking, sedentary behavior), or psychological
factors as the cause of the CHD-related mortality. As a result, it can be
concluded that while anxiety disorders, and PD in particular, is associated
with increased incidence of cardiovascular morbidity, the direction of this
causality remains unclear (Chignon, 1993; Fleet, Lavoie, & Beitman, 2000).
Equally important, contrary to the above studies, another albeit smaller body
of published research with follow-up time periods ranging from 7–14 years
conducted with psychiatric samples (some identified as outpatients with anxiety
neurosis) who were initially free of CHD (Hippisley-Cox, Fielding, & Pringle,
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 prospec-
tive studies. And the claim that self-reported anxiety confers CHD risk appears
to be most persuasive in studies with initially healthy samples; this is particu-
larly 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.
Prevalence of Anxiety Disorders in Patients with CHD
Although the experiences of anxiety and fear are universal, research examining
the incidence of clinically significant anxiety in CHD has received considerably
less attention. Accumulating data support a high rate of comorbid anxiety
disorders in patients with CHD. Although strictly prospective research
examining anxiety disorders as risk factors for CHD is absent, correlational
and retrospective research supports an anxiety disorder-CHD association.
Incidentally, the prevalence of anxiety disorders in CHD appears to at least
parallel the high rate of depressive disorders in this group (Gonzalez et al., 1996;
Hance, Carney, Freedland, & Skala, 1996).
A high proportion of patients with estabshed CHD suffer from anxiety
disorders (Fleet et al., 2000; Goldberg et al., 1990). One of the first systematic
studies of anxiety disorders in cardiology outpatients was conducted by
288 K. S. White
Beitman and colleagues, who examined the prevalence of PD in patients with

documented CAD (Beitman, Basha, & Flaker, 1987). In this study, 53% of
patients with documented CAD met criteria for PD assessed by a validated
structured clinical interview; and this percentage may be an underestimate as
the majority of patients (36 out of the 47) did not undergo coronary arterio-
graphy to determine the presence of CAD. In a subsequent study conducted by
this same group (Basha et al., 1989), the authors found support for this
increased rate of PD in CAD patients and concluded that this association
may be more common in patients with atypical chest pain. In a more recent
cohort study examining the association between PD and CHD using a large
national managed care database, researchers found that patients with PD
showed a nearly 2-fold increase in their risk for CHD, even after controlling
for CHD risk factors (Gomez-Caminero, Blumentals, Russo, Brown, &
Castilla-Puentes, 2006). In addition to increased prevalence of PD, other
anxiety disorders occur at an increased rate in CHD patients including
generalized anxiety disorder and PTSD (Bankier, Januzzi, & Littman, 2004).
Despite the fact that most research in this area has been restricted in scope to
only one disorder at a time, one particularly persuasive study systematically
examined a set of psychological disorders (assessed using the Structured
Clinical Interview for the Diagnostic and Statistical Manual of Mental
Disorders [SCID]) in outpatients with CHD (Bankier et al., 2004). In addition
to an increased rate of depressive disorders, current anxiety disorders including
GAD (24%) and PTSD (29%) were identified at a high rate. Indeed, among
nonclinical and representative samples, elevated CHD risk (as indicated by
self-reported smoking status, body mass index, and medication use for
hypertension, hypercholesterolemia, and diabetes) has been associated with
GAD (Barger & Sydeman, 2005).
Though the generalizability of past research is nearly exclusive to cardiology
settings, some research has explored the anxiety disorder-CHD connection in
other settings. Fleet and colleagues examined this prevalence in consecutive
patients presenting to the emergency department; these researchers found that
34% of patients with documented CAD (i.e., determined by previous MI,
bypass surgery, angioplasty, an angiogram indicating 50% stenosis in one
major coronary artery or positive nuclear stress test) met criteria for current PD
(Fleet et al., 1996). Because many CHD patients also experience atypical chest
pain and are referred for gastroenterological evaluation, Kane and colleagues
retrospectively examined the prevalence of anxiety disorders in patients with
CAD referred to a digestive disease laboratory. These researchers found that
among patients with known CHD more than 70% of these patients met criteria
for Generalized Anxiety Disorder, 49% met criteria for PD, and 31% who met
criteria for Major Depression (Kane, Strohlein, & Harper, 1991). Notably,
though findings of this study suggest an increased prevalence of Axis I disorders
in patients with CAD, results need to be interpreted with some caution because
‘‘diagnoses’’ were established through a mailed questionnaire and it is not
known how ‘‘known heart disease’’ was determined in this group of patients.
Other correlational studies show that anxiety, particularly PD, is prevalent in

individuals with CHD. In the 1990s, Weissman and colleagues showed PD and
CHD were significantly associated using data from the Epidemiological
Catchment Area database (Weissman, Markowitz, Ouellette, Greenwald, &
Kahn, 1990). Falger and colleagues reported that veterans exposed to
war-related traumatic events in World War II showed not only increased
incidence of PTSD but also increased medical morbidity including cardiovas-
cular disease (Falger et al., 1992). In short, these studies conducted with
psychiatric samples seem to indicate that anxiety and anxiety disorders may
precipitate or exacerbate CHD.
Anxiety in Patients with Non-Cardiac Chest Pain
One diagnostic category of patients that often present to cardiology settings but
whom are less well understood is those experiencing non-cardiac chest pain
(NCCP). In contrast to patients who have a detectible cardiovascular cause for
their chest pain, the majority of patients who experience recurrent chest pain are
found to have normal coronary angiograms and show no other identifiable
medical condition (Fleet & Beitman, 1997). It has been estimated that more
than 6 million people present annually to US emergency departments with chest
pain suggestive of MI (American Heart Association, 2006), however, the
majority of these individuals do not receive an organic explanation for their
chest pain (Kroenke & Mangelsdorff, 1989). Ten to 13 billion dollars is spent
annually to care for patients who are admitted with suspected ischemic
symptoms but who do not sustain acute MI (Roberts & Kleinman, 1994).
Despite their apparently favorable cardiac prognosis, patients with NCCP
show poor outcomes that are comparable to patients who are diagnosed with
CHD (Eifert, Hodson, Tracey, Seville, & Gunawardane, 1996). In fact, when
compared to cardiac patients, surgical patients, and normal controls, indivi-
duals with NCCP (i.e., often accompanied by subjective heart-focused anxiety)
experience more physical symptoms and are as equally fearful of these physical
sensations as cardiac patients (Eifert et al., 1996). This attention to and fear of
heart-related problems (often termed heart-focused or cardiac anxiety) has been
shown to be predictive of the severity of the chest pain as well (Zvolensky,
Eifert, Feldner, & Leen Feldner, 2003). Heart-focused anxiety, as assessed via
the Cardiac Anxiety Questionnaire (Eifert, Thompson et al., 2000), is thought
to be conceptually distinct from trait anxiety, anxiety sensitivity, and other
forms of health anxiety (Eifert, Zvolensky, & Lejuez, 2000) and shares only
moderate zero-order correlations with the ASI. For example, trait anxiety taps
into anxiety-based negative affect generally, heart-focused anxiety relates to
specific fears of cardiac-related events, physical sensations, and functioning.
Research has demonstrated the prevalence and costs associated with NCCP,
however, factors associated with its onset, severity, and persistence are not
290 K. S. White
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 char-
acterized 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 preven-
tion 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; anxi-
ety 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
assigned an Axis I anxiety disorder; the most common anxiety disorders

assigned were PD, social phobia, and generalized anxiety disorder. Mood
disorders were present in 17% of patients. In other studies comparing chest
pain patients with and without CAD, the presence of psychiatric diagnosis has
been significantly higher among patients without CAD (Cormier et al., 1988;
Katon et al., 1988). Several studies have documented the greater prevalence of
PD in patients with NCCP as compared to those with cardiac chest pain
(Beitman & Basha, 1992; Dammen, Arnesen, Ekeberg, & Friis, 2004; Fleet
et al., 1996) with few exceptions (Yingling, Wulsin, Arnold, & Rouan, 1993).
Unfortunately, this research signifying an increased rate of anxiety
disorders in patients with NCCP has been used to suggest that the etiology
and clinical presentation of NCCP is psychological in nature (Beitman et al.,
1991; Yingling et al., 1993). Although these diagnostic studies are informative,
it may be premature to conclude that NCCP is entirely psychological in the
absence of a systematic investigation of cardiac risk factors in this patient
group (White, Raffa et al., in press) and more longitudinal work. Recent
reviews showing less favorable outcomes (Bugiardini & Bairey Merz, 2005)
combined with findings from recent studies showing a high incidence of CHD
risk factors in patients with NCCP (White, Malone et al., 2006) indicate that
this group of patients warrants more investigation. It may be that NCCP
patients who show increased CHD risk are worried prematurely for current
heart disease but may be ideal for risk factor modification given the high
incidence of risk factors that has been demonstrated in this population. The
importance of this question is underscored by the recent studies showing that
anxiety may be an independent risk factor for CHD. Research by Gomez-
Caminero and colleagues (2006) found that the presence of anxiety (i.e., PD)
increased the risk of CHD (Gomez-Caminero et al., 2006), and others have
found that general anxiety (Kubzansky et al., 2006) and phobic anxiety are
associated with an increased risk of fatal CHD in both men (Kawachi, Colditz
et al., 1994; Kawachi, Sparrow et al., 1994), and women (Albert et al., 2005). It
may be that the occurrence of NCCP presents a potential ‘‘teachable moment’’
to engage patients in CHD risk factor management (i.e., smoking cessation,
weight management). Patients with chest pain that is not of cardiac origin may
be uniquely open to considering options to modify and lessen their risk of
developing CHD (White, Malone et al., 2006).
Some Caveats in the Interpretation of Past Studies
Descriptive epidemiological studies have generally revealed that anxiety is

predictive of CHD morbidity and mortality, even after controlling for
traditional CHD risk factors (Booth-Kewley & Friedman, 1987; Gallo &
Matthews, 2003; Hemingway & Marmot, 1999; Kubzansky & Kawachi, 2000;
Matthews, 1988; Rugulies, 2002). At first blush, these findings appear to be
292 K. S. White
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 assess-
ment), 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 consid-
ered both gold-standard and empirically-based measures of anxiety (Antony,
Orsillo, & Romer, 2001). For instance, most research to date on the
anxiety-CHD link has examined a self-reported construct of ‘‘phobic anxiety’’

measured by the 8-item Crown-Crisp experiential index. This scale appears to
be particularly predictive of mortality (risk ratios = 3.0 to 3.8) (Haines et al.,
1987; Kawachi, Colditz et al., 1994). Scores range from 0–16, with higher
scores indicative of more phobic anxiety, and the majority of items are related
to symptoms of agoraphobia (e.g., concerns about going out alone, concerns
about crowds) and simple phobias (e.g., fear of heights) with some association
with generalized worry (e.g., concerns when relatives are late coming home).
Although this may indicate that the plain presence of anxious symptoms is a
risk factor for CHD, this also may indicate that the assessment was less than
optimal, necessitating other problems in interpretation (Kubzansky et al.,
1998). Importantly, validity studies provide some reassurance and show that
elevated scores on the phobic anxiety subscale can successfully discriminate
phobic disorders from other diagnostic groups in psychiatric patients (Crisp,
Jones, & Slater, 1978; Mavissakalian & Michelson, 1981). How this scale
relates to the broader domains of anxiety and panic, including anxiety sensi-
tivity, remains to be seen. Moreover, how phobic anxiety relates to other
negative emotions (e.g., fear, anxiety, hostility, depression) and related
disorders is unclear.
It is noteworthy that past research that has found significant anxiety-CHD
associations, even when most studies have not used gold-standard measures of
anxiety or anxiety disorders (e.g., Anxiety Disorders Interview Schedule for
DSM [ADIS], Structured Clinical Interview for the DSM [SCID]). And even
when an anxious individual does not meet diagnostic criteria for a clinical
disorder, they still often suffer from multiple difficulties (Kessler et al., 2003)
and may show comparable functional impairment to those with clinical anxiety
disorders (Fifer et al., 1994). Future research is needed to clarify some of these
basic issues of construct definition and psychopathology including diagnosis
and comorbidity. Little research has explored the extent to which current
diagnoses, current comorbidities, and lifetime/past diagnoses influence the
anxiety-CHD relation. For instance, it may be that the comorbidity of a PD
and Major Depressive Disorder is particularly lethal, resulting in a synergistic
or more weighty influence on CHD morbidity and mortality. Future
research examining the clinical experience of anxiety may help improve our
understanding of the anxiety-CHD connection.
Construct Definition Overlap
Unequivocal evidence that ‘‘pure’’ anxiety plays an independent role in CHD

has yet to be broadly determined or accepted. Few studies have considered the
independent and combined contributions of these negative emotions and CHD.
Many studies have examined only one psychological construct at a time making
it ‘‘impossible to compare the prognostic importance of the different concepts in
294 K. S. White
the same individuals. . . to know whether any apparent prognostic importance

relationships are due to a specific psychological construct or one or more
hidden underlying dimensions’’ (p. 627) (Frasure-Smith & Lesperance, 2003).
One particularly revealing recent study examined the shared and unique con-
tributions of anger, anxiety, and depression to CHD using data from the
Normative Aging study. Kubzansky and colleagues found that each of the
emotions was associated with CHD risk. However, when considered simulta-
neously, only anxiety and the shared general distress factor were uniquely
associated with the occurrence of CHD (Kubzansky et al., 2006). Although
some of the newest research has been acutely attuned to these issues and
distinctions (Kubzansky et al., 2006), future research studies designed to deal
with issues of construct overlap as well diagnostic comorbidity in CHD are
needed. As has been recently speculated by Suls and Bunde, it may that
inconsistent findings are the result of a failure to distinguish between state
and trait anxiety in CHD patients (Suls & Bunde, 2005). Or another possibility,
in light of the apparent comorbidity of anxiety and depression, is that it may be
that it is exclusively depression rather than anxiety that is relevant to CHD.
The construct of negative affectivity which may encompass the underlying
structure of both anxiety and depression may be a more complete reflection
of the emotional factors associated with CHD. Theoretical and empirical
distinctions can be made between the constructs of depression and anxiety,
and these two negative emotions can be assessed as unique emotional states.
Nevertheless, when discussed among clinicians and researchers alike, the
constructs of depression and anxiety are not always separated, and it is not
clear to what extent this distinction is necessary or meaningful in practice.
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 experien-
cing 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.
Potential Mechanisms in the Anxiety-CHD Association
Anxiety may manifest in CHD through a number of pathways. In response to

the growing evidence supporting the anxiety-CHD connection accumulated
over the past few decades, the field has evolved toward a greater focus on the
mechanisms and pathophysiological pathways by which negative emotions
influence disease onset, development, and progression. A sizable body of both
animal and human research has supported the long held belief that psycholo-
gical factors contribute to CHD and SCD (Kamarck & Jennings, 1991; Niaura
& Goldstein, 1992; Rozanski, Blumenthal, Davidson, Saab, & Kubzanksy,
2005; Rozanski, Blumenthal, & Kaplan, 1999). Research has identified beha-
vioral, biological, and physiological pathways that may account for how these
emotional processes may give rise to CHD development and progression (Fleet
et al., 2005; Grippo & Johnson, 2002; Krantz & Manuck, 1984). Naturally,
because psychological factors and behavioral stresses tend to occur and change
in tandem together over time, it is a challenge to study the independent mechan-
isms and their effects.
Research examining the mechanisms connecting anxiety and CHD is still in
the early stages and is far from definitive conclusions. Nevertheless, several
potentially important interconnected mechanisms have been put forward
to explain why negative emotions in general, and anxiety in particular, are
implicated in CHD occurrence and progression (Everson-Rose & Lewis,
2005; Kubzansky et al., 1998; Rozanski et al., 1999; Smith & Ruiz, 2002).
Anxiety may exert its influence on CHD through vulnerability toward
health-compromising behavior. Other possible mechanisms put forward have
ranged from direct effects (e.g., anxiety may directly influence the progression
of atherosclerosis) to more indirect effects (e.g., anxiety may lower the threshold
for ventricular arrhythmia and SCD). Several of the more promising possibi-
lities are reviewed here.
Anxiety and Health-Compromising Behaviors
First, one possible mechanism that may mediate the anxiety-CHD link is via
health-compromising behaviors. Specifically, it may be that anxiety gives rise to
health-compromising behaviors (e.g., physical inactivity, smoking, caloric
intake, lack of sleep, poor diet, alcohol consumption, drug use, and lack of
compliance with medications). Perhaps initially providing some temporary
relief, these negative health behaviors may grow to become habitual and
mediate the anxiety-CHD relationship. Although a sizable research has
examined and shown positive correlational associations between anxiety and
health-compromising behaviors (Breslau, Kilbey, & Andreski, 1991; Fisher,
Schneider, Pegler, & Napolitano, 1991; Hayward, 1995), truly prospective
296 K. S. White
designs with initially healthy samples with documentation of onset of both

anxiety, health-compromising behaviors, and CHD risk factors are scarce.
That said, individuals with anxiety and anxiety disorders are prone to more
unhealthy lifestyle behaviors (Kawachi, Colditz et al., 1994; Kawachi, Sparrow,
Vokonas, & Weiss, 1995). For example, cross-sectional studies have demon-
strated that 1 out of every 4 cases of obesity are associated with a mood or
anxiety disorder (Simon et al., 2006), and anxiety is elevated among those
individuals with obesity (Tuthill, Slawik, O’Rahilly, & Finer, 2006). Although
the causal relationship and complex interplay between anxiety and CHD risk
factors is still unclear, the available research seems to indicate that obesity is
associated with increasing rates of psychiatric comorbidity, including major
depression and PD. To this end, perhaps even low levels of anxiety may serve to
hasten CHD risk course. As another example, strong evidence shows that
psychiatric illness in general is associated with cigarette smoking, and this is
true for increased anxiety, particularly the panic-spectrum (e.g., panic attacks,
anxiety sensitivity, panic disorders) among smokers (Haines, Imeson, & Meade,
1980). Indeed, a disproportionate number of individuals with PD smoke cigar-
ettes (Zvolensky, Schmidt, & McCreary, 2003), and anxiety sensitivity may be
an important individual difference variable in this relationship (Zvolensky et
al., 2006). It may be that there are higher rates of smoking and other CHD
health-compromising behaviors (e.g., hypertension, hypercholesterolemia,
physical inactivity) among individuals with anxiety disorders. This may result
in a fatal confluence of risk.
Anxiety and Atherosclerosis
Another possible mechanism by which anxiety has its effect on CHD is through
the progression of atherosclerosis. Using a broadly-defined condition of anxiety
neurosis, Sims and Prior found a higher death rate from atherosclerotic disease
among those with anxiety neurosis (Sims & Prior, 1982). Several factors are
thought to contribute to atherosclerosis including elevated cholesterol and
triglyceride in the blood (hypercholesterolemia), high blood pressure (hyperten-
sion), and cigarette smoking. Elevated cholesterol levels have been documented
among patients with anxiety disorders (Huang, Wu, Chiang, & Chen, 2003;
Peter, Goebel, Muller, & Hand, 1999; Peter et al., 2002); indeed, Peter and
colleagues found that patients with anxiety disorders have elevated or high
cholesterol levels almost three times as often as control subjects, even after
controlling for anxiety-specific avoidance of physical exercise and special
dietary habits (Peter et al., 1999). With regard to hypertension, one study that
specifically examined predictors of blood pressure changes in middle-aged
women found that women experiencing anxiety showed greater increases of
systolic blood pressure over a 3-year follow-up period (Markowitz, Matthews,
Wing, Kuller, & Meilahn, 1991). Several more studies of anxiety (as assessed by
the Framingham Tension Scale) showed that anxiety is associated with

hypertension among initially normotensive men (but not women) (Markovitz,
Matthews, Kannel, Cobb, & D’Agostino, 1993). In a cohort study of 2,992
normotensive individuals over a followed-up period of 7 to 16-years, research-
ers found that both anxiety and depression were predictive of subsequent
hypertension and prescription treatment for hypertension (Jonas, Franks, &
Ingram, 1997). In addition to research with initially normotensive subjects,
other research on anxiety and hypertension has been derived from studies
with psychiatric samples. An increased incidence of hypertension has been
found among patients with anxiety disorders (Noyes, Clancy, Hoenk, &
Slymen, 1978; Wells, Golding, & Burnam, 1989). Matthews, Owens, Kuller,
Sutton-Tyrrell, and Jansen-McWilliams (1998) followed 200 healthy women
prospectively, and measures of atherosclerosis were obtained using
ultrasound of carotid arteries to measure intima-media thickness (IMT; a
marker of atherosclerosis) at 10-year follow-up (Matthews, Owens, Kuller,
Sutton-Tyrrell, & Jansen-McWilliams, 1998). After controlling for risk factors
(e.g., smoking, triglycerides, and pulse pressure), early anxiety (and hostility)
was predictive of atherosclerotic disease symptoms. In another interesting line
of research examining psychosocial risk and atherosclerosis, researchers
worked with non-human primates, cynomolgus monkeys. Primates were
assigned a stressed living condition (i.e., high or low) and were fed a diet high
in fat, intended to mimic the diet consumed in North America (Kaplan et al.,
1996; Manuck, Marsland, Kaplan, & Williams, 1995). After two years,
dominant primates living in the stressed condition showed more than twice
the amount of atherosclerosis than dominant primates residing in the low stress
condition. Along these lines, some researchers have speculated that it is acute
anxiety rather than more-trait-like anxiety that triggers ruptures of
atherosclerotic plaques in the coronary arteries leading to SCD or other acute
cardiac events (Davies & Thomas, 1984; Falk, 1983). Empirical research is
needed to examine this possibility.
Anxiety and Altered Cardiac Function
Anxiety is one of several psychosocial stressors that may bring about chronic
autonomic imbalance with sympathetic predominance. Altered cardiac auto-
nomic tone is a credible explanation for why anxiety may be associated with
increased CHD risk. This possible mechanism could involve amplified sympa-
thetic stimulation (that is associated with the occurrence of arrhythmias and
SCD) or impaired vagal control (that is also associated with CHD mortality)
(Farrell et al., 1987; Lown, Verrier, & Corbalan, 1973; Rich et al., 1988).
Evidence supporting these hypotheses includes findings that individuals with
anxiety disorders have a reduced HRV (Kawachi et al., 1995), consequently,
indicating an alteration in autonomic tone.
298 K. S. White
Reduced Heart-Rate Variability (HRV). The healthy heart displays beat-

to-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 auto-
nomic 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). More-
over, 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 mor-
tality 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 under-
lying 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.,
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
300 K. S. White
compared to age- and sex-matched controls, patients with cardiac arrhythmia

were significantly more anxious; assessment of anxiety was based on the
Multiple Affect Adjective Checklist Anxiety Scale and the Psychasthenia Scale
of the Minnesota Multiphasic Inventory (MMPI) (Katz, Martin, Landa, &
Chadda, 1985). Based on these findings, it is conceivable then that increased
risk of CHD and CHD-related mortality may be associated with anxiety
through altered electrical stability of the heart.
Related Pathophysiological Mechanisms
Emotionally stressful events have been shown to trigger onset of MI (Mittleman

et al., 1995). Laboratory studies of mental stress (commonly defined by the
acute experience of negative emotions including anxiety, depression, and anger)
can induce MI in 50–70% of patients with positive nuclear exercise tests (Jiang
et al., 1996; Rozanski et al., 1988), and this may be particularly important for
personally relevant tasks. Laboratory mental stress tasks commonly include
challenges associated with arithmetic, public speaking, gaming challenges, or
other stressful tasks. Indeed, mental-stress induced ischemia has been shown to
be a more potent predictor of cardiac events at long-term (> 3 years) follow-up
than exercise-induced ischemia; patients with mental-stress induced ischemia
showed markedly higher rates of cardiac events (both fatal and nonfatal) even
after controlling for other risk factors (e.g., age, previous MI, initial left
ventricular ejection fraction) (Jiang et al., 1996). In fact, even among individuals
without any coronary disease, severe and sudden emotional distress can
precipitate reversible left ventricular dysfunction (or ‘‘stress cardiomyopathy’’)
(Wittstein et al., 2005), however, the mechanism for this is unknown (Grawe,
Katoh, & Kuhl, 2006).
It stands to reason then that the recurrent, intense, and often private experi-
ence of panic attacks, a common comorbidity of anxiety and mood disorders,
may serve as a more potent stressor than laboratory-based mental tasks. Panic
attacks can be considered acute psychological stressors and are accompanied by
increased heart rate and blood pressure, as described more completely else-
where with respect to PD (Fleet et al., 2000). It may be that patients with CHD
and clinically significant anxiety or mood disorders (and/or panic attacks in
particular) may experience more substantial and/or potent stress associated
with induced myocardial ischemia. One study using 35% carbon dioxide
challenge tests found that panic attacks preferentially provoked myocardial
perfusion defects in CAD patients with PD compared to those without PD
(Fleet et al., 2005). More controlled studies to determine the relative risk and
underlying mechanisms supporting this possibility are needed.
Because persistent overactivity of the SNS increases cardiovascular
workload and hemodynamic stress, anxious individuals may be predisposed
to experience a number of other adverse cardiovascular effects including
endothelial dysfunction, coronary spasm, left ventricular hypertrophy,

dysrhythmias, platelet activation, and thrombosis (Curtis & O’Keefe, 2002;
Das & O’Keefe, 2006). One study found reduced baroreflex cardiac control
(a particularly important risk factor for sudden death) in anxious patients
(Watkins, Grossman, Krishnan, & Sherwood, 1998). In addition, platelets
play an important role in hemostasis and also in the pathophysiology of CAD
(Camacho & Dimsdale, 2000). Because platelets are affected by diverse
stressors, including psychological ones, platelets offer an interesting vantage
point for understanding the neurophysiology of various psychiatric disorders
(Camacho & Dimsdale, 2000). Also, studies have demonstrated that
stress-induced sympathetic activation and increased cortisol production can
predispose individuals to hypertension and the metabolic syndrome (a possible
precursor to coronary disease) (Brunner et al., 2002). Both elevated SNS
activity and dysregulation of the hypothalamic pituitary-adrenal (HPA) axis
have been found in medically healthy patients with major depression, as
indicated by elevated plasma and urinary catecholamines and their metabolites
(Esler et al., 1982; Roy, Pickar, De Jong, Karoum, & Linnoila, 1988; Veith
et al., 1994) and by elevated plasma and urinary cortisol (Roy et al., 1988).
These symptoms have been linked to arterial damage and risk for CHD. Similar
studies with anxiety are needed.
In addition, research examining other possible pathophysiological mechan-
isms purported in the stress and depression-CHD link may be beneficial in
understanding the link with anxiety including increases in inflammatory
proteins (i.e., C-reactive protein, interleukin-6) (Anisman & Merali, 2002) and
a hyperactive 5-hydroxytryptamine (5-HT) transporter2A receptor signal
system (Schins, Honig, Crijns, Baur, & Hamulyak, 2003). In one study,
Kamarck and colleagues demonstrated the broad impact of daily life stress
(i.e., psychological demands) and their association with CHD. Using carotid
IMT assessed via ultrasonography, healthy older adults who reported higher
daily life task demands showed larger IMT, after adjusting for covariates
(Kamarck et al., 2004). Carotid IMT is used as a marker for atherosclerosis
(Lorenz, Markus, Bots, Rosvall, & Sitzer, 2007). In another study conducted
over 4 years, sustained anxiety increased carotid IMT (Paterniti et al., 2001).
Other research has demonstrated that a history of major depressive disorder is
related to low-grade systematic inflammation, which promotes the process
(Danner, Kasl, Abramson, & Vaccarino, 2003). Anxiety may assist in this
process via the anxiety-depression comorbidity and CHD (Grippo & Johnson,
2002). Notably, Brydon and colleagues found that inflammatory cytokine
expression (i.e., interleukin-1b, interleukin-6) is positively associated with
both cardiovascular responses and anxiety symptoms (Brydon et al., 2005);
IL-1b and IL-6 are inflammatory cytokines that play an essential role in
atherosclerosis. The definitive causal direction of these relationships remains
to be seen. Even though depression has been extensively investigated, additional
prospective work is needed to examine the mechanisms underlying cardiovas-
cular morbidity and mortality among patients with anxiety and anxiety
302 K. S. White
disorders. Studies examining how the negative emotions (e.g., anxiety,

depression) have their direct and combined pathophysiological effects may be
most revealing.
Therapeutic Approaches Targeting the Anxiety-CHD Association
Cardiac rehabilitation is a medically supervised program designed to help

patients recover from a cardiac event and to reduce the risk of another cardiac
event or to keep an already present cardiac condition from worsening.
Comprehensive programs offer health education, exercise program develop-
ment, and assistance with cardiac risk factor modification (i.e., hypertension,
hypercholesterolemia, smoking, obesity, diabetes, physical inactivity).
Behavioral and psychosocial interventions are increasingly included in compre-
hensive cardiac rehabilitation programs partly due to the fact that the long-term
success of these secondary prevention programs depends heavily on patient
compliance. Moreover, in light of the increasing evidence revealing the negative
impact of depression and other psychological factors on cardiac morbidity and
mortality, truly comprehensive programs include psychological interventions
(Skala, Freedland, & Carney, 2005). The psychological interventions often
include stress management programs that are designed to reduce stress as a
single endpoint or to reduce cardiac risk further in CHD patients. The stress
management component tends to be skills-based and includes relaxation tech-
niques alone or in combination with other more potent cognitive-behavioral
strategies, including problem-solving skills, coping strategies, cognitive restruc-
turing, and behavioral activation. A complete review of secondary and
psychological interventions for coronary heart disease is beyond the scope of
this chapter; for a more complete discussion see (Clark, Hartling, Vandermeer,
& McAlister, 2005; Rees, Bennett, West, Davey Smith, & Ebrahim, 2004; Skala
et al., 2005).
Overall, psychosocial interventions for CHD (broadly-defined) have demon-
strated that these often wide-ranging interventions do produce small reductions
in anxiety in CHD patients but do not have an effect on subsequent cardiac
morbidity or mortality. Anxiety (assessed by various measures) has been
reported in fewer than 10 published clinical trials with mixed intervention
results (Lewin, Robertson, Cay, Irving, & Campbell, 1992; Oldenburg, Martin,
Greenwood, Bernstein, & Allan, 1995; Stern, Gorman, & Kaslow, 1983), and
pooled results suggest that reductions in anxiety are associated with interven-
tion effects (Rees et al., 2004). Composite measures of anxiety and depression
are reported by other clinical trials and showed similar beneficial reductions
(Black, Allison, Williams, Rummans, & Gau, 1998; Brown, Munford, &
Munford, 1993; Rees et al., 2004).
Published studies to date have not exclusively or independently targeted
anxiety or anxiety disorders in patients with CHD, however, important findings
regarding depression may be helpful in approaching treatment of anxiety in

CHD. The first study to show that an antidepressant is safe for treating
depression early after an acute event is the SADHART trial, Sertraline
Antidepressant Heart Attack Randomized Trial (Swenson et al., 2003).
Unfortunately, sertraline was only modestly effective in treating major depres-
sion. Partly due to drug-drug interactions that may be problematic and the
modest findings, researchers have attempted to more fully integrate other
empirically supported treatments for mood in patients with CHD (Skala
et al., 2005). Inclusive reviews of psychological interventions with CHD
patients have indicated that overall, such programs appear to have a modest
effect on anxiety, depression, and non-fatal reinfarction; no effect on total or
cardiac mortality is evident from the available data (Jordan et al., 2007; Rees
et al., 2004). Perhaps the most weighty results for the impact of psychosocial
interventions on reinfarction are reported in the large multicenter randomized
controlled trial conducted with patients recovering from MI, Enhancing
Recovering in Coronary Heart Disease (ENRICHD) trial (Berkman et al.,
2003; Carney et al., 2004). The ENRICHD trial examined whether a
cognitive-behavioral intervention for depression or low social support would
reduce mortality and reinfarction in 2,481 patients post-MI. The treatment
consisted of 11 individual sessions of cognitive behavior therapy, with group
treatments when possible, over the course of 6 months; patients who
experienced a less than 50% reduction in depression (as assessed by the Beck
Depression Inventory) after 5 weeks also received medication. Results indicated
that the intervention had important and significant impact on reducing depres-
sion and increasing social support, however, the hard endpoints of total
mortality and non-fatal MI were not significantly different between the treated
and usual care groups. Interestingly, patients in the usual care condition showed
‘‘substantial improvement’’ (p. 3106) and as result, group differences were less
than expected (Berkman et al., 2003). Both assessment and treatment research
on negative emotions and CHD has tended to focus on one negative emotion at
a time, however, in light of the independent role of anxiety, symptoms
of anxiety may need to be considered in risk stratification and treatment of
emotionally distressed patients with CHD. Early recognition and treatment of
anxiety in patients with CHD may minimize risk for future cardiac events.
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 80–90% of patients who developed clinically significant CHD and more
than 95% of patients who experienced a fatal CHD event had at least on major
304 K. S. White
modifiable risk factor (i.e., smoking, diabetes, hypertension, and hypercholes-

terolemia) (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 cardio-
toxic 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 condi-
tions 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
of intervention. With regard to directionality, the most compelling evidence for

directionality can be drawn from studies that examine the anxiety-CHD link
using the continuum of anxiety (i.e., ranging from low, subclinical to
clinical anxiety disorders), the spectrum of health-compromising behaviors
(i.e., ranging from overeating to obesity), and CHD. Future research
using sophisticated research designs are needed to unravel these issues of
directionality.
In light of the strong psychosocial influences on CHD, risk reduction pro-
grams will continue to be developed, particularly for secondary prevention of
CHD. If anxiety continues to show independent association with CHD, there
will likely be less resistance from the medical community to such programs.
It may be particularly rewarding to evolve treatments to fit with these empirical
associations. Controlled intervention studies targeting individuals with these
factors for proven risk-reduction therapies, or specifically treating these factors
with available therapies, are few. One particularly interesting line of recent
inquiry is designed to examine the extent that positive psychological factors
(i.e., optimism, gratitude, altruism) may reduce physiological hyperresponsive-
ness that may in turn reduce clinical events (Rozanski & Kubzanksy, 2005).
Finally, the wealth of scientific knowledge in our understanding of the role
psychosocial factors may have in CHD could not have been accomplished
without the tremendous interdisciplinary cooperation and coordination
spanning many disciplines. Future collaborative research examining the risk
and protective factors that contribute to anxiety and CHD may provide
information to better understand the experience of anxiety in CHD and begin
to identify the individuals most in need of intervention.
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HIV and Anxiety
Conall O’Cleirigh, Trevor A. Hart, and Carolyn A. James
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 suscept-
ibility to HIV infection and interfere with adaptive disease management. It is
plausible, for example, that the presence of anxiety disorders may interfere with
an individual’s 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 com-
promise 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 O’Cleirigh
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.
Ó Springer 2008
318 C. O’Cleirigh et al.
disorders may be over-represented in particular HIV risk groups. Thirdly, we

examine the role of anxiety in sexual risk for HIV infection and transmission
among HIV-negative and positive individual respectively. We next review the
literature on the role of anxiety symptoms and disorders in the management of
HIV with reference to medication adherence and substance use. Finally we
examine the relationship between anxiety and functional impairment and con-
sider some of the neurobiological mechanisms common to anxiety and the
pathophysiology of HIV. We conclude with some specific recommendations
for directed clinical research.
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 occupa-
tional 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 African-
Americans 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 CD4þ 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 CD4þ cell
decline and is followed by a prolonged asymptomatic phase during which the
individual remains healthy. During this phase gradual CD4þ cell decline con-
tinues and in the absence of antiretroviral treatment HIV viral load increases.
CD4þ cell number and HIV viral load are the principal biological measures of
disease progression and predict clinical outcomes and survival. As the CD4þ
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 CD4þ 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., Kaposi’s Sarcoma,
HIV wasting syndrome, lymphoma) as the immune system becomes seriously
compromised. The insidious depletion of CD4þ cells results in inverted
CD4þ/CD8þ ratios and the functional capacity of T-lymphocytes and
HIV and Anxiety 319
proliferative responses are progressively impaired and natural killer cell cyto-
toxicity (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 antiretro-
viral 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 pre-
vention of future cases of HIV infection as a continued public health concern.
Prevalence of Anxiety Disorders in People Living with HIV
In the U.S., estimates of lifetime anxiety disorders among HIVþ individuals range
from 3.6% to 19% (e.g., Johnson, Williams, Rabkin, Goetz, & Remien, 1995;
Sewell, Goggin, Rabkin, Ferrando, McElhiney, & Evans, 2000). These estimates
appear to be somewhat lower than in the general population where prevalence of
lifetime anxiety disorders is estimated to be approximately 29% (Kessler, Chiu,
Demler, & Walters, 2005). Estimated rates of current anxiety disorders among
HIVþ individuals range widely from less than 1% to 43% (e.g., Chandra, Ravi,
Desai, & Subbakrishna, 1998; Johnson et al., 1995; Perretta et al., 1996;Perkins
et al., 1994; Savard, Laberge, Gauthier, Ivers & Bergeron, 1998; Sewell et al., 2000).
This wide variability in prevalence estimates is likely due to several factors, one
of which is the variation in measures used to assess anxiety. Higher prevalence
rates (36–43%)have been found in studies using clinical cutoffs on screening
measures such as the Hospital Anxiety and Depression Scale (HADS; Zigmond &
Snaith, 1983) as opposed to a diagnosis based on the Structured Clinical
Interview for the Diagnostic and Statistical Manual (DSM) (under 20%)
(SCID; Spitzer Williams, Gibbon et al., 1995). Additionally, the variability in
prevalence estimates likely results from the small sample sizes that have been used
to assess the prevalence of any anxiety disorder. Among the studies noted above,
the largest sample size was 442 (Brown et al., 1992) with the remainder having
sample sizes below 200 (Chandra et al., 1998; Perretta et al., 1996).
There may also be variation in the prevalence of any anxiety disorders by

subgroup of HIVþ individuals, although the extent of this variation is
difficult to determine because studies have focused primarily on MSM.
Based on the available literature, rates of any anxiety disorders by sub-
groups of HIVþ individuals seem comparable. The prevalence of any cur-
rent anxiety disorder is approximately 1–12% for MSM (Johnson et al.,
1995; Perkins et al., 1994; Rosenberger et al., 1993; Sewell et al., 2000), and
12% for men in general (Brown et al., 1992), which seem similar to rates
among HIVþ individuals in general (6.6–12%; Holmes, Bix, Meritz, Turner,
& Hutelmyer., 1997; Perretta et al., 1996). Unfortunately, no known
research has examined the prevalence rates of overall anxiety disorders
among HIVþ women.
The evidence is equivocal as to whether or not the prevalence of current
anxiety disorders is higher among those who are HIVþ compared to the
general population. A study of 442 HIVþ male U.S. Air Force personnel
found that nearly 12% met criteria for a current anxiety disorder, which
was significantly higher than rates among age-matched men in the commu-
nity, who had a prevalence of 4.7% (Brown et al., 1992). However other
studies have reported no difference in rates of current anxiety disorders
among HIVþ and HIV-negative individuals (e.g., Rosenberger et al., 1993;
Sewell et al., 2000). Given inconsistencies in findings and given that many
of the studies were conducted over ten years ago when the HIV epidemic
was significantly less associated with heterosexual sex in Western societies
than it is currently, it is unclear whether rates of anxiety disorders differ
from those in the general population. However, specific anxiety disorders
may be more common among HIVþ individuals than in the general
population.
HIV and Post Traumatic Stress Disorder (PTSD). Much of the research
examining the rates of anxiety disorders among individuals with HIV has
focused on PTSD. Estimates of the rates of PTSD among HIVþ individuals
vary widely, and seem to depend on the patient population under examina-
tion. For example, although studies report prevalence rates of PTSD ranging
from approximately 10% to 54% (e.g., Kelly et al., 1998; Kimerling, Calhoun,
Forehand et al., 1999; Olley, Zeier, Seedat, & Stein, 2005; Smith, Egert,
Winkel, & Jacobson, 2002; Tsao, Dobalian, Moreau, & Dobalian, 2004a)
rates may be higher among specific populations such as MSM (e.g., Kelly
et al., 1998), minority women (e.g., Kimerling et al., 1999) and those with
persistent pain (e.g., Smith et al., 2002) compared to those in nationally
representative samples (e.g., Tsao et al., 2004a). Overall, rates of PTSD
among HIVþ individuals seem to be higher than in the general population
(Kessler et al., 2005) and may be higher than among other medical patient
groups (Tedstone & Tarrier, 2003). As is found in the general population,
among those with HIV, rates of PTSD seem to be higher among women than
men (Olley et al., 2005).
HIV and Anxiety 321
Among HIVþ individuals, PTSD is frequently comorbid with other psy-

chiatric diagnosis, particularly major depression, substance abuse and other
anxiety disorders. In a study using a nationally representative probability
sample of over 1400 HIVþ individuals, Tsao and colleagues (2004a) found
that among those with a PTSD diagnosis, 36.5% had comorbid Major Depres-
sive 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 HIVþ
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 HIVþ 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 11–16% 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 psy-
chiatric disorders among HIVþ 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 HIVþ 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 12-
month 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 HIVþ 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 HIVþ individuals. In a sample
of 190 HIVþ 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 HIVþ individuals.
HIVþ MSM and Anxiety Disorders. Studies focusing on anxiety disorders
among HIVþ MSM have yielded inconsistent results in terms of prevalence
rates, with rates of current and lifetime anxiety disorders ranging from
3–12% to 7–19% respectively (Perkins et al., 1994; Rosenberger et al., 1993;
Sewell et al., 2000). Several studies have reported no differences in rates of
anxiety disorders between HIVþ and HIV-negative MSM (Perkins, et al., 1994;
Rosenberger et al., 1993; Sewell et al., 2000). For example, a two-year long-
itudinal study of HIVþ 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).
HIVþ 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 HIVþ 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 (30–42%; Jordan, Schlenger,
Fairbank, & Caddell, 1996; Teplin, Abram, & McClelland, 1996). Although
high-risk HIVþ women appear to be at greater risk for anxiety disorders,
particularly PTSD, this risk may not apply to HIVþ women in general. A
study comparing HIVþ and –negative women without current substance
abuse found that the two groups did not differ in their rates of anxiety disorders,
although the HIVþ 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 HIVþ indivi-
duals 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.
Anxiety and Risk for HIV Infection or Transmission
Few studies specifically examine the role of anxiety in risk for contraction or
transmission of HIV. Most research examining the role of psychological dis-
tress in HIV risk investigates other phenomena such as depression or substance
use (e.g., Johnson, Cunningham-Williams, & Cottler, 2003; Stall et al., 2003).
Further, the research is limited by methodological problems regarding the
HIV and Anxiety 323
measurement of anxiety. Earlier HIV risk studies discussing fear or anxiety

actually appear to not to have assessed anxiety per se, but related constructs
such as negative and stereotypic attitudes about AIDS (Tashakkori &
Thompson, 1992) or intent to avoid contracting a sexually transmitted disease
(Katz, Gipson, Kearl, & Kriskovich, 1989). More recent research on HIV risk
has employed measures of general emotional distress containing anxiety-related
items (e.g., Heckman, Anderson, Sikkema, Kochman, Kalichman, & Anderson,
2004), or screening measures such as the anxiety subscales of the Brief Symptom
Inventory (Derogatis & Melisatatos, 1983). A meta-analysis of the literature
found extremely weak associations between anxiety measures and unprotected
sex (r = 0.03; Crepaz & Marks, 2001). However, the lack of anxiety-specific
measures may have led to false conclusions regarding the possible influences of
anxiety on HIV risk and prevention. It has therefore been suggested that more
sensitive and specific anxiety measures be used in future studies of examining
HIV risk cognition and behavior (Kalichman & Weinhardt, 2001).
Few studies have found an association between anxiety and HIV risk
behavior, defined here as either 1) drug use where blood contact between an
HIVþ and an HIV-negative person may take place, such as in injection drug use
or sharing of other drug paraphernalia where blood droplets may be present, or
2) unprotected female-male or male-male sexual intercourse (Centers for
Disease Control and Prevention, 2005). General emotional distress measures
combining anxiety and depression have not been reliably associated with HIV
risk behaviors among MSM or adolescent females (e.g., Dudley, Rostosky,
Korfhage, & Zimmerman, 2004; Ethier, Kershaw, Lewis, Milan, Niccolai, &
Ickovics, 2006).
Studies using the anxiety subscale of the Brief Symptom Inventory have not
had reliable associations with HIV sexual risk behavior. For example, some
research has found no association between anxiety and unprotected sex among
HIVþ individuals (e.g., Kalichman, 1999), other work have found a negative
association between anxiety and unprotected sex among HIVþ women but
not among HIVþ men (e.g., Kennedy et al., 1993), and yet another study
suggested an association between scores on the anxiety scale and unprotected
insertive and unprotected receptive anal intercourse in the past three months
among HIVþ MSM (e.g., O’Leary, Purcell, Remien, & Gomez, 2003).
Trait Anxiety and HIV Risk. High trait anxiety scores, especially in the
context of high sexual inhibitions due to threat of sexual performance failure,
were associated with a reduced profile regarding unprotected anal intercourse in
a sample of over 550 gay and bisexual men (Bancroft, Janssen, Strong, Carnes,
Vukadinovic, & Long, 2003). Similarly, higher trait anxiety has also been
associated with greater risk behavior in a group of 557 Puerto Rican injection
drug users, including sharing injection drug paraphernalia and unprotected
vaginal sex (Reyes et al., 2007).
Social Anxiety and HIV Risk. In a recent study among over 100 gay and
bisexual youth Hart and colleagues reported a positive association between
social anxiety about being observed by others or performing a task, or social
performance anxiety, and prevalence of unprotected insertive anal intercourse

over the past six months (Hart & Heimberg, 2005, Hart, Purcell, & Farber,
2004). Other studies that have not formally assessed social anxiety also seem to
suggest a direct effect of social anxiety on unprotected anal intercourse. For
example, using content analysis on focus groups of 41 gay men, Offir and
colleagues (1993) found that individuals often modified their sexual behavior
because of concerns about AIDS, but their safer sex behaviors remained incon-
sistent. Social anxiety may also be implicated in other risk factors for engaging
in unprotected sex such as embarrassment discussing or using condoms as
reported among small samples of heterosexual youth (Abel & Fitzgerald,
2006; Hingson et al., 1990), or crystal methamphetamine use among
MSM (Green & Halkitis, 2006; Halkitis, Parsons, & Wilton, 2003; Semple,
Patterson, & Grant, 2002). Recent studies of both HIVþ and HIV-negative gay
men suggest that men with greater fears of offending a sexual partner have
greater difficulty asserting condom use and/or safer sex (Adam, Husbands,
Murray, & Maxwell, 2005; Murray & Adam, 2001; Seal et al., 2000). In another
study, 32% of gay men reported being less likely to use condoms when they did
not wish to offend their partner or if they were concerned their partner would
react negatively (Offir et al., 1993). Fears of rejection appear to be greater when
one perceives a partner to be more sexually desirable. Although other factors
have been identified in cross sectional studies of small cohorts of HIV-infected
men and women that may influence perceptions of sexual desirability including
physical attractiveness (Murray & Adam, 2001), and fear being rejected because
of their HIV serostatus (Klitzman, 1999; Siegel & Schimshaw, 2003).
PTSD and HIV Risk. Controlling for cocaine or heroin dependence, current
HIV status, and demographic variables, lifetime prevalence of PTSD was
associated with a 1.7 times greater likelihood of engaging in anal sex and a
1.6 times greater likelihood of engaging in prostitution (Hutton et al., 2001).
These findings may partially explain why PTSD might have a higher
prevalence among HIVþ individuals. However, PTSD has not consistently
been associated with unprotected sex among adolescent girls (Smith, Leve, &
Chamberlain, 2006) or adult HIVþ women (Myers et al., 2006). It is therefore
unclear that PTSD is a risk factor for unprotected sex, or if it is fact a proxy
variable for having experienced traumatic events that are also associated with
risky sex among both MSM and heterosexual samples, such as childhood sexual
and physical abuse (Smith et al., 2006; O’Leary et al., 2003). In fact, the
documented relationships between childhood sexual abuse and risky sexually
behavior appear to be similar for HIV negative (Kalichman, Gore-Felton,
Benotsch, Cage, & Romapa, 2004; Stall et al., 2003) and positive (O’Leary
et al., 2003) men.
Other Anxiety and HIV Risk. Consistent with Snell (2001), physiological
symptoms of anxiety also were associated with recent sexual activity among
HIV-infected adolescents (Murphy et al., 2001). Health anxiety, or feelings of
anxiety related to the possibility of becoming ill, also was associated with recent
sexual activity in this sample. Murphy et al. (2001) posit that health anxiety may
HIV and Anxiety 325
increase sexual behavior paradoxically by increasing attempts to reduce anxiety

via alcohol and drug use in this population. Worries about vulnerability to
HIV infection are associated with reducing frequency of sexual activity and
increasing condom use because of AIDS (Zimet et al., 1992). Similar to findings
regarding anxiety about romantic attachments and HIV-related beliefs, among
high-risk, young pregnant U.S. women recruited from urban prenatal clinics,
anxiety about romantic attachments is associated with greater HIV risk beha-
vior. Specifically, anxiety about romantic attachments was associated with a
lower percentage of condom use in the past six months and ever having
unprotected sex with a risky partner (e.g., a partner with a history of a sexually
transmittednfection or with HIV) in the past six months (Kershaw et al., 2006).
Mechanisms of Anxiety-related HIV Sexual Risk. It has been suggested that
high awareness that one can contract HIV through sexual behavior may have
paradoxical effects (McKirnan, Ostrow, & Hope, 1996) because of its anxio-
genic effects. In this model, HIV risk awareness may increase anxiety, which
may in turn increase cognitive disengagement, an avoidant coping strategy.
Avoidance of anxious thoughts through pleasurable activities (e.g., sexual
activity, substance use) may well interfere with safer sex negotiation and
condom use. As both PTSD and childhood sexual abuse have been associated
with unprotected sexual intercourse, anxiety has also been suggested as a
mediator of the relationship between childhood sexual abuse and sexual risk
behavior (e.g., O’Leary et al., 2003). This is particularly relevant as the pre-
valence of PTSD and childhood sexual abuse are significantly higher among
MSM (e.g., Kelly et al., 1998) and minority women (e.g., Wyatt et al., 2002;
Kimerling et al., 1999), two groups at increased risk for HIV infection. In
addition to anxiety, hostility and suicidality (O’Leary et al., 2003), low self-
esteem, substance abuse (Rosario, Scrimshaw, & Hunter, 2006), depression
(Miller 1999; O’Leary et al., 2003) and dissociation (Kalichman et al., 2001)
have been identified as mediators of the relationship between childhood sexual
abuse and sexual risk behavior. In combination, anxiety, hostility and suicid-
ality mediated the relationship between childhood sexual abuse and unpro-
tected receptive anal intercourse among HIVþ MSM (O’Leary et al., 2003),
although among gay and bisexual youth (Rosario et al., 2006), childhood sexual
abuse had a direct association with unprotected receptive anal intercourse.
These results suggest that anxiety may play a more significant role in the path-
way from childhood sexual abuse to sexual risk taking among MSM who are
HIVþ compared with those who are not.
Conclusions. Among women, the evidence seems to suggest that severity of
the abuse history (Wyatt et al., 2002) is associated with increased risk for HIV
and increased HIV sexual risk behavior (Bensley, Eenwyk, & Simmons, 2000).
Generally, the consequences of childhood sexual abuse or adult sexual assault
appear to have more consistent associations with HIV sexual risk behavior than
diagnostic measures of PTSD or other anxiety measures. Recent studies using
more specific measures of anxiety have had somewhat greater success in identi-
fying anxiety-related risk factors for HIV risk behavior. However, conclusions
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 unpro-
tected 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)
Anxiety and HIV Disease Management
There is considerable variation in HIV disease progression and there is a com-

pelling body of research identifying the psychosocial (e.g., depression, life stress)
and behavioral (e.g., medication adherence, substance use) factors that account
for some of this variation (see Leserman, 2003 for a review). The presence of a
pre-existing anxiety disorder in HIVþ patients or the emergence of anxiety in
response to HIV may impair the patient’s ability to approach the distress
associated with was variety of disease related stressors (e.g., diagnosis, access
to health care, medication adherence, symptom onset). Anxious avoidance of
HIV-related distress can interfere with the individual’s ability to effectively
manage his or her disease (Antoni, 2003). In addition, the relationship between
anxiety and physical functioning in HIV is particularly relevant as the physical
symptoms of anxiety overlap with many of the symptoms of advancing HIV
disease (e.g., fatigue, disturbances of sleep and appetite) and with side effects
of antiretroviral therapy (e.g., abdominal pain, reduced appetite, chills, consti-
pation, diarrhea, dizziness, fatigue, insomnia) (Hofman & Nelson, 2006).
There is limited longitudinal research linking anxiety disorders to acceler-
ated disease course in HIV. However, several studies have reported significant
predictive relations between avoidant coping (a coping response to stress
consistent with anxious responding) and accelerated HIV disease progression
(e.g., Ironson, O’Cleirigh, Fletcher, et al., 2005; Leserman, Petitto, Golden,
et al., 2000). Similarly, Boarts, Sledjeski, Bogart and Delahanty (2006)
reported that diagnostic levels of PTSD symptoms in 57 HIVþ men and
women were significantly associated with increased plasma RNA viral load
at 3-month follow-up. It is plausible that anxiety may exert its influence on
HIV disease progress through its relationship with health behaviors or physical
functioning. The relationships between anxiety and medication adherence,
substance use and health-related quality of life are examined below.
HIV and Anxiety 327
HIV, Anxiety, and Health Behaviors
Anxiety and Medication Adherence in HIV. Adherence to antiretroviral medica-

tions is critical for suppression of viral replication (< 50 viral copies/mL), the
goal of antiretroviral therapy (ART). It has been estimated that 90% adherence
or greater is necessary to achieve this goal (Paterson, Swindells, Mohr, 2000;
Bartlett, 2002). There is a large and growing body of literature identifying the
psychosocial and behavioral barriers to medication adherence in HIV (for
review see Ammassari et al., 2002). The relationship with medication adherence
in HIV and anxiety has been examined with anxiety generally assessed and with
specific anxiety disorders.
Ammassari, et al. (2002) examined the relationship between anxiety as measured
by the Mental Health Index-5 (Wu, Rubin, Mathews, et al., 1991) and self-reported
adherence among a diverse cohort of 358 Italians living with HIV. In multivariate
analysis, they found that anxiety symptoms were independently associated with
non-adherence to antiretroviral medication in the past three days. Similarly, Van
Servellen, Chang, Garcia and Lombardi (2002) found that HADS anxiety score
was significantly related to both self-reported non-adherence and clinician evalu-
ated adherence based upon patient chart review. Anxiety, assessed through the
anxiety subscale of the Brief Symptom Inventory, was the only measure related to
sub-optimal adherence in a non-psychiatric sample of patients receiving primary
HIV care at outpatient clinic (Schönnesson, Williams, Ross, Bratt & Keel, 2006).
Interestingly, severity of intrusion and avoidance symptoms associated with
trauma, was associated with better adherence to medication schedule.
Several studies have examined the impact of disorder specific anxiety symp-
toms on medication adherence in patients with HIV. As part of the HIV Cost
and Services Utilization Study (Tucker, Burnam, Sherbourne, Kung & Gifford,
2003) using a probability sample of 1,910 adults with HIV, those meeting
diagnostic criteria for generalized anxiety disorder and panic disorder
(Composite International Diagnostic Interview-Short Form; CIDI-SF, World
Health Organization, 1998) were more than twice as likely to be non-adherent
than those without a psychiatric disorder. Non-adherence was also significantly
associated with depression, substance use and heavy alcohol use. Screening
positive for any anxiety disorder (by CIDI-SF) was positively associated with
taking medication as directed, whereas social phobia was significantly asso-
ciated with running out of medications (Ingersoll, 2004).
The evidence for a relationship between PTSD symptom severity and med-
ication adherence is mixed. Boarts, Sledjeski, Bogart and Delahanty (2006)
reported that severity of depression but not PTSD predicted self-reported
adherence at 3-month follow-up in a small group of HIVþ patients. Although
the severity of PTSD avoidance and intrusion symptoms related to receiving an
HIV diagnosis were both related to estimates of skipped medications and off-
schedule doses assessed for various time frames during the previous 3 months
(Delahanty, Bogart, & Figler, 2004).
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 symp-
toms. 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 HIVþ 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 naı̈ve HIVþ 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).
HIV and Anxiety 329
In summary, there is good evidence from large and nationally representative

samples of HIVþ patients identifying the comorbidity of anxiety and substance
use disorders. In these samples the prevalence substance use disorders are
dramatically higher than in the general population and the presence of sub-
stance use disorders appears to be positively associated with the presence of
mood/anxiety disorders. There is initial evidence that anxiety symptom severity
among HIVþ substance users is associated with increase sexual risk behavior
and that substance use and anxiety disorders are associated with poorer
response to antiretroviral treatment. Although substance use impediments to
adaptive HIV disease management have been well described, it is likely that
comorbid anxiety and substance use disorders interact to create unique path-
ways to HIV sexual transmission risk (O’Cleirigh & Safren, 2007) and elucidat-
ing these mechanisms may help to specify targets to support both anxiety
treatment and HIV prevention efforts.
HIV, Anxiety and Health-Related Quality of Life
The success of highly active antiretroviral therapy (HAART) in containing HIV

viral replication, delaying symptom onset and extending life has focused
increased attention on health-related quality of life (HQOL) in people living
with HIV. In addition, higher HRQOL has been shown to be predictive of
improved survival in patients with advanced HIV (Jacobson, Wu, & Feinberg,
2003). In HIV/AIDS, there is little research examining the relationship between
anxiety disorders and HRQOL and much of it is limited by cross-sectional
designs.
Orlando and colleagues (2005) constructed a probability sample of 2,864
HIV-infected adults representing 231,400 patients in care in the United States in
1996. HQOL measures of general health and lack of pain significantly predicted
less generalized anxiety and panic symptoms severity at 8-month follow-up.
However, baseline anxiety was not significantly related measures of HRQOL at
follow-up although depressive symptoms were. In the only other examination
of these relationships over time Sewell, et al. (2000), found that, among a group
of HIVþ MSM, general measures of anxiety and anxiety disorders assessed
through Structured Clinical Interview Diagnostic (SCID: Spitzer et al., 1995)
were significantly related to fatigue, physical limitations and to current HIV
symptoms at each of the six-month assessments over 2 years. These results
maintained when the physical symptoms of anxiety were removed from the
anxiety measures. Anxiety was not significantly related to either CD4 cell count
or to HIV viral load.
Two separate studies reported significant cross-sectional relationships
between PTSD symptom severity and health related measures of physical
functioning. Leserman et al. (2005) reported that PTSD symptoms were sig-
nificantly associated with more pain and poorer physical and role functioning
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.
HIV and the Pathophysiology of Stress Hormones in Anxiety
The neurobiology of anxiety disorders is complex and our understanding of the

mechanisms is limited. However, there is a growing body of research that points
to disruption of the hypothalamic pituitary adrenocortical (HPA) and sympa-
thetic adrenal medullary (SAM) systems in the pathophyisology of anxiety with
associated dysregulation of cortisol and norepinephrine respectively. These are
the two core systems that modulate the biological response to stress. For
HIV and Anxiety 331
example elevated norepinephrine reactivity to stressors has been shown in

patients with PD, GAD, and social anxiety disorder (Brawman-Mintzer et al.,
1997; Tancer et al., 1993; Abelson et al., 1991) and elevated baseline levels of
norepinephrine in patients with PTSD (van der Kolk, 1994). Similarly disrup-
tion of cortisol and its precursor, corticotropoin releasing factor (CRH), have
been observed in patients with social anxiety disorder, GAD and PTSD
(Resnick, Yehuda, Foy, & Pitman, 1995; Abelson et al., 1991).
The dysregulation of the HPA and SAM systems in people with anxiety
disorders who are also living with HIV is of critical importance as elevated levels
of both norepinephrine and cortisol have been independently linked to accel-
erated disease progression in HIV (Ironson et al., 2006; Leserman, Petitto,
Golden, et al., 2000). It has been suggested that the stress hormones cortisol
and norepinephrine (NE) may represent potential pathways linking psycholo-
gical stress response to health outcomes in HIV (Schneiderman, Ironson, &
Siegel, 2005). Specifically, cortisol, has been associated with down regulation of
the immune system (Munck & Guyre, 1991) and increased HIV infection of
lymphocytes (Markman, Salahuddin, Veren, Orndorff, & Gallo, 1986) and
elevated levels of norepinephrine enhance viral entry into target lymphocytes
and increase HIV viral replication (Cole, Korin, Fahey, & Zack, 1998; Cole,
Kemeny, Fahey, Zack, & Naliboff, 2003). In addition, higher levels of auto-
nomic nervous system activity have also been associated with impaired response
to HAART (Cole, Naliboff, Kemeny, et al., 2001). Efficacious treatments for
anxiety disorders may well allow people living with HIV to reap the physiolo-
gical benefit of treatment related regulation of the stress hormones cortisol and
norepinephrine.
In summary, the presence of anxiety disorders may place people living with
HIV at a physiological disadvantage through dysregulation of the stress hor-
mones norepinephrine and cortisol. Elevated levels of these hormones are
associated with down regulation of the immune system, more rapid HIV viral
replication, and impaired response to HAART which may well be the pathways
linking elevated levels of stress hormones to poorer HIV disease course.
Directions for Future Research
There is a lack of focused and programmatic research on HIV and anxiety. We

present some general recommendations to highlight some of the gaps in the
scientific knowledge base.
Although there is evidence that PTSD and GAD may be more prevalent in
people with HIV (particularly among MSM and high risk women) than in the
general population, a comprehensive picture of the prevalence rates of anxiety
disorders in people living with HIV is unavailable. Studies examining these rates
are hampered by inadequate sample sizes and wide spread variation in the
measurement of anxiety. Large scale, epidemiological studies are needed to
reliably estimate the prevalence of anxiety disorders in HIV particularly if

useful estimates of the prevalence across HIV risk groups is to be obtained.
A preliminary and emerging picture of the relationships between anxiety and
outcomes important in HIV is presented in Fig. 1. The model depicts two
putative pathways from anxiety to health outcomes, one mediated through
health behaviors and the other physiologically mediated though stress hor-
mones. Although there is evidence for many of the direct relationships depicted
here the mediated relationships await empirical verification. In general pro-
grammatic research elucidating the relationships depicted here will help
improve our understanding of the role of anxiety in HIV. In particular, it is
apparent that the relationship between anxiety and risk of HIV infection or
transmission is complex, with some evidence suggesting that social performance
anxiety is associated with increased risk. Further, higher levels of anxiety appear
to combine with substance use disorders to increase sexual risk behavior and
substantially interfere with HIV treatments. Certainly, additional research more
fully elucidating the relationship between anxiety and sexual risk behavior is
needed. However, recent research has articulated the need to address comorbid
psychosocial issues in HIV prevention (Stall et al., 2003; Koblin et al., 2004) and
the adaptation of traditional HIV prevention interventions to address anxiety
(e.g., social anxiety disorder) and substance use issues may improve prevention
intervention outcomes and help illuminate these relationships.
Behaviors
Medication Adherence
Substance Use
Transmission Risk
Behavior (STIs,
superinfection)
Individual Resources Clinical Disease

(e.g., trauma history, Anxiety Profile Biological Markers Outcomes
Stress Hormones of HIV Disease
time since HIV Anxiety Disorder Norepinephrine Survival
diagnosis, access to Anxious Symptoms CD4+ cells Clinical Progression
Cortisol HIV Viral Load
care, etc) 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.
HIV and Anxiety 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 HIVþ 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, O’Cleirigh, & 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 treat-
ments for PTSD is a priority. In particular, the development of psychosocial
interventions, or the adaptation of existing technologies, with specific appli-
cation 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 pro-
gression, increased symptom burden, poorer medication adherence, and cor-
tisol 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 incorpora-
tion of biological measures of disease progression (CD4þ 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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Physical Illness and Treatment of Anxiety
Disorders: A Review
Norman B. Schmidt, Meghan E. Keough, Lora Rose Hunter, and Ann P. Funk
Physical Illness and Anxiety Psychopathology
Anxiety psychopathology represents one of the most prevalent and debilitating

forms of mental illness (Kessler, Chiu, Demler, & Walters, 2005; Weissman,
Markowitz, Ouellette, Greenwald, & Kahn, 1990). Extrapolating from epide-
miological studies, it may be conservatively estimated that 25% of the popula-
tion will suffer from clinically significant anxiety at some point in their lives with
a 12-month prevalence rate of approximately 18% (Kessler et al., 2005). Anxi-
ety disorders generally maintain a chronic course when untreated (Pine, Cohen,
Gurley, Brook, & Ma, 1998) and result in substantial impairment across the
lifespan (Ferdinand & Verhulst, 1995). In addition to the immense personal
suffering created by anxiety psychopathology, these disorders create a consid-
erable public expense that includes treatment costs, lost work time, and mor-
tality. In addition, anxiety psychopathology is associated with increased
utilization of non-psychiatric medical services (Greenberg et al., 1999).
The issue of increased medical utilization indirectly speaks to the topic at
hand since it appears that one reason for medical utilization in these patients
includes the high co-occurrence of physical illness with anxiety disorders. For
example, there are well-established associations between panic disorder and
cardiorespiratory disorders such as asthma, chronic obstructive pulmonary
disease, and mitral valve prolapse (Gorman, Goetz, Fyer, & King, 1988;
Karajgi, Rifkin, Doddi, & Kolli, 1990; Weissman et al., 1990; Zandbergen
et al., 1991). Epidemiological reports indicate that chronic medical conditions
are more prevalent in those with a lifetime history of an anxiety disorder (Wells,
Golding, & Burnam, 1989). Longitudinal evaluation of anxiety patients has
indicated an increased risk for chronic medical conditions (e.g., hypertension,
migraine headaches, ulcer, thyroid disease) compared to the general population
(Rogers, White, Warshaw, & Yonkers, 1994).
Norman B. Schmidt
Department of Psychology, Florida State University, Tallahassee, FL 32306-1270, Tel: (850)
644-1707, Fax: (850) 644-7739
schmidt@psy.fsu.edu
Ó Springer 2008
Table 1 Summary of cited studies
342
Primary
Primary Primary Diagnostic Tools Primary Diagnostic
Diagnosis Medical Design Sample used to Assess Tools used to Assess
Study Evaluated Comorbidity Treatment (groups) Size Psychopathology Physical Illness
CCAP Panic Medical CBT plus Randomized 232 -CIDI -RxRisk-V score
Roy-Byrne, Disorder Illness Medication Control
Stein et al., burden Management
2005 vs. Usual
Care
CCAP Panic Medical CBT plus Randomized 232 -CIDI -WHO Disability Scale
Roy-Byrne, Disroder Disability Medication Control -Fear
Craske Management Questionnaire
et al., 2005 vs. Usual -Anxiety
Care Sensitivity
Index
CCAP Panic Medical CBT plus Combined 111 -CIDI -WHO Disability Scale
Craske Disorder Disability Medication Analysis (sub- -Fear
et al., 2005 vs. from sample Questionnaire
Medication Control and of -Anxiety
Treatment study Sensitivity
Groups total) Index
Schmidt & Panic Health CBT-G No Control 71 -SCID-NP -General Health
Telch, 1997 Disorder Perceptions Survey
Chronic
Health
Condition
Schmidt et al., Panic Health CBT-G Randomized 46 -SCID-NP -General Health
2003 Disorder Perceptions Waitlist Survey
Control -Physical Health
Rating Form
Klein et al., Panic Health CBT (delivered Randomized 55 -ADIS-IV -Self-reported number
N. B. Schmidt et al.
2006 Disorder Perceptions via the Control of visits to physician

Table 1 (continued)
Primary
Medical internet or -Self-rating of physical
Usage manual) health
Ross et al., Panic Asthma CBT-G plus Randomized 25 -ADIS-IV -Physician Diagnosis
2005 Disorder Asthma Waitlist
Education Control
Kissane et al., Anxiety Breast Cancer Cognitive- Randomized 303 -HADS -Physician Diagnosis -
2003 Depression Existential Control -Affect Balance confirmed by
Group Scale Histology reports
Therapy plus
Relaxation
vs.
Relaxation
Bryant et al., PTSD Mild CBT vs. Randomized 24 -Acute Stress -Glasgow Coma Scale
2003 Acute Stress Traumatic Supportive Control Disorder
Disorder Brain Injury Counseling Inventory
-Clinician
Administered
Physical Illness and Treatment of Anxiety Disorders: A Review
PTSD Scale
Shemesh PTSD Myocardial CBT plus Non- 14 -Impact Event -Physician Diagnosis
et al., 2006 Infarction Education vs. Randomized Scale confirmed by study
Education -PTSD Cardiologist
Diagnostic
Scale
-SCID-P
Kennedy Anxiety Spinal Cord Cognitive Non- 85 -STAI -Physician Diagnosis
et al., 2003 Depression Injury Effectiveness Randomized -BDI
Training Matched
343
Historic
Control
Table 1 (continued)
Primary
344

Craig et al., Anxiety Spinal Cord CBT-G Non- 58 -STAI -Physician Diagnosis
1998 Depression Injury Randomized -BDI
Control
Speca et al., Mood Cancer Mindfulness Randomized 90 -Profile of Mood -Past cancer diagnosis
2000 disturbance Meditation- Waitlist States
Stress Based Stress Control -Symptoms of
Reduction Stress
program Inventory
Anson & Range of Traumatic CBT-G Randomized 31 -HADS -TBI rehailitation
Ponsford, Anxiety and Brain Injury Waitlist -Sickness Impact patient
2006 Mood Control Profile
diagnoses -Rosenberg Self-
Esteem
Suh et al., Anxiety End-Stage Regular No Control 14 -Self-rating -Current hemodialysis
2002 Depression Renal Exercise Depression treatment
Disease Scale
-STAI
Gothelf et al., Range of Childhood SSRI - No Control 15 -K-SADS-PL -Current pediatric
2005 Anxiety and Cancer Fluvoxamine -CDI hematology-
Mood -BDI oncology center
diagnoses -SCARED patients
Massand Range of Irritable SSRI - No Control 20 -SCID -IBS Rome I criteria
et al., 2002 Anxiety and Bowel Paroxetine -confirmed by flexible
Mood Syndrome sigmoidoscopy
diagnoses
Creed et al., MDD Severe Psychodynamic Randomized 257 -SCAN -Gastroenterology
2005 GAD Irritable Interpersonal Control -clinician Clinic Patients -
Panic Bowel Therapy vs. administered Rome I Criteria -
N. B. Schmidt et al.
Disorder Syndrome SSRI - HDRS SF36 scores

Paroxetine vs.
usual medical
cares
Table 1 (continued)
Primary
Lee et al., GAD Migraine Selective Randomized 74 -DSM-IV GAD -International
2005 Disorder Serotonin Double- Criteria Headache Society
Agonist – Blind -HAM-A criteria
Buspirone Placebo -Migraine Disability
Controlled Asessment Score
(MIDAS)
l Anxiety Disorders Interview Schedule (ADIS-IV)
l Beck Depression Inventory (BDI)
l Cognitive Behavioral Group Therapy (CBT-G)
l Children’s Depression Inventory (CDI)
l Composite International Diagnostic Inventory (CIDI)
l State Trait Anxiety Inventory (STAI)
l Hamilton Depression Rating Scale (HDRS)
l Hospital Anxiety and Depression Scale (HADS)
l Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID)
l Schedules for Clinical Assessment in Neuropsychiatry (SCAN)
l Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version (K-SADS-PL)
Physical Illness and Treatment of Anxiety Disorders: A Review
l Hamilton Anxiety Rating Scale (HAM-A)
l Screen for Child Anxiety Related Emotional Disorders (SCARED)
l World Health Organization (WHO)
l Short Form-36 (SF36)
l Major Depressive Disorder (MDD)
l Generalized Anxiety Disorder (GAD)
l Post Traumatic Stress Disorder (PTSD)

345
346 N. B. Schmidt et al.
The relationship between anxiety disorders and non-psychiatric medical

illness is complex. It appears that anxiety psychopathology can contribute to
the development of physical conditions and/or exacerbate existing physical
conditions (Karajgi et al., 1990; Kawachi, Sparrow, Vokonos, & Weiss,
1994). In addition, non-psychiatric medical conditions can contribute to the
development of anxiety disorders (Kahn, Drusin, & Klein, 1987; Raj, Corvea, &
Dagon, 1993) and/or exacerbate anxiety disorder symptoms (McCue & McCue,
1984). Alternatively, the mechanisms that account for comorbidity may be
completely independent.
Determining whether concurrent non-psychiatric medical conditions are a
cause, consequence, or independent of an anxiety disorder is often difficult, but
currently held psychological models of anxiety provide an explanatory frame-
work for some of these linkages. Consider some of the prominent psychological
theories of anxiety psychopathology (Barlow, 1988; Clark, 1986). These models
describe two mechanisms for the generation and/or maintenance of anxiety and
panic including: (1) cognitive misappraisal that may often involve the misap-
praisal of benign bodily sensations and, (2) interoceptive conditioning that links
bodily cues with sympathetic arousal. Bodily perturbations are a common and
necessary element for the generation of fear in each of these mechanisms. In the
context of these mechanisms, it is apparent that the presence of physical con-
ditions that create perceivable bodily perturbations will necessarily place an
individual at greater risk for both catastrophic misappraisal of sensations and
an interoceptively mediated fear response. In line with these psychological
models of anxiety and panic, non-psychiatric medical morbidity may contribute
to or maintain anxiety problems when the physical condition produces bodily
sensations that are likely to be misattributed. Whatever the relationship, the
interplay between the anxiety disorder and physical conditions is likely to
influence response to treatment.
Treatment of Anxiety Psychopathology
Despite the high prevalence and impairment created by anxiety psychopathol-

ogy, the evolution in psychological and pharmacological treatments has made
tremendous strides in the past 20–30 years. Fortunately, efficacious treatments
for anxiety are available including several types of pharmacotherapy as well as
cognitive behavioral therapy (CBT; Schmidt, Koselka, & Woolaway-Bickel,
2001). Antidepressants such as monoamine oxidase inhibitors (MAOIs), tricyc-
lic antidepressants (TCAs), and serotonin selective reuptake inhibitors (SSRIs)
are among the psychotropic medications that have demonstrated the highest
levels of efficacy in the treatment of anxiety disorders (see Sammons & Schmidt,
2001, for a review). Antidepressants have become the medication of choice in
the pharmacological treatment of anxiety problems, reducing anxiety symp-
toms without causing the withdrawal and dependency that can occur with
Physical Illness and Treatment of Anxiety Disorders: A Review 347
benzodiazepines. Yet, benzodiazepines are appealing in that they provide more

rapid anxiolytic effects and therefore continue to also serve as a common
treatment for certain anxiety disorders.
In terms of psychotherapy, research has consistently demonstrated that CBT
is one of the most efficacious treatments for most forms of anxiety (see Nathan
& Gorman, 1998, for a review). CBT for anxiety disorders is a highly structured,
skill-based treatment in which the therapist works with patients to modify
thinking and behaviors that maintain anxiety. Techniques utilized in CBT
include education, cognitive reappraisal, anxiety management procedures
such as progressive muscle relaxation and breathing control skills, as well as
various exposure-based interventions. These include interoceptive exposure
(i.e., repeated exposure to bodily sensations associated with a fear response),
in vivo exposure (i.e., exposure to external situations connected to fear) and
imaginal exposure (i.e., exposure to feared internal thoughts and cues).
The high rates of comorbidity evident for anxiety disorders have naturally
led to evaluation of the effects of co-occurring conditions on treatment out-
come. In the case of psychiatric comorbidity, Mellman and Uhde (1987) found
poorer response to pharmacotherapy in patients with panic disorder and
comorbid obsessive-compulsive disorder. Pollack, Otto, Rosenbaum, and
Sachs (1992) reported poorer outcome for panic disorder patients with comor-
bid Axis II disorders. However, Brown, Antony, and Barlow (1995) found that
co-occurring Axis I diagnoses did not differentially affect treatment outcome.
While we are beginning to appreciate some of the complications arising from
treating patients with anxiety plus other psychiatric conditions, there is very
little work exploring the comorbidity of anxiety with physical illness.
The focus of this chapter is to review studies that have evaluated treatment
effects for those with comorbid anxiety and physical illnesses. In regard to
inclusion and exclusion criteria for this review, there are many studies that include
some assessment of anxiety in the context of physical illness (see Table 1).
However, we excluded a good number wherein anxiety assessment was not a
primary focus of the paper, and was not particularly relevant to our
understanding of the treatment of Axis I anxiety problems. Generally this
occurred when the anxiety symptom outcomes were based on brief, self-report
instruments; the symptoms themselves were most likely attributable to a
threatening medical condition or procedure (e.g., receiving a cancer diagnosis
or undergoing chemotherapy); the study did not adequately assess for clinically
significant anxiety; or the treatment of physical illness was the primary focus. We
did, however, include and briefly summarize a few studies where these limitations
existed, because the investigations raised interesting points.
Due to the general lack of research in this area, there is not a well-definelitera-
ture on specific sets of anxiety condition and physical illness. As a result, definitive
conclusions about specific pairings of conditions are necessarily limited. In the
first review section, we consider available research assessing all forms of anxiety
and physical illness comorbidity in the context of psychosocial treatments.
Because there are a number of studies varying significantly in methodology, this
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.
Psychosocial Treatment of Physical Illness and Anxiety
Randomized with Treatment Comparison Group
The Collaborative Care for Anxiety and Panic study (CCAP) (Craske et al.,
2005; Roy-Byrne, Craske et al., 2005; Roy-Byrne, Stein et al., 2005) sought to
investigate the effectiveness of CBT and medication combined versus usual care
in the treatment of patients with panic disorder in primary care settings. This was
a multi-site study involving six clinics from three different cities. Participants
were recruited through brief screenings in the clinic waiting room or referrals
from medical providers. Eligibility was determined over the telephone using the
Composite International Diagnostic Interview (CIDI; World Health Organiza-
tion, 1997). Patients met DSM-IV criteria for panic disorder and were randomly
assigned to care as usual or to the combined CBT and medication treatment
condition. In the treatment condition, participants were assigned to a health care
specialist who delivered six in-person sessions of CBT along with six brief
booster sessions via the telephone. The CBT techniques employed were relaxa-
tion, exposure to feared situations, homework, provision of information about
panic attacks, identification of cognitive errors, challenge of cognitive errors and
modification of behavioral response to feared bodily sensations. The health care
specialist also coordinated the medication management for each participant.
Published reports from CCAP study have indicated that the combination of
CBT plus medication outperformed usual care in terms of number of remitters
and responders as well as greater improvement in functional status and health
related quality of life (Roy-Byrne, Craske et al., 2005). Further comparison of
individuals who received CBT plus medication versus medication alone, regard-
less of randomized condition, also revealed an advantage to the combined
treatment (Craske et al., 2005). Of particular interest to the current review,
a medical illness burden score was calculated based on the number and type of
prescription medications participants reported taking along with their self-
reports of chronic disease (Roy-Byrne, Stein et al., 2005). Based on this calcula-
tion, 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 counter-
parts. 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 adminis-
tered 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 organiza-
tion. 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 num-
ber 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
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 psy-
chotherapy (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 partici-
pants were randomly assigned to receive relaxation classes or CEGT plus
relaxation. During three relaxation sessions, participants were taught progres-
sive 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 thera-
pists 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 pretreat-
ment 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 adminis-
tered 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 sub-
stantially lower rates of PTSD development at both post-treatment (d = 1.16)
and at 6-month follow-up (d =0.87).
Randomized with Waitlist
Individuals with panic disorder frequently report a comorbid nonpsychiatric

medical illness. While there is extensive support of CBT’s effectiveness in
treating the anxiety condition in such persons, few have investigated whether
CBT would also improve concommitant physical health. Schmidt et al. (2003)
studied panic disorder and general health. After diagnosis via a clinical inter-
view (SCID-NP; First, Spitzer, Gibbon, & Williams, 1994), participants were
randomly assigned to 12 weeks of group CBT or to a waitlist condition. The
group CBT was a structured, manualized treatment that focused on four main
objectives: education and feedback regarding the development and mainte-
nance of panic disorder, identification and alteration of faulty panic related
appraisals, interoceptive exposure, and exposure to feared external situations.
The Panic Disorder Severity Scale (PDSS; Shear et al., 1997), Sheehan
Patient-Rated Anxiety Scale (SPRAS; Sheehan, 1983), General Health Survey
(GHS; McHorney, Ware, & Raczek, 1993) and Physical Health Rating Form
(PHRF; Orts et al., 1995) were administered to all participants at baseline and
post-treatment. Fifty-six percent reported at least one chronic health condi-
tion at baseline on the GHS. The treatment group reported both a significant
reduction in anxiety symptoms and an improvement in their physical health.
Analyses of clinical significance showed that being in the CBT group
accounted for 13% of the change in the PHRF scores, 18% of the change
in the SPRAS, and 27% of the change in the PDSS. Further, mediational
analysis indicated that the gains in physical health were independent of
improvement in anxiety symptoms.
Ross, Davis, and MacDonald (2005) focused on individuals with comorbid
panic disorder and asthma and assessed the combined treatment of CBT and
asthma education. Asthmatics report a higher rate of panic disorder than the
general population. In this study, individuals with panic disorder were identi-
fied using the Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV;
Brown et al., 1994). Participants diagnosed with panic disorder were rando-
mized to either a treatment or waitlist condition. Treatment included twelve
90-minute sessions administered in small groups over eight weeks. The CBT
protocol focused on four main objectives: education and corrective feedback
regarding the nature, etiology and maintenance of panic disorder; identification
and alteration of faulty anxiety and panic related appraisals; and training in
slow diaphragmatic breathing and interoceptive exposure. Asthma related
indices were attained using the Asthma Quality of Life Questionnaire (Juniper,
Guyatt, Ferrie, & Griffith, 1993) and the Asthma Symptoms Diary (Ross et al.,
2005). At post treatment, the treatment group evidenced significant decreases in
panic frequency, general anxiety, anxiety sensitivity, as well as increases in
morning peak-flow expiratory rate and asthma-related quality of life. Anxiety
related gains were maintained at 6 months, whereas the pulmonary function
gains were not.
Nonrandomized with Control Group
Shemesh et al. (2006) reported on individuals who met PTSD threshold on the
Impact Event Scale (IES; Horowitz, Wilner, & Alvarez, 1979) following a
myocardial infarction (MI). Original MI diagnoses based on symptoms, electro-
cardiogram changes and enzymes changes were confirmed by a study cardiolo-
gist. All participants received an informational session regarding the importance
of following medical advice after an MI. Additionally, a self-selected subset also
participated in four to five sessions of CBT focused on their traumatic symptoms.
All self-selected participants also met criteria for PTSD on the Structured Clinical
Interview for DSM-IV (First, Spitzer, Gibbon, & Williams, 2001). The abbre-
viated CBT administered in this study was manualized, provided by a psychiatrist
and focused on relaxation, exposure and cognitive reprocessing. The psycholo-
gical measures were the IES, the Posttraumatic Stress Disorder Diagnostic Scale
(PDS; Foa, Cashman, Jaycox, & Perry, 1997), the Beck Depression Inventory
(BDI; Beck, Ward, Mendelson, Mock, & Erbough, 1967), and the SCID-IV.
Participants in the information only group showed significant improvement only
in adherence to aspirin treatment. Those in the CBT group exhibited significant
improvement in aspirin adherence, several medical risk factors (reduced high
blood pressure, smoking and cholesterol) and anxiety symptoms (reduced PDS
scores by 57% and IES scores by 22%).
Kennedy, Duff, Evans, and Beedie (2003) evaluated inpatients from a
rehabilitation unit who had suffered a recent traumatic spinal cord injury
(SCI). This group was of particular interest because of their previously reported
increased risk for developing psychopathology, particularly anxiety and depres-
sion. Anxiety and depression were assessed using the state portion of the State
Trait Anxiety Inventory (Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983)
and the BDI (Beck et al., 1967). Patients were invited to participate in coping
effectiveness training, which was based on Lazarus and Folkman’s cognitive
theory of stress and coping (1984) as well as CBT techniques. Sessions were
devoted to normalizing stress reactions; assessing typical appraisal and coping
techniques; developing appraisal and coping skills; examining the connections
and distinctions between thoughts, feelings and behaviors; increasing pleasant
activities and relaxation; and challenging negative thoughts. The intervention
consisted of seven 60- to 75-minute small group sessions. For analyses, partici-
pants were matched with an archival sample of SCI patients. When compared to
the control group, the intervention group showed a significant reduction in
anxiety and depression symptoms but no improvement in coping strategies as
assessed by the COPE (Carver, Scheier, & Weintraub, 1989).
Another study among spinal cord injury patients was designed to immunize
participants against depression and anxiety (Craig, Hancock, Chang, &
Dickson, 1998). Previous work indicates that approximately 30% of individuals
with an SCI exhibit elevated levels of depression and anxiety up to two years
following the injury (Craig, Hancock, & Dickson, 1994). Participants were
receiving standardized hospital rehabilitation following an acute spinal cord

injury at the time of study enrollment. Depression and anxiety were assessed at
pretreatment, post-treatment, 1 year follow-up and 2 year follow-up using the
Beck Depression Inventory (Beck et al., 1967) and the trait portion of the State
Trait Anxiety Inventory (Spielberger et al., 1983). Treatment consisted of
10 weekly sessions of CBT delivered in a small group format. CBT components
included relaxation techniques (progressive muscle relaxation, visualization
and self-hypnosis), cognitive restructuring, attentional distraction, pain rein-
terpretation, education regarding sexuality after an SCI, assertiveness training,
social skills training and increased pleasant activities. All participants including
the nonrandomized control group were followed for two years. The treatment
group did not experience a significant decrease in anxiety or depression. How-
ever, more focused analyses examining only those participants with elevated
anxiety or depression scores at baseline indicated larger reductions in symptoms
for the treatment group.
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 (SCID-
NP; 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 techni-
ques 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 treat-
ment 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 indi-
viduals 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
were encouraged to perform twice daily for fifteen minutes. Half of the parti-
cipants 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 reduc-
tion 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
CBT’s effectiveness in improving traumatic brain injury patients’ coping stra-
tegies 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 psycho-
social 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
improvements–even in more impaired populations–may 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 asth-
matics 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 demon-
strated, the potential mechanisms for change are largely unclear. Very few
studies investigated the moderating effect of health status on the relationship
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 treat-
ment duration to be considered remitted. Further investigation into the modera-
tional role of health status on treatment response is warranted to determine what
impact it has on the different medical-anxiety illness comorbidities.
Pharmacological Treatment of Physical Illness and Anxiety
Medication side effects are a major concern in the pharmacological treatment of

comorbid chronic physical illness and anxiety disorders. Psychological benefits
must be weighed against the physical tolerability of the psychotropic drugs.
Recently, Gothelf et al. (2005) preliminarily investigated the physical and
psychological correlates of fluvoxamine treatment in youth cancer patients
who also suffered from comorbid depression, anxiety, or both.
Gothelf et al. (2005) recruited patients from a pediatric cancer hospital for
their open trial study of fluvoxamine tolerability. The diagnosis of psychologi-
cal disorders was based on recommendations of the American Academy of
Pediatrics, and quite thorough. First, healthcare providers specially instructed
in the identification of mood disorders identified 74 potential candidates age 7
to 20 years old. The second tier screening asked patients to fill out self-report
measures; children aged 7–13 completed the Children’s Depression Inventory
(CDI; Kovacs, 1992), and adolescents aged 14–20 completed the BDI. All
participants completed the Screen for Child Anxiety Related Emotional Dis-
orders (SCARED; Birmaher et al., 1997). Based on cutoff scores for the CDI
(10), BDI (10), and SCARED (15), patients were referred for more comprehen-
sive psychiatric evaluation involving structured clinical interviews of the child,
the child’s parents, and the child’s primary nurse. All of the interviews were
completed by a psychiatrist specializing in children and adolescents. The psy-
chiatrist used the affective and anxious items of the Schedule for Affective
Disorders and Schizophrenia for School-Age Children, Present and Lifetime
Version (K-SADS-PL; Shanee, Apter, & Weizman, 1997). For our purposes we
will focus on only those diagnosed with anxiety or mixed anxiety and depres-
sion. Sixty-three subjects received psychiatric evaluation; of those 9 (14.3%)
met DSM-IV criteria for an anxiety disorder, and 8 (12.7%) met criteria for
comorbid MDD and an anxiety disorder. Because the K-SADS-PL includes a
retrospective report section, the researchers were able to identify two patients
who had anxiety disorders prior to their cancer diagnoses. Anxiety disorder
diagnoses included generalized anxiety disorder, PTSD, and separation anxiety
disorder.
The nature of each child’s 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 medica-
tions 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 Children’s Depression Rating Scale-
Revised (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 psychopathol-
ogy 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. Conse-
quently, 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 interven-
tion consisted of six weeks of SSRIs with dose titration. However, if a partici-
pant had already had two unsuccessful trials of treatment with SSRIs, other
medications including benzodiazepines and tricyclic antidepressants were tried

first. The results suggest combined CBT and pharmacotherapy is most effective.
In addition, both high and low physical illness groups had comparable response
rates at the end of treatment. However, at follow-up the high physical illness
participants experienced more symptoms than their low counterparts. This
study suggests physical illness comorbidity does not necessarily affect responses
to pharmacological interventions, though it may impact duration. Collabora-
tion between care-givers in medical and psychological fields is in the best
interest of patients.
Irritable bowel syndrome (IBS) is a medical condition that causes significant
abdominal pain, discomfort, and bowel irregularities. In addition, IBS is fre-
quently comorbid with anxiety disorders. Studies have shown that 37% to
41.9% of individuals with anxiety disorders have comorbid IBS, as compared
to only 2.5% to 11% of age and sex-matched controls (Noyes, Cook, Garvey, &
Summers, 1990; Tollefson, Tollefson, Pederson, Luxenberg, & Dunsmore,
1991). Moreover, researchers have found that the serotonin pathways impli-
cated in IBS are the same as those acted upon by SSRIs (Read & Gwee, 1994).
There is significant data supporting the treatment of IBS using SSRIs. Clouse,
Lustman, Geisman, and Alpers (1994) found that 89% of individuals with IBS
treated with antidepressants reported improvement and 61% reported com-
plete remission. Because of the evidence for shared etiology, high rates of
comorbidity, and treatment of IBS using SSRIs, Masand et al. (2002) con-
ducted an open-trial to investigate whether outcomes from treating IBS with
paroxetine were different in individuals with versus individuals without a
comorbid anxiety disorder.
In the Masand et al. (2002) open label study, 10 IBS patients with a history of
an anxiety disorder and 10 IBS patients without it were compared. Anxiety
disorders were assessed at baseline by clinician-administered SCID, an empiri-
cally supported structured interview. The diagnoses included specific phobia,
panic disorder without agoraphobia, panic disorder with agoraphobia, social
anxiety disorder, and PTSD. Three patients had comorbid psychological
disorders including major depressive disorder, dysthymia, and adjustment
disorder. IBS was diagnosed using the Rome I criteria, which is the medical
profession standard. In addition, patients underwent physical testing to
confirm the diagnosis as well as to rule out other conditions. The examination
included a blood count, blood chemistry test, fecal occult blood tests, and a
flexible sigmoidoscopy. Both the physical and anxiety conditions were deter-
mined using structured interview criteria. However, the IBS diagnosis also
benefited from additional objective symptom measurement.
The intervention consisted of 12 weeks of a 20 mg/day dose of paroxetine. If
patients showed a partial response after 4 weeks, their dose was increased to
40 mg/day. The average dose received overall was 31 mg/day. One of the
strengths of this study was the use of an interactive telephone interviewing
system for daily monitoring of symptoms. Patients provided self-ratings over
the phone for the Hamilton Rating Scale for Depression (Hamilton, 1967), the
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. Indivi-
duals with anxiety disorders experienced somewhat greater alleviation of symp-
toms 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 sig-
nificantly 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 psychody-
namic interpersonal therapy, paroxetine, or routine IBS care from a gastro-
enterologist 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 signifi-
cant 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 symp-
toms, the researchers concluded that the health-related outcomes in IBS result-
ing 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 disor-
der. Anxiety disorders were diagnosed according to the Diagnostic and Statis-
tical Manual, fourth edition (DSM-IV) criteria for GAD, in combination with a
score of 18 or more on the Hamilton Anxiety Rating Scale (HAM-A; Hamilton,

1967), however there are several concerns about assessment adequacy. It was
not clear whether structured clinical interviews were used to diagnose anxiety
disorders. In addition, there was little rationale for the exclusion and differen-
tial diagnosis of anxiety disorders other than GAD. According to the DSM-IV,
GAD frequently co-occurs with not only stress conditions including IBS and
migraine disorder, but also with other anxiety disorders including panic dis-
order, social phobia, and specific phobia. The effective assessment of GAD
requires a thorough process of differential diagnoses, which was not mentioned
in this study.
Migraine disorder without aura was diagnosed according to the criteria of
the International Headache Society (IHS; Headache Classification Subcommit-
tee of the International Headache Society, 2004). Patients were screened
using the Migraine Disability Assessment Score (MIDAS; Stewart, Lipton,
Kolodner, Liberman, & Sawyer, 1999) and completed several self-report mea-
sures including the Headache Self-Efficacy Scale (HMSE; Martin, Holroyd, &
Rokicki, 1993) and the Headache Disability Inventory (HDI; Jacobson,
Ramadan, Aggarwal, & Newman, 1994). Additionally, patients kept a diary
in which they recorded headache frequency and intensity during the two-week
baseline period and six weeks of treatment. These two variables were used to
calculate the headache index (HI) every two weeks. When patients came to the
lab biweekly, they also filled out the HAM-A and the headache self-report
measures.
The buspirone group showed a significant decrease in headache frequency
after the six weeks of treatment and at three-month follow up (of 26 patients).
Headache intensity and scores on the HDI did not differ between the two
groups. HAM-A scores in the buspirone condition were significantly lower
than the placebo group. The researchers also considered the emotional compo-
nent of the HDI, which was significantly reduced in the buspirone condition.
Bivariate correlation analysis showed no significant correlation between HI
reduction and HAM-A improvement. The researchers (Lee et al., 2005) sug-
gested these results were indicative of the specificity of buspirone effects on the
frequency of migraines and this effect was independent, not secondary to, the
anxiolytic effects of the drug.
Lee et al. (2005) investigated the usefulness of a psychotropic medication on
a physical illness and mental disorder with purported similar neurological
substrates that appear to contribute to the expression and severity of one
another. While it was impossible in this study to clearly separate the anxiolytic
effects of buspirone from the prophylactic effects on migraine, it suggests
psychotropic treatment may be useful not only because it limits the exacerba-
tion of physical illness by anxiety, but also because psychotropic drugs can
directly affect aspects of the physical illness.
In sum, this limited literature suggests pharmacological treatments for anxiety
disorders can be safe and effective in individuals with even severe comorbid
physical illnesses (Gothelf et al., 2005; Roy-Burne et al., 2005). In some cases,
specifically, IBS and Migraine disorder, pharmacological treatments for anxiety

disorders not only alleviate symptoms of anxiety, but also have an additional and
potentially separate effect on physical symptoms of comorbid conditions (Lee
et al., 2005). It has been speculated that these dual effects may occur because
both the physical illness and the anxiety disorder share the same biological
substrates.
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 treat-
ment 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 ill-
nesses and anxiety. First, people with a wide range of physical illnesses (cardi-
opulmonary, 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 asth-
matics 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 over-
lap 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,
relaxation training, cognitive therapy, problem-solving skills training, and sleep

management skills. The second is CBT-BA: the creation of a behavioral activity
hierarchy to both increase pleasure (a key component in treating depression) and
provide exposure to anxiety producing situations. Treatment involves eight (one-
hour) weekly group sessions, and includes discussion relevant to how managing
anxiety, depression, and somatic symptoms may interrelate, complementing or
conflicting. For example, starting an exercise program may increase shortness of
breath thereby increasing anxiety in the short term but decreasing it in the long run
as interoceptive fears diminish. Exercise may also increase physical fatigue in the
short run but decrease fatigue over the long term due to lessened depression and
improved cardiopulmonary functioning. Though efficacy trials for these interven-
tions are ongoing, they appear to be very promising.
Future Methodological Considerations
One method of considering these studies is to put them into the context of what
might be considered ideal designs for the evaluation of treatment outcome in
comorbid physical illnesses and anxiety. The first criterion that should be
considered involves standardized, clinical assessments of both conditions. An
ideal study should have comprehensive medical determination of illness con-
ducted by physicians. Many of the studies reviewed relied on patient self-reports
of physical illness. Although there are data suggesting that people can validly
report physical conditions, medical evaluation should be considered the gold
standard for future work. Similarly, the assessment of anxiety psychopathology
should be determined by a structured diagnostic interview and conducted by
trained clinicians. It may be fruitful to simply assess anxiety symptoms, as was
done in a number of the reports reviewed. Certainly self-report assessments of
symptoms can complement diagnostic assessments. However, the evaluation of
clinical syndromes is compelling not only in terms of public health significance,
but because Axis I conditions may yield different treatment results if they are
discontinuous from subclinical or nonclinical expressions of anxiety (Kotov,
Schmidt, Lerew, Joiner, & Ialongo, 2005; Schmidt et al., 2007). Moreover, the
symptom overlap between certain physical illnesses and anxiety problems is
considerable. These comprehensive assessments are needed to ensure accuracy
of differential diagnoses (i.e., between physical and psychiatric diagnoses). In
addition, standardized medical and psychiatric interviews should be repeated at
posttreatment and follow-up. This will allow researchers to ascertain whether
the intervention yielded any changes in terms of the medical as well as the
psychiatric problems. In this review, very few reports implemented this standard.
A second criterion needed for clarification of the effects of comorbidity
on outcomes involves the implementation of standardized, empirically
supported treatments. In this regard, our review suggests that the literature has
done a fairly good job of utilizing empirically supported treatments. However,
these studies have largely focused on treatments aimed at the psychiatric condi-
tion. As we noted in the introduction, very few studies using empirically sup-
ported medical treatments that are designed to intervene on a physical illness
appear to be concerned with the co-occurrence of Axis I anxiety psychopathol-
ogy. 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) modera-
tor 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 respon-
sible 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 under-
standing of the interplay between physical illnesses and anxiety and how this
impacts treatment interventions.
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Index
Acute exercise, effects on anxiety, 88–89 disorders involving, 35

Acute pain, in PTSD patients, 213, 214 effects of pharmacological treatment for1
ADIS, see Anxiety disorders interview anxiety on, 45
schedule (ADIS) among HIV patients, prevalence of, 328
Adolescent anxiety and puberty psychological effects of, 35
anxiety problems, 155 symptoms of alcohol use disorders, 37
future perspectives, 167, 168 Allergic asthma, 239
puberty operationalization and Amnesia, 350
assessment, 156–160 Anaerobic exercise, effects of, 96
researches, 166, 167 Anal intercourse, 323, 324
See also Puberty, role in adolescent Angina
anxiety: theory and evidence development of, 283
Adolescents microvascular, 290
asthma with, anxiety in, 241, 247 Anhedonic depressive symptoms, 69
relation between, 242–246 Anti-basal ganglia antibodies (ABGA), 142
HIV-infected, sexual activity among, 324 Antiretroviral therapy (ART)
Adrenal hormones, in puberty, 158 goal of, 327
A2 and 1adrenergic agonist, treatment of side effects of, 326
anxiety and sleep-related viral replication, suppression of, 327
problems, 114 Anxiety
Adulthood, with asthma symptoms, obesity in asthma
in, 239 cognitive behavioral model, 269
Adults cognitive behavioral treatment,
asthma and anxiety in, 247, 259 268–270
relation between, 248–258 in asthmatic adults, see Asthma and
Agoraphobia, 139, 140 anxiety
as complication of panic disorder, 5 in asthmatic children/adolescents, see
diagnostic criteria for, 4 Asthma and anxiety
panic disorder and anxiety disorder with, and CHD, see Coronary heart disease
DSM-IV for diagnosis of, 61 (CHD), and anxiety
AIDS, casualties since beginning, 318 and depression
Alcoholics Anonymous (AA), group-based in cardiac events, effects of, 285
treatment modality, 45 in CHD, comorbidity of, 294
Alcohol-induced anxiety, 34 comorbidity of, 280
Alcohol use, 317 as predictive of hypertension, 297
among asthma patients, 259 STAI and BDI for, 352, 353
anxiety and other health behaviors, 41 and HIV, see HIV (Human
cognitively-mediated tension reduction immunodeficiency virus), and
effect of, 38 anxiety
367
368 Index
Anxiety (cont.) Anxiety disorders

and hostility, as predictive of alcohol role in development of, 37
atherosclerotic disease, 297 and alcohol use disorders, odds ratios
and its disorders in asthma, see Asthma (ORs) to quantify relationship
and anxiety disorders between, 31
in NCCP patients, 289–291 and alcohol use, etiological theories of
and physical illness, see Physical illness relationship between, 29
and anxiety anxiety symptoms and increased
and risk for HIV infection or vulnerability of developing, 35
transmission, 322–326 in CHD patients, prevalence of, 281, 282,
role in CHD, 292 287–289
role in HIV, 332 and chronic pain
See also HIV (Human immunodeficiency assessment methods, 223–225
virus), and anxiety associations, 215–217
and sleep disorder, primary classification course of, 214, 215
for diagnosis, 106 issues and researches on treatment,
Anxiety and insomnia 227–229
criteria for support physiological arousal, 220–222
different disorders, 109 prevalence of, 209–214
single-spectrum disorder, 108 treatment and therapies, 225–227
third factor models, 109–110 comorbid anxiety, 329
evidence supports to models in context of mood disorder, 64
age of onset, 110–111 diagnosis of, 42
course, 112–113 exercise role in, 81
gender distribution, 111 GAD, prevalence of, 321
neuroanatomy and pharmacology, HADS anxiety score, 327
113–117 health anxiety and sexual behavior,
symptoms and sleep EEG, 111–112 324–325
Anxiety and menstrual cycle disorders and health behaviors, link between, 131
anxiety sensitivity, 189, 190 and HIV infection risks, 322–326
assessment measures, 184, 185 in HIV patients, prevalence of, 319, 332
and biological factors, 193 generalized anxiety disorder (GAD), 321
health behaviors, 196, 197 MSM and anxiety disorder, 321
premenstrual exacerbation and panic disorder (PD), 321
comorbidity, 185, 186 PTSD, 320–321
premenstrual symptoms and disorders, women, anxiety disorders in, 322
182, 183, 190–192 illicit drug use comorbidity, 71
researches on, 197–199 panic disorder, prevalence of, 321
retrospective and prospective studies, pathophysiology of stress hormones in,
183 330–331
treatments and therapies, 194–196 and physical illness
Anxiety and physical illness link, method of comorbidity, 129
assessment treatment of, see Physical illness and
generalized anxiety disorder (GAD), anxiety
141–142 in prediction of development of alcohol
obsessive-compulsive disorder (OCD), dependence, 34
142–143 prevalence and impact among asthmatic
panic disorder (PD), 136–140 patients, 241
posttraumatic stress disorder (PTSD), prevalence in
132–136 HIVþ individuals, 319
social anxiety disorder, 143–144 HIVþ MSM, 320–322
specific or simple phobia, 144–145 programmatic research in, importance of,
See also Physical illness and anxiety 331–333
Index 369
PTSD, 324 Asthma, 341

prevalence rates of, 320–321 adults with, anxiety in, see Asthma and
relationship between anxiety and anxiety
alcohol, 31 anxiety-asthma relation, specificity of,
relationships with illicit drug use, 58 265–266
screening measures, 319 and anxiety disorders, 237
semi-structured interviews, 223, 224 prevalence and impact of, 241
social anxiety, 323–324 anxiety in, CBT for, 268–270
specific rates of co-occurrence for, 8 anxiety vulnerabilities on, 264–265
stress hormones, dysregulation of, 331 Atopy syndrome in, 240
symptomatic and syndromal levels of bronchoconstriction, 262, 264, 266
enquiry in, 29–31 children/adolescents with anxiety in, see
temporal order of, 64 Asthma and anxiety
tobacco use on, 3 classification, 238
trait anxiety, 323 dysfunctional beliefs, 267–268
treatment outcome and relapse in, 43 and mental health, 240–241
Anxiety disorders and specific illnesses, 129 non-psychological risk factors for,
observed relationships, explanations for 239–240
direct and indirect causal relationship, occurrence and symptoms, 237, 238
130 and panic differentiation in asthma
shared risk factors, 131 treatment, 269
Anxiety disorders interview schedule panic disorder in, specificity of, 260–261
(ADIS), 293 P-F levels in, 264
for DSM-IV, 351 and psychopathology, relation
Anxiety management, in asthma between, 259
treatment, 269 related QoL, effect of anxiety on, 263
Anxiety neurosis, 286 self management, in asthma
atherosclerosis among, 296 treatment, 269
Anxiety-premenstrual cycle phase symptom severity, and anxiety, 262–263
interaction models, 192–194 Asthma and anxiety
Anxiety psychopathology in adults, 247, 259
assessment of, 361 outcomes of various studies, 259
and physical illness, 341, 346 relation between, 248–258
studies on, 342–345 in children/adolescents, 241, 247
treatment of, 346–348 relation between, 242–246
Anxiety-related HIV sexual risk, cognitive-behavioral model of co-
mechanisms of, 325 occurrence of, 266–268, 269
Anxiety sensitivity (AS), 40, 67 extant research, 270–271
and adolescent anxiety, 171 limitations, and future directions,
in asthma-anxiety association, 264–265 271–272
in chronic musculoskeletal pain and Asthma Symptom Checklist (ASC), 260, 264
PTSD patients, 218, 219 Astrand-Ryhming ergometer test, 83
in premenstrual disorder, 189–190 Atherosclerosis
treatment for heroin users, 72 in anxiety-CHD association, 296–297
Anxiety symptoms, 131–132 anxiety for progression of, 295
Anxiolysis, 116 cause of, 281
Arrhythmias inflammatory cytokines in, role of, 301
anxiety in, examination of, 285 product of, 280
occurrence of, 297 risk factors of, 297
ventricular Atopy syndrome, in asthma, 240
anxiety in, 295 Autonomic nervous system (ANS)
susceptibility to, 299 dysregulation, in PTSD and
Aspirin treatment, for improved PTSD, 352 chronic pain, 221, 222
370 Index
Average sleep duration, 118 patients with NCCP, anxiety in,

Axis I anxiety disorder in NCCP, 291 289–291
terminology and background in,
Beck Anxiety Inventory (BAI), 40 280–281
Beck depression inventory (BDI), for Causal risk factor, and puberty, 159
depression and anxiety, 352, 353 CBT, see Cognitive behavioral therapy
Benzodiazepines, 347, 357 (CBT)/ Cognitive-behavioral
efficacy of, 93 treatment (CBT)
Blood pressure CCAP study, see Collaborative care for
changes, as symptom of partial anxiety and panic study (CCAP),
seizures, 138 for effectiveness of CBT
elevated, in pain and anxiety, 220 CD4þ cell and HIV infection, 318
high CDI, see Children’s Depression Inventory
as cardiovascular risk factor, 133, 282 CEGT, see Cognitive-existential group
endothelial damage in atherosclerosis psychotherapy (CEGT)
due to, 281 Central nervous system (CNS),
as factor contributing to hyperexcitability of, 35
atherosclerosis, 296 Central neurotransmitter function, 92
influence of CBT over, 352 CHD, see Coronary heart disease (CHD)
in panic disorder patients, 136, 300 Chest pain (CP), 279
Brain injury, 354, 360 non-cardiac (NCCP), anxiety in patients
Breast cancer, 354 with, 289–291
CEGT for, 350 Childhood sexual abuse
Breathing, diaphragmatic, 351 among IDUs, rates of, 328
Bronchitis, chronic, 240 and PTSD, prevalence of, 325
Buspirone, effects on migraine disorder, Children, with asthma and anxiety
358, 359 disorder, relations between, 241,
242–246, 247
CAD, see Coronary artery disease (CAD) Children’s Depression Inventory, 355
Cancer, 360 Chronic insomniacs, 117
breast, 354 Chronic musculoskeletal pain
CEGT for, 350 and anxiety disorders, 208–212
in youth, fluvoxamine for treatment exposure therapy and graded activities,
of, 355 226, 227
Cardiac anxiety, in NCCP, 289 Chronic obstructive pulmonary disease
Cardiac death, and anxiety, association (COPD), 137, 138, 341, 360
between, 284 patients with anxiety and depression,
Cardiac function, altered, in anxiety-CHD CBT for, 360
association, 297–300 Chronic Pain Coping Inventory (CPCI),
Cardiac morbidity, negative impact of in anxiety disorder assessment, 225
depression on, 302 Chronic pain, in PTSD patients, 213, 214
Cardiorespiratory disorders, 341 Cigarette smoke, 281
Cardiovascular disease (CVD) and anxiety, 279 See also Smoking
future directions, 303–305 Clinical anxiety, exercise training programs
increased risk for CHD, 281–287 for, 89–92
See also Coronary heart disease (CHD), Clinical Global Index, 45
and anxiety Cognitive behavioral therapy (CBT), 136
past studies on, caveats in interpretation for anxiety, 346
of, 291 anxiety disorder and pain treatment, 225
conceptualizations of anxiety, for depression, efficacy of, 333
292–293 for improved QoL among individuals
construct definition overlap, 293–294 with asthma, 270
directionality, 294 for PMS treatment, 195, 196
Index 371
randomized trials for anxiety disorders in psychosocial influences on, 279

HIV patients, 330 risk factors in, 281
to improve anxiety and problematic NCCP patients, 291
drinking symptoms in comorbid ventricular arrhythmia, 299–300
patients, 45 Coronary heart disease (CHD), and anxiety
Cognitive-behavioral treatment (CBT) association between, potential
for anxiety disorders, 346, 347 mechanisms in
in HIV patients, 330 altered cardiac function in, 297–300
of anxiety in asthma, 268–279 atherosclerosis in, 296–297
CBT-RADAR for reducing anxiety and health-compromising behaviors in,
depression among COPD 295–296
patients, 360 pathophysiological mechanisms of,
CCAP for effectiveness of, 348 300–302
for depression in HIV, 333 increased risk for, 281
for depression in smokers, 18 epidemiological studies on, 282–284
for GAD and primary insomnia, 120 studies in psychiatric samples, 286–287
for obsessive compulsive disorder, 92 studies in samples with known CHD,
for panic disorder, 349 284–285
for panic disorder target anxiety pathophysiological mechanisms of,
sensitivity, 90 300–302
for PPV and panic disorder, 353 therapeutic approach for targeting of,
for PTSD, 350 302–303
for substance dependence, 72 Corticotrophin releasing factor (CRF), 67
Cognitive-existential group psychotherapy Cortisol
(CEGT), 350 dysregulation of, 331
for women with breast cancer, 350 role in HIV, 331
Cognitive refocusing and self-efficacy, 94
Cognitive strategies in anxiety, and pain Dehydroepiandrosterone (DHEA), 158, 188
treatment, 226 Depression
Collaborative care for anxiety and panic in asthma, prevalence of, 237
study (CCAP), for effectiveness of on cardiac morbidity, negative impact
CBT, 348 of, 302
Concurrent treatment of PTSD and cocaine in HIV, CBT for, 333
dependence (CTPCD), 72 sertraline for, 303
Confidence interval (CI), 239 severity of, 327
Congenital analgesia, 208 Depression and anxiety
Conjunctivitis, allergic, 240 in cardiac events, effects of, 285
COPD, see Chronic obstructive pulmonary in CHD, comorbidity of, 294
disease (COPD) comorbidity of, 280
Coronary artery disease (CAD), 137, 280 as predictive of hypertension, 297
pathophysiology of, 301 STAI and BDI for, 352, 353
patients with PD Depressive disorders, in CHD, rate of, 287
morbidity and mortality among, 298 Dermatophystosis, 110
myocardial perfusion defects in, 300 Diabetes mellitus, 281, 288, 290, 304
prevalence of, 288 Diabetes, type, 2, 110
Coronary heart disease (CHD) Drugs
family history of, 290 properties of drowsiness and
morbidity sedation, 116
predictive of, 291 use in diagnoses, 56
weighty influence on, 293 Z, for reducing anxiety, 116
occurrence of, 294 DSM-IV (Diagnostic and Statistical
patients with, prevalence of anxiety Manual of Mental Disorders,
disorders in, 287–289 fourth edition)
372 Index
DSM-IV (cont.) Generalized anxiety disorder (GAD)

ADIS for, 351 assessment of, 359
anxiety disorder of PD with with asthma
agoraphobia, 61 diagnoses of, 247
anxiety disorders, 59, 60, 85 presence of, 259
as classification system for diagnosis of cardiovascular and gastrointestinal
anxiety and sleep disorders, disease, 141
106, 116 diagnostic criteria for, 327
criteria for GAD, 120, 358, 359 endocrine/metabolic/autoimmune
diagnosis of alcohol abuse or dependence disease, 141–142
according to, 30 in HIV, prevalence of, 321
diagnosis of PTSD, 132, 135, 322 in menstrual cycle, 185, 191, 192
diagnostic criteria for CHD, 304 NE reactivity in patients with, 331
for disorder classification, 59 obsessive-compulsive disorder (OCD),
on illicit drugs, 55, 56 142–143
inclusion of PMDD in, 182 in pain patients, 209–212
for PD, 286, 348 in risk of CHD, presence of, 291
structured clinical interview (SCI) for, 352 Group A-Hemolytic Streptococcus
symptoms of a panic attack listed (GABHS), 142, 143
in, 136
Dysthymia, asthma with, 259 HAART, see Highly active antiretroviral
therapy (HAART)
Early Adulthood Research Project HADS, see Hospital anxiety and depression
(EARP), 62 scale
Eczema, 240 Headache index (HI), 359
EEG-assessed sleep, 117 Headaches, migraine, 341
Emotional stress, measures of, 326 Health behaviors, and HIV and anxiety,
Emphysema, 240 327–329
Enhancing Recovering in Coronary Heart Health-compromising behaviors
Disease (ENRICHD), 303 in anxiety-CHD association, 295–296
Epidemiological Catchment Area (ECA), 56 spectrum of, 305
Epilepsy, 138 Health Professionals Follow-up Study of
Exercise anxiolysis, mechanisms of, 92 anxiety-CHD link, 283
Exercise interventions, parameters of, 89 Health-related quality of life (HRQOL),
Exposure therapy in PTSD and pain and HIV and anxiety, 329–330
treatment, 226, 227 Heart attacks, PTSD symptoms as risk
of, 283
Fluvoxamine Heart deaths, 286
safety and benefits of, 356 Heart disease, anxiety in, 292
in youth cancer, treatment of, 355 Heart-focused anxiety, in NCCP, 289
Follicle stimulating hormone (FSH) in Heart problems, psychological factors
puberty, 158 in, 279
Forced expiratory volume in 1 second Heart-rate variability (HRV), reduced, in
(FEV1), 238 anxiety disorder, 298
Framingham heart study of anxiety-CHD Highly active antiretroviral therapy (HAART)
link, 283 anxiety and substance use, 328
autonomic nervous system activity
GABAergic-benzodiazepine-chloride response to, 331
(GBC), 115 health-related quality of life (HQOL), 329
GABAergic systems, for biological and HIV survival, 319, 329
functions, 114, 115 Histamine, role in asthma, 262
GAD, see Generalized anxiety disorder HIV (Human immunodeficiency virus)
(GAD) and anxiety, 317
Index 373
disease management, 326 HADS anxiety score, 327

disorder specific anxiety symptoms, HIV screening measures, 319
impact of, 327–328 Hospital anxiety and depression scale
future research in, 331–333 (HADS), for anxiety disorders in
health and disease outcomes in, direct HIV patients, 319
and mediated relationships Hostility, 279, 325
between, 332 HPA systems, see Hypothalamic pituitary
and health behaviors, 327–329 adrenocortical systems,
and HRQOL, 329–330 dysregulation of
management of, 326 HRQOL, see Health-related quality of life
medication adherence in, 327–328 (HRQOL), and HIV and anxiety
overview of, 318–319 5-Hydroxyindoleacetic acid (5-HIAA), 170
prevention, comorbid psychosocial 5-Hydroxytryptamine (5-HT), 301
issues in, 332 Hypercholesterolemia, 110, 281, 288, 304
prevention interventions, traditional, Hypertension, 281, 288, 290, 304, 341
332 anxiety and depression as predictive of
psychosocial and behavioral factors, prescription treatment in
326 normotensive individuals, 297
risk of infection or transmission, Hypothalamic pituitary adrenocortical
322–326 systems, dysregulation of, 331
and self-reported adherence, Hypothalamic pituitary axis (HPA), 188
relationship between, 326 in depression, dysregulation of, 301
stress hormones in, pathophysiology
of, 330–331 IBS, see Irritable bowel syndrome (IBS)
substance use and disease progression, ICD-10 (International Classification of
328 Diseases, tenth edition), as
anxiety disorders in HIV patients, classification system for diagnosis
prevalence of, 319–322 of anxiety and sleep disorders, 106
See also Anxiety disorders in HIV IDUs, see Injection drug users (IDUs),
patients, prevalence of childhood sexual abuse among,
association with heterosexual sex, 320 rates of
CD4þ cell decline in, 318 IgE role in asthma, 238
clinical presentation of, 318 IHD, see Ischemic heart disease (IHD),
disease management, 326 chronic
and GAD, 321 Illicit drugs
infection risks, role of anxiety in categories of, 56
emotional stress, 326 in context of mood disorder, 64
PTSD, 324 factors associated with vulnerability
social anxiety, 323–324 for, 69
trait anxiety, 323 lifetime prevalence rates of, 60
and panic disorder (PD), 321 reinforcing effects of, 66
programmatic research in, importance of, relationships with specific anxiety
331–333 disorders, 59
and PTSD, 320 temporal order of, 64
retrovirus, 318 usage relationships with anxiety
screening measures, 319 disorders, 58
sexual risk behavior Imagery exposure, problem solving, and
abuse history associated with, 325 relapse prevention in asthma
anxiety, 323 treatment, 269
stress hormones in, 330–331 Immune system response, HIV infection, 318
HIVþ MSM and anxiety disorders, 321–322 Immunoglobulin E (IgE), mediated asthma, 238
HIV wasting syndrome, 318 Injection drug users (IDUs), childhood
Hospital anxiety and depression scale sexual abuse among, rates of, 328
374 Index
Insomnia See also DSM-IV (Diagnostic and

age of onset for, 111 Statistical Manual of Mental
risk factor, gender distribution, 111 Disorders, fourth edition)
with secondary anxiety, 112–113 Mental health and asthma, 240, 241
Intercourse, anal, 323, 324 Mental illness, forms of, 341
Irritable bowel syndrome (IBS), 139, 140 Methamphetamine, use among MSM, 324
and asthma, individuals with, 261 Migraine disorders
SSRIs for treatment of, 357, 358 buspirone effects on, 359
Ischemic heart disease (IHD), chronic, 280 role of serotonin in, 358
Migraine headaches, 341
Kaposi’s Sarcoma, 318 Minnesota Multiphasic Personality
Kindling-stress hypothesis, 35 Inventory (MMPI), 263, 300
MI-related PTSD, 133
Late Luteal Phase Dysphoric Disorder Mitral valve prolapse, 341
(LLPDD), 182, 183 Monoamine oxidase inhibitors
biological factors, 193, 194 (MAOIs), 346
biopsychosocial factors, 194 Mood disorders
Leutinizing hormone (LH), in puberty, 158 comorbidity of, 292, 300
Locus ceruleus (LC), 114 in NCCP patients, prevalence of, 290
Lung functioning assessment, in asthma, 238 Mood symptom fluctuation in women,
Lymphoma, 318 reproductive hormones role, 193
MSM (men who have sex with men), 317
Major depressive disorder (MDD) HIVþ, and anxiety disorders, 321
with asthma, presence of, 259 methamphetamine use among, 324
comorbidity of, 293 prevalence of anxiety disorder, 320
in HIV, prevalence of, 321 Multiaxial Assessment of Pain (MAP), 220
for psychiatric comorbidity, 296 Multidimensional Pain Inventory (MPI) in
MAOIs, see Monoamine oxidase inhibitors anxiety disorder assessment, 224
(MAOIs) Multiple sclerosis, single-spectrum
Marijuana withdrawal symptoms, 68 disorder, 108
MDD, see Major depressive disorder (MDD) Multiple sleep latency testing (MSLT), 106
Medical illness, burden of, 349 Mutual maintenance model for pain and
Medical utilization, 341 anxiety disorders, 215, 216
Medication adherence, 326 Myocardial infarction (MI), 280, 352, 354
in HIV, anxiety and, 327 anxiety in, examination of, 285
Menstrual cycle and anxiety disorders, 181 anxiety with, 283
anxiety sensitivity, 189, 190 chest pain suggestive of, 289
assessment measures, 184, 185 trigger onset of, 300
biological factors, 193
biopsychosocial factors, 194 NAS, see Nucleus accumbens septi
health behaviors, 196, 197 National Comorbidity Survey (NCS), 131
premenstrual exacerbation and National Epidemiological Survey on
comorbidity, 185, 186 Alcohol and Related Conditions
premenstrual symptoms and disorders, (NESARC), 57, 60
182, 183 NCCP, see Non-cardiac chest pain (NCCP)
researches on, 197–199 anxiety in patients, 289–291
retrospective and prospective axis I anxiety disorder, 291
assessments, 183 risk factors, 290
treatments and therapies, 194–196 Neurobiological disorder, 108
Menstrual distress and health behaviors, Neurobiological models, of drug addiction, 66
196, 197 Neuropathy, peripheral, 318
Menstrual reactivity hypothesis, 190 Neurotransmitter-neuromodulatory
Mental disorders, DSM for, 30 receptor systems, 113
Index 375
Night sweats, 318 cardiovascular disease, 136–137

Non-cardiac chest pain (NCCP), 280 endocrine/metabolic disease, 140
CVD patients with, anxiety in, 289–291 gastrointestinal (GI) disease, 139–140
Non-psychiatric medical services, utilization neurological disease, 138–139
of, 341 respiratory disease, 137–138
Norepinephrine (NE) asthma with, 259
in patients with HIV, changes in, 333 diagnoses of, 247
in patients with PTSD, levels of, 331 specificity of, 260–261
Normative aging study of anxiety-CHD CAD patients with
link, 283 morbidity and mortality among, 298
Northwick study of anxiety-CHD link, 282 myocardial perfusion defects in, 300
Nucleus accumbens septi, 93 prevalence of, 288
Nurses’ health study of anxiety-CHD CBT for, 90, 349, 353
link, 283 in CHD-anxiety association, 286
CHD patients with, prevalence of, 289
Obesity comorbidity of, 293
in adulthood with asthma symptoms, 239 diagnostic criteria for, 327
for psychiatric comorbidity, 296 drinking frequency and quantity in non-
Obsessive compulsive disorder (OCD), 347 alcoholic drinkers with, 38
CBT for, 92 DSM-IV for diagnosis of, 286, 348
in menstrual cycle, 190 efficacy of aerobic exercise for, 91
in pain patients, 209–212 in HIV, prevalence of, 321
in incidence of cardiovascular morbidity,
Pain 294
and anxiety disorders NCCP patients with, prevalence of, 291
assessment methods, 223–225 norepinephrine reactivity in patients
associations, 215–217 with, 331
course of, 214, 215 in pain patients, 209–212
issues and researches on treatment, for psychiatric comorbidity, 296
227–229 related symptoms for, 62
physiological arousal, 220–222 and symptoms in menstrual cycle, 185,
prevalence of, 209–214 190, 191
treatment and therapies, 225–227 treatment-seeking smokers with, 13
concept of, 208, 209 Panic psychopathology
prevalence in anxiety disorder patients, addictive use of cigarettes, rates of
213, 214 occurrence in, 9
-related emotion and ANS responses, 221 behavior pattern characterized by
-related stimuli, attention, 219, 220 consistent avoidance of
Pain Anxiety Symptoms Scale (PASS), in threatening situations in, 4
anxiety disorder assessment, current knowledge regarding, 13
224, 225 development of, 16
Panic attack management in asthma diagnostic criteria for agoraphobia, 4
treatment, 269 distinction from other anxiety disorders, 8
Panic disorder (PD), 341, 347 lifetime estimates of panic disorder, 4
in adolescent anxiety, 169 persons with, rates of smoking among, 8
mediators of, 170 prevention programs for, application
moderators of, 171, 172 to, 17
with agoraphobia and anxiety disorder, and tobacco use
DSM-IV for diagnosis of, 61 co-occurrence rates between, 10
application of exercise interventions nature of associations between, 5, 11
for, 89 prevalence of, 7–11
association with Panic-specific emotional symptoms, degrees
cancer, 140 of, 14
376 Index
PD, see Panic disorder (PD) asthma with, diagnoses of, 259
Peak expiratory flow (PEF), 238 in CAD patients, prevalence of, 288
Pediatric anxiety rating scale (PARS), for CBT for, 350
anxiety disorder, 356 and childhood sexual abuse, prevalence
Pediatric autoimmune neuropsychiatric of, 325
disorders associated with childhood sexual abuse and, 325
streptococcus infection and chronic musculoskeletal pain
(PANDAS), 142, 143 patients, 207–216
Peptic ulcer disease (PUD), 141 assessment methods, 223–225
Peripheral neuropathy, 318 hypoalgesia/analgesia in, 222
Pharmacotherapy, in PTSD and pain physiological arousal, 220, 221
treatment, 227 symptom overlap and anxiety
Phobias, 110 sensitivity, 218, 219
social phobia, 328 treatments and therapies, 225–227
Phobic anxiety, 293 concurrent treatment of, 72
anxiety-CHD for construct of, 293 depression, substance abuse and anxiety
CHD risk factors associated with, disorders, 321
284, 291 diagnostic criteria for, 59
as risk of SCD, 282, 299 drug use disorder, 61
Phobic disorders, prevalence of, 283 and health-related physical functioning,
Phobic postural vertigo (PPV), effects of relationship between, 330
CBT for, 353 in HIV-infected women, 322
Physical functioning, health-related, in HIV patients, prevalence of, 320
relationship between PTSD and HIV risk, 324
and, 330 in menstrual cycle, 192
Physical illness and anxiety NE in patients with, levels of, 331
future directions for, 360–361 prevalence rate in HIVþ individuals, 320
future methodological considerations for, symptoms of, 283
361–362 treatments for, 333
pharmacological treatment of, 355–360 PPV, see Phobic postural vertigo (PPV),
psychosocial treatment of, 348 effects of CBT for
no comparison group, 353–355 Premenstrual anxiety
nonrandomized with control group, health behaviors, 196, 197
352–353 research
randomized with treatment in normal women, 187–188
comparison group, 348–350 in women with PMDD, 189
randomized with waitlist, 351 in women with PMS, 188–189
Physiological arousal, in pain and anxiety treatments and therapies, 194–196
disorders, 220, 221 Premenstrual Dysphoric Disorder
Pittsburgh Sleep Quality Index (PSQI), (PMDD), 182
117, 118 assessment measures, 183–186
Polymorphous light eruption (PLE), 110 cognitive-behavior therapy, 195, 196
Pontine nucleus locus ceruleus, 114 diagnosis of, 183
Poor sleep, 117, 118 research on, 189
Postsynaptic serotonin receptors, down- selective serotonin reuptake inhibitor,
regulation of, 93 196
Posttraumatic stress disorder (PTSD), 283 Premenstrual exacerbation (PME), and
association with comorbidity, 185, 186
cancer, 135–136 Premenstrual symptoms, and anxiety
cardiovascular disease, 133 disorders
endocrine/metabolic/autoimmune assessment measures, 182–186
disease, 134–135 interaction models, 192–194
neurologic disease, 133–134 OCDs and GADs, 191, 192
Index 377
panic disorder, and symptoms, 190, 191 role in adolescent anxiety: theory and
PTSD, 192 evidence, 155
Premenstrual syndrome (PMS), 182 conceptually-driven suggestions,
and biological factors, 193 167–172
cognitive-behavior therapy, 195, 196 future perspectives, 167
research on women, 188, 189 operationalization and assessment,
selective serotonin reuptake 156–160
inhibitor, 196 psychological problems, 155, 156
Present pain index (PPI), in SF-MPQ, 224 pubertal status and timing effects
Primary anxiety disorder, observations, 106 puberty assessment, 156–160
Primary insomnia, 106 research, 166, 167
Progressive resistance training (PRT), 96 undesirable bodily events, 156
Prototypical panic psychopathology, 14 Puberty-anxiety association, researches,
Pseudoseizure, and psychogenic seizure, 133 166–169
Psychedelic abuse, and dependence, 62
Psychiatric comorbidity, 349 QT interval variability (QTV), 298
obesity, PD and MDD for, 296 Quality of life (QOL)
Psychiatric illness, and NCCP, relationship anxiety disorders for negative impact
between, 290 on, 241
Psychocardiology, 280 asthma related, effect of anxiety on, 263
Psychoeducation, in anxiety and pain and HIV, 329–330
treatment, 225
Psychogenic nonepileptic seizure (PNES), Reduced heart-rate variability (HRV),
133, 134 298–299
Psychological distress Reductions, in anxiety with exercise, 87
in asthma, importance of, 241 Relaxation training in anxiety and pain
in HIV risk, role of, 322 treatment, 226
Psychopathology Renal failure, 354
of anxiety Rhinitis, treatment of, 240
assessment of, 361 Rutgers Alcohol Problem Index (RAPI), 47
physical illness and, 341
treatment of, 346–348 SAM systems, see Sympathetic adrenal
and asthma, relation between, 259 medullary systems,
Psychosocial clinical intervention research, dysregulation of
importance of, 333 Schedules for clinical assessment in
Psychosocial treatment, for physical illness neuropsychiatry (SCAN), for
and anxiety, 348 anxiety disorders, 358
Psychotherapy Schizophrenia, 355
effects of, 354 Screen for Child Anxiety Related Emotional
in premenstrual anxiety, 195 Disorders (SCARED), 355
PTSD, see Posttraumatic stress disorder Seizure, 138
(PTSD) Selective serotonin reuptake inhibitors
Pubertal hormones (SSRI), 117
and anxiety, 162, 163 in PMS and PMDD treatment, 196
in puberty assessment, 158, 159 Serotonergic receptor system, 114, 116
Pubertal status Serotonin, role in migraine disorders, 358
and anxiety, 160–162 Serotonin selective reuptake inhibitors
in puberty assessment, 157 (SSRIs), 346
Pubertal timing for treatment of IBS, 357, 358
and anxiety, 163–166 Sertraline, for depression, 303
in puberty assessment, 157–159 Sexual activity, among HIV-infected
Puberty adolescents, 324
and risk factor, 159, 160 Sexually transmitted disease (STD), 323
378 Index
Shared vulnerability/stress models for pain Spinal cord injury (SCI), 354
and anxiety disorders, 216, 217 with depression and anxiety, 352
Shingles, 318 Spirometry role, in FEV1 measurement, 238
Short Form McGill Pain Questionnaire SSRIs, see Serotonin selective reuptake
(SF-MPQ), in anxiety disorder inhibitors (SSRIs)
assessment, 224 State trait anxiety inventory (STAI), for
Simple phobia (SP) in premenstrual anxiety and depression, 352, 353
anxiety, 185 Stress
Single spectrum disorder model, anxiety and cardiomyopathy, 300
insomnia, 107, 108 for low SES and asthma symptoms, 239
Sleep deprivation, 110, 117, 118, 156 Stress hormones in anxiety
panic induced by, 118 HIV and pathophysiology of, 330–331
Sleeping difficulties, and insomnia-like HPA and SAM systems, dysregulation
symptoms, 111 of, 330–331
Sleep polysomnography (PSG), 117 Structured clinical interview diagnostic
Sleep restoration, mechanism of, 93–94 (SCID)
Sleep restriction, 118 for assessment of anxiety disorders, 329
Slow wave sleep (SWS), 94 for DSM, 293
Smokeless tobacco, developmental course Subacute cutaneous lupus erythematosus
for, 13 (SCLE), 109
Smoking, 287, 304 Substance use, 317, 322, 325, 326
for development of asthma, 240 in HIV, anxiety and, 328
Smoking behavior, conceptualization and Substance use disorders (SUD), 71, 328
measurement of, 18 anxiety and medication adherence,
Smoking cessation, 291 relationships with, 326–327
Smoking-panic relations and anxiety-related HIV sexual risk, 325
cross-sectional tests to clarify factors in asthma, prevalence of, 237
affecting, 14 comorbidity of, 329
psychopathology of, 12 in HIV patients, 328
study of, 15 Sudden cardiac death (SCD), 280
tests for examining moderating factors anxiety for, 295
affecting, 16 emotion of anxiety in development
Social anxiety of, 280
and HIV risk occurrence of, 297
gay and bisexual youth, 323 due to phobic anxiety, 282, 299
unprotected sex, 324 predictor of, 298
impact on drinking behavior of Suicidal ideation, in asthma, 241
undergraduate student, 40 Suicidality, 325
Social anxiety disorder Sympathetic adrenal medullary systems,
autoimmune disease, 144 dysregulation of, 331
endocrine/metabolic disease, 143–144
gastrointestinal disease, 143 Tachycardia, ventricular, 298
in pain patients, 209–212 Tanner staging system, in pubertal status
Social phobia (SP), 118 assessment, 157
asthma with, 259 T-helper cells, and HIV infection, 318
diagnoses of, 247 Third factor model, anxiety and insomnia,
Specific anxiety disorders, relationships with 108, 109
illicit drug use, 59 apolipoprotein E gene polymorphism, 110
Specific or simple phobia cardiovascular disease, 110
cancer, 145 Threat-related stimuli, attention, 219, 220
endocrine/metabolic disease, 144–145 Thyroid disease, 341
gastrointestinal disease, 144 Tobacco-panic comorbidity, nature of, 10
respiratory disease, 144 Tobacco-panic psychopathology linkages, 11
Index 379
Tobacco use, 281, 290 Ultraviolet light/sun exposure, 109

cigarette smoking, 6
co-occurrence rates between panic Variable risk factor, and puberty, 159
psychopathology and, 10 Ventral lateral preoptic nucleus (VPLO), 114
current knowledge regarding, 11 Ventricular arrhythmia
effects on persons with a lifetime history anxiety for, 295
of panic psychopathology, 9 in CHD, 299–300
lifetime nicotine dependence diagnosis, 9 Ventricular premature beat (VPB), as risk of
multiple forms of, 10 SCD, 299
nature of associations between panic Veterans Administration Normative Aging
psychopathology and, 11 Study of anxiety-CHD link, 283
nature of association with panic Veterans Administration (VA) Health Care
psychopathology, 5 System, 214
smokeless application, 6–7 Visual analogue scale (VAS), in SF-MPQ, 224
See also Smoking Vulnerability nomenclature, risk factors
Tourette’s syndrome, 142 associated with, 5–6
Trait anxiety, 326
and cardiac events, relation between, 284 Wakefulness-promotion, 114
in CHD patients, 294 Women
and HIV risk, 323 with breast cancer, CEGT for, 350
prediction of, 260 HIVþ, and anxiety disorders, 322
Transtheoretical Model (TTM), 84 increase in CHD risk for, 283
Traumatic event exposure, in adolescents, 155 World Mental Health Survey (WMH),
Treatment rationale and education, in 110, 111
asthma treatment, 269 on relation between asthma and
Tricyclic antidepressants (TCAs), 346 psychopathology, 259
Triiodothyronine (T3), arousal features in Worry cognitive process, 106
PTSD, 134
Twelve-Step Facilitation (TSF), 45 Z drugs, reducing anxiety, 116

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Anxiety in Health Behaviors

and Physical Illness

ACCEPTANCE AND MINDFULNESS-BASED APPROACHES TO ANXIETY

CONCEPTS AND CONTROVERSIES IN OBSESSIVE-COMPULSIVE DISORDER

SOCIAL ANXIETY AND SOCIAL PHOBIA IN YOUTH

TREATING HEALTH ANXIETY AND FEAR OF DEATH

ANXIETY IN HEALTH BEHAVIORS AND PHYSICAL ILLNESS

ISBN 978-0-387-74752-1 e-ISBN 978-0-387-74753-8

Library of Congress Control Number: 2007935078

© 2008 Springer Science+Business Media, LLC

Printed on acid-free paper.

April 2007 Michael J. Zvolensky, Ph.D.

Part I: Health Behaviors and Anxiety Disorders

Tobacco Use and Panic Psychopathology: Current Status and Future

Alcohol Use and Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Illicit Drug Use Across the Anxiety Disorders: Prevalence, Underlying

The Promise of Exercise Interventions for the Anxiety Disorders . . . . . . . . 81

Anxiety and Insomnia: Theoretical Relationship and Future

Part II: Physical Conditions and Anxiety Disorders

Anxiety Disorders and Physical Illness Comorbidity: An Overview . . . . . . 131

The Relation Between Puberty and Adolescent Anxiety: Theory

Anxiety, Anxiety Disorders, and the Menstrual Cycle . . . . . . . . . . . . . . . . 181

Pain and Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Asthma in Anxiety and Its Disorders: Overview and Synthesis . . . . . . . . . . 237

Cardiovascular Disease and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

HIV and Anxiety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

Physical Illness and Treatment of Anxiety Disorders: A Review . . . . . . . . . 341

Murray P. Abrams, B.A., Anxiety Bernadette M. Cortese, Ph.D.,

Trevor A. Hart, Ph.D., Mark B. Powers, Ph.D., Department

Chris Hayward, M.D., M.P.H., Laura E. Reardon, M.A.,

Carolyn A. James, M.A., Department Tanya Sala, M.D., FRCPC,

Meghan E. Keough, M.S., Jitender Sareen B.Sc., M.D., FRCPC,

Carl W. Lejuez, Ph.D., Center for Norman B. Schmidt, Ph.D.,

Bunmi O. Olatunji, Ph.D., Jasper A. J. Smits, Ph.D.,

Michael W. Otto, Ph.D., Center for Sherry H. Stewart, Ph.D.,

Matthew T. Tull, Ph.D., Center Kamila S. White, Ph.D., University

Michael J. Zvolensky, Teresa Leyro, Amit Bernstein, Matthew T. Feldner,

M. J. Zvolensky, J. A. Smits (eds.), Anxiety in Health Behaviors and Physical Illness. 3

The term ‘‘panic psychopathology’’ is used in this chapter to denote panic

threat-relevant (e.g., anything from being in crowds to certain substances like

Explicit delineation of terminology facilitates efforts to understand the nature

A risk factor also can be contrasted with a maintenance factor. A mainte-

Tobacco Use: Definition, Nature, and Prevalence

Cigarette smoking. Cigarette smoking is widely recognized as the most popular

Prevalence of Comorbid Tobacco Use and Panic Psychopathology

There have been both representative surveys and community-based studies

15 to 54 years. Among individuals diagnosed with panic attacks, panic disorder,

Second, there are a number of issues central to the generalizability of the

Nature of the Associations Between Tobacco Use

Developmental course. As a basis for understanding the nature of the relations

Future directions. Again, it is important to highlight that work in this

Although cross-sectional data are informative in the study of tobacco-panic

smoking-related problems and processes (i.e., motivational processes) as

Marshall (2006) found anxiety sensitivity was significantly associated with

Panic psychopathology or pre-morbid risk factors also appear to be related

The present chapter provides an updated review of extant empirical work

About: Smoking Cessation (2006). Retrieved October 1, 2006 from http://quitsmoking.about.

Brigitte C. Sabourin and Sherry H. Stewart

M. J. Zvolensky, J. A. Smits (eds.), Anxiety in Health Behaviors and Physical Illness. 29

Symptomatic and Syndromal Levels of Enquiry

Alcohol abuse is characterized by ‘‘recurrent and significant adverse conse-

Epidemiological Findings on the Anxiety – Alcohol Relationship

Etiological Models of the Relationship