# 14 - 9 Anxiety Disorders

# 01 - 9.1 Overview

# 9.1 Overview

Anxiety Disorders
 9.1 Overview
Anxiety represents a core phenomenon around which considerable psychiatric theory
has been organized. Thus, the term “anxiety” has played a central role in
psychodynamic theory, as well as in neuroscience-focused research and various schools
of thought heavily influenced by cognitive-behavioral principles. Anxiety disorders are
associated with significant morbidity and often are chronic and resistant to treatment.
Anxiety disorders can be viewed as a family of related but distinct mental disorders,
which include (1) panic disorder, (2) agoraphobia, (3) specific phobia, (4) social anxiety
disorder or phobia, and (5) generalized anxiety disorder. Each of these disorders is
discussed in detail in the sections that follow.
A fascinating aspect of anxiety disorders is the exquisite interplay of genetic and
experiential factors. Little doubt exists that abnormal genes predispose to pathological
anxiety states; however, evidence clearly indicates that traumatic life events and stress
are also etiologically important. Thus, the study of anxiety disorders presents a unique
opportunity to understand the relation between nature and nurture in the etiology of
mental disorders.
NORMAL ANXIETY
Everyone experiences anxiety. It is characterized most commonly as a diffuse,
unpleasant, vague sense of apprehension, often accompanied by autonomic symptoms
such as headache, perspiration, palpitations, tightness in the chest, mild stomach
discomfort, and restlessness, indicated by an inability to sit or stand still for long. The
particular constellation of symptoms present during anxiety tends to vary among
persons (Table 9.1-1).
Table 9.1-1
Peripheral Manifestations of Anxiety

Fear versus Anxiety
Anxiety is an alerting signal; it warns of impending danger and enables a person to
take measures to deal with a threat. Fear is a similar alerting signal, but it should be
differentiated from anxiety. Fear is a response to a known, external, definite, or
nonconflictual threat; anxiety is a response to a threat that is unknown, internal, vague,
or conflictual.
This distinction between fear and anxiety arose accidentally. When Freud’s early
translator mistranslated angst, the German word for “fear,” as anxiety, Freud himself
generally ignored the distinction that associates anxiety with a repressed, unconscious
object and fear with a known, external object. The distinction may be difficult to make
because fear can also be caused by an unconscious, repressed, internal object displaced
to another object in the external world. For example, a boy may fear barking dogs
because he actually fears his father and unconsciously associates his father with barking
dogs.
Nevertheless, according to postfreudian psychoanalytic formulations, the separation
of fear and anxiety is psychologically justifiable. The emotion caused by a rapidly
approaching car as a person crosses the street differs from the vague discomfort a
person may experience when meeting new persons in a strange setting. The main
psychological difference between the two emotional responses is the suddenness of fear
and the insidiousness of anxiety.
In 1896, Charles Darwin gave the following psychophysiological description of acute
fear merging into terror:
Fear is often preceded by astonishment, and is so far akin to it, that both lead to the
senses of sight and learning being instantly aroused. In both cases the eyes and mouth
are widely opened, and the eyebrows raised. The frightened man at first stands like a
statue motionless and breathless, or crouches down as if instinctively to escape
observation. The heart beats quickly and violently, so that it palpitates or knocks

against the ribs; but it is very doubtful whether it then works more efficiently than
usual, so as to send a greater supply of blood to all parts of the body; for the skin
instantly becomes pale, as during incipient faintness. This paleness of the surface,
however, is probably in large part, or exclusively, due to the vasomotor center being
affected in such a manner as to cause the contraction of the small arteries of the skin.
That the skin is much affected under the sense of great fear, we see in the marvelous
and inexplicable manner in which perspiration immediately exudes from it. This
exudation is all the more remarkable, as the surface is then cold, and hence the term a
cold sweat; whereas, the sudorific glands are properly excited into action when the
surface is heated. The hairs also on the skin stand erect; and the superficial muscles
shiver. In connection with the disturbed action of the heart, the breathing is hurried.
The salivary glands act imperfectly; the mouth becomes dry, and is often opened and
shut. I have also noticed that under slight fear there is a strong tendency to yawn.
One of the best-marked symptoms is the trembling of all the muscles of the body; and
this is often first seen in the lips. From this cause, and from the dryness of the mouth,
the voice becomes husky or indistinct, or may altogether fail....
As fear increases into an agony of terror, we behold, as under all violent emotions,
diversified results. The heart beats wildly or may fail to act and faintness ensues;
there is a deathlike pallor; the breathing is labored; the wings of the nostrils are
widely dilated; there is a gasping and convulsive motion on the lips, a tremor on the
hollow cheek, a gulping and catching of the throat; the uncovered and protruding
eyeballs are fixed on the object of terror; or they may roll restlessly from side to side.
The pupils are said to be enormously dilated. All the muscles of the body may become
rigid, or may be thrown into convulsive movements. The hands are alternately
clenched and opened, often with a twitching movement. The arms may be protruded,
as if to avert some dreadful danger, or may be thrown wildly over the head....In other
cases there is a sudden and uncontrollable tendency to headlong flight; and so strong
is this, that the boldest soldiers may be seized with a sudden panic.
Is Anxiety Adaptive?
Anxiety and fear both are alerting signals and act as a warning of an internal and
external threat. Anxiety can be conceptualized as a normal and adaptive response that
has lifesaving qualities and warns of threats of bodily damage, pain, helplessness,
possible punishment, or the frustration of social or bodily needs; of separation from
loved ones; of a menace to one’s success or status; and ultimately of threats to unity or
wholeness. It prompts a person to take the necessary steps to prevent the threat or to
lessen its consequences. This preparation is accompanied by increased somatic and
autonomic activity controlled by the interaction of the sympathetic and parasympathetic
nervous systems. Examples of a person warding off threats in daily life include getting
down to the hard work of preparing for an examination, dodging a ball thrown at the
head, sneaking into the dormitory after curfew to prevent punishment, and running to

catch the last commuter train. Thus, anxiety prevents damage by alerting the person to
carry out certain acts that forestall the danger.
Stress and Anxiety
Whether an event is perceived as stressful depends on the nature of the event and on the
person’s resources, psychological defenses, and coping mechanisms. All involve the ego,
a collective abstraction for the process by which a person perceives, thinks, and acts on
external events or internal drives. A person whose ego is functioning properly is in
adaptive balance with both external and internal worlds; if the ego is not functioning
properly and the resulting imbalance continues sufficiently long, the person experiences
chronic anxiety.
Whether the imbalance is external, between the pressures of the outside world and the
person’s ego, or internal, between the person’s impulses (e.g., aggressive, sexual, and
dependent impulses) and conscience, the imbalance produces a conflict. Whereas
externally caused conflicts are usually interpersonal, those that are internally caused are
intrapsychic or intrapersonal. A combination of the two is possible, as in the case of
employees whose excessively demanding and critical boss provokes impulses that they
must control for fear of losing their jobs. Interpersonal and intrapsychic conflicts, in
fact, are usually intertwined. Because human beings are social, their main conflicts are
usually with other persons.
Symptoms of Anxiety
The experience of anxiety has two components: the awareness of the physiological
sensations (e.g., palpitations and sweating) and the awareness of being nervous or
frightened. A feeling of shame may increase anxiety—“Others will recognize that I am
frightened.” Many persons are astonished to find out that others are not aware of their
anxiety or, if they are, do not appreciate its intensity.
In addition to motor and visceral effects, anxiety affects thinking, perception, and
learning. It tends to produce confusion and distortions of perception, not only of time
and space but also of persons and the meanings of events. These distortions can
interfere with learning by lowering concentration, reducing recall, and impairing the
ability to relate one item to another—that is, to make associations.
An important aspect of emotions is their effect on the selectivity of attention. Anxious
persons likely select certain things in their environment and overlook others in their
effort to prove that they are justified in considering the situation frightening. If they
falsely justify their fear, they augment their anxieties by the selective response and set
up a vicious circle of anxiety, distorted perception, and increased anxiety. If,
alternatively, they falsely reassure themselves by selective thinking, appropriate anxiety
may be reduced, and they may fail to take necessary precautions.
PATHOLOGICAL ANXIETY

Epidemiology
The anxiety disorders make up one of the most common groups of psychiatric disorders.
The National Comorbidity Study reported that one of four persons met the diagnostic
criteria for at least one anxiety disorder and that there is a 12-month prevalence rate of
17.7 percent. Women (30.5 percent lifetime prevalence) are more likely to have an
anxiety disorder than are men (19.2 percent lifetime prevalence). The prevalence of
anxiety disorders decreases with higher socioeconomic status.
Contributions of Psychological Sciences
Three major schools of psychological theory—psychoanalytic, behavioral, and
existential—have contributed theories about the causes of anxiety. Each theory has both
conceptual and practical usefulness in treating anxiety disorders.
Psychoanalytic Theories.
 Although Freud originally believed that anxiety
stemmed from a physiological buildup of libido, he ultimately redefined anxiety as a
signal of the presence of danger in the unconscious. Anxiety was viewed as the result of
psychic conflict between unconscious sexual or aggressive wishes and corresponding
threats from the superego or external reality. In response to this signal, the ego
mobilized defense mechanisms to prevent unacceptable thoughts and feelings from
emerging into conscious awareness. In his classic paper “Inhibitions, Symptoms, and
Anxiety,” Freud states that “it was anxiety which produced repression and not, as I
formerly believed, repression which produced anxiety.” Today, many neurobiologists
continue to substantiate many of Freud’s original ideas and theories. One example is the
role of the amygdala, which subserves the fear response without any reference to
conscious memory and substantiates Freud’s concept of an unconscious memory system
for anxiety responses. One of the unfortunate consequences of regarding the symptom
of anxiety as a disorder rather than a signal is that the underlying sources of the anxiety
may be ignored. From a psychodynamic perspective, the goal of therapy is not
necessary to eliminate all anxiety but to increase anxiety tolerance—that is, the
capacity to experience anxiety—and use it as a signal to investigate the underlying
conflict that has created it. Anxiety appears in response to various situations during the
life cycle, and although psychopharmacological agents may ameliorate symptoms, they
may do nothing to address the life situation or its internal correlates that have induced
the state of anxiety. In the following case, a disturbing fantasy precipitated an anxiety
attack.
A married man 32 years of age was referred for therapy for severe and
incapacitating anxiety, which was clinically manifested as repeated outbreaks of
acute attacks of panic. Initially, he had absolutely no idea what had precipitated his
attacks, nor were they associated with any conscious mental content. In the early
weeks of treatment, he spent most of his time trying to impress the doctor with how

hard he had worked and how effectively he had functioned before he was taken ill. At
the same time, he described how fearful he was that he would fail at a new business
venture he had embarked on. One day, with obvious acute anxiety that practically
prevented him from talking, he revealed a fantasy that had suddenly popped into his
mind a day or two before and had led to the outbreak of a severe anxiety attack. He
had had the image of a large spike being driven through his penis. He also recalled
that, as a child of 7, he was fascinated by his mother’s clothing and that, on occasion,
when she was out of the house, he dressed himself up in them. As an adult, he was
fascinated by female lingerie and would sometimes find himself impelled by a desire
to wear women’s clothing. He had never yielded to the impulse, but on those
occasions when the idea entered his consciousness, he became overwhelmed by acute
anxiety and panic.
To understand fully a particular patient’s anxiety from a psychodynamic view, it is
often useful to relate the anxiety to developmental issues. At the earliest level,
disintegration anxiety may be present. This anxiety derives from the fear that the self
will fragment because others are not responding with needed affirmation and
validation. Persecutory anxiety can be connected with the perception that the self is
being invaded and annihilated by an outside malevolent force. Another source of
anxiety involves a child who fears losing the love or approval of a parent or loved
object. Freud’s theory of castration anxiety is linked to the oedipal phase of
development in boys, in which a powerful parental figure, usually the father, may
damage the little boy’s genitals or otherwise cause bodily harm. At the most mature
level, superego anxiety is related to guilt feelings about not living up to internalized
standards of moral behavior derived from the parents. Often, a psychodynamic
interview can elucidate the principal level of anxiety with which a patient is dealing.
Some anxiety is obviously related to multiple conflicts at various developmental levels.
Behavioral Theories.
 The behavioral or learning theories of anxiety postulate that
anxiety is a conditioned response to a specific environmental stimulus. In a model of
classic conditioning, a girl raised by an abusive father, for example, may become
anxious as soon as she sees the abusive father. Through generalization, she may come to
distrust all men. In the social learning model, a child may develop an anxiety response
by imitating the anxiety in the environment, such as in anxious parents.
Existential Theories.
 Existential theories of anxiety provide models for
generalized anxiety, in which no specifically identifiable stimulus exists for a chronically
anxious feeling. The central concept of existential theory is that persons experience
feelings of living in a purposeless universe. Anxiety is their response to the perceived
void in existence and meaning. Such existential concerns may have increased since the
development of nuclear weapons and bioterrorism.

Contributions of Biological Sciences
Autonomic Nervous System.
 Stimulation of the autonomic nervous system
causes certain symptoms—cardiovascular (e.g., tachycardia), muscular (e.g., headache),
gastrointestinal (e.g., diarrhea), and respiratory (e.g., tachypnea). The autonomic
nervous systems of some patients with anxiety disorder, especially those with panic
disorder, exhibit increased sympathetic tone, adapt slowly to repeated stimuli, and
respond excessively to moderate stimuli.
Neurotransmitters.
 The three major neurotransmitters associated with anxiety on
the bases of animal studies and responses to drug treatment are norepinephrine (NE),
serotonin, and γ-aminobutyric acid (GABA). Much of the basic neuroscience information
about anxiety comes from animal experiments involving behavioral paradigms and
psychoactive agents. One such experiment to study anxiety was the conflict test, in
which the animal is simultaneously presented with stimuli that are positive (e.g., food)
and negative (e.g., electric shock). Anxiolytic drugs (e.g., benzodiazepines) tend to
facilitate the adaptation of the animal to this situation, but other drugs (e.g.,
amphetamines) further disrupt the animal’s behavioral responses.
NOREPINEPHRINE. Chronic symptoms experienced by patients with anxiety disorder, such
as panic attacks, insomnia, startle, and autonomic hyperarousal, are characteristic of
increased noradrenergic function. The general theory about the role of norepinephrine
in anxiety disorders is that affected patients may have a poorly regulated noradrenergic
system with occasional bursts of activity. The cell bodies of the noradrenergic system are
primarily localized to the locus ceruleus in the rostral pons, and they project their axons
to the cerebral cortex, the limbic system, the brainstem, and the spinal cord.
Experiments in primates have demonstrated that stimulation of the locus ceruleus
produces a fear response in the animals and that ablation of the same area inhibits or
completely blocks the ability of the animals to form a fear response.
Human studies have found that in patients with panic disorder, β-adrenergic receptor
agonists (e.g., isoproterenol [Isuprel]) and α2-adrenergic receptor antagonists (e.g.,
yohimbine [Yocon]) can provoke frequent and severe panic attacks. Conversely,
clonidine (Catapres), an α2-receptor agonist, reduces anxiety symptoms in some
experimental and therapeutic situations. A less consistent finding is that patients with
anxiety disorders, particularly panic disorder, have elevated cerebrospinal fluid (CSF) or
urinary levels of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol
(MHPG).
HYPOTHALAMIC–PITUITARY–ADRENAL AXIS. Consistent evidence indicates that many forms of
psychological stress increase the synthesis and release of cortisol. Cortisol serves to
mobilize and to replenish energy stores and contributes to increased arousal, vigilance,
focused attention, and memory formation; inhibition of the growth and reproductive
system; and containment of the immune response. Excessive and sustained cortisol

secretion can have serious adverse effects, including hypertension, osteoporosis,
immunosuppression, insulin resistance, dyslipidemia, dyscoagulation, and, ultimately,
atherosclerosis and cardiovascular disease. Alterations in hypothalamic–pituitary–
adrenal (HPA) axis function have been demonstrated in PTSD. In patients with panic
disorder, blunted adrenocorticoid hormone (ACTH) responses to corticotropin-releasing
factor (CRF) have been reported in some studies and not in others.
CORTICOTROPIN-RELEASING HORMONE (CRH). One of the most important mediators of the
stress response, CRH coordinates the adaptive behavioral and physiological changes that
occur during stress. Hypothalamic levels of CRH are increased by stress, resulting in
activation of the HPA axis and increased release of cortisol and dehydroepiandrosterone
(DHEA). CRH also inhibits a variety of neurovegetative functions, such as food intake,
sexual activity, and endocrine programs for growth and reproduction.
SEROTONIN. The identification of many serotonin receptor types has stimulated the
search for the role of serotonin in the pathogenesis of anxiety disorders. Different types
of acute stress result in increased 5-hydroxytryptamine (5-HT) turnover in the prefrontal
cortex, nucleus accumbens, amygdala, and lateral hypothalamus. The interest in this
relation was initially motivated by the observation that serotonergic antidepressants
have therapeutic effects in some anxiety disorders—for example, clomipramine
(Anafranil) in obsessive-compulsive disorder (OCD). The effectiveness of buspirone
(BuSpar), a serotonin 5-HT1A receptor agonist, in the treatment of anxiety disorders also
suggests the possibility of an association between serotonin and anxiety. The cell bodies
of most serotonergic neurons are located in the raphe nuclei in the rostral brainstem and
project to the cerebral cortex, the limbic system (especially, the amygdala and the
hippocampus), and the hypothalamus. Several reports indicate that metachlorophenylpiperazine (mCPP), a drug with multiple serotonergic and nonserotonergic
effects, and fenfluramine (Pondimin), which causes the release of serotonin, do cause
increased anxiety in patients with anxiety disorders; and many anecdotal reports
indicate that serotonergic hallucinogens and stimulants—for example, lysergic acid
diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA)—are associated
with the development of both acute and chronic anxiety disorders in persons who use
these drugs. Clinical studies of 5-HT function in anxiety disorders have had mixed
results. One study found that patients with panic disorder had lower levels of circulating
5-HT compared with control participants. Thus, no clear pattern of abnormality in 5-HT
function in panic disorder has emerged from analysis of peripheral blood elements.
GABA. A role of GABA in anxiety disorders is most strongly supported by the undisputed
efficacy of benzodiazepines, which enhance the activity of GABA at the GABA type A
(GABAA) receptor, in the treatment of some types of anxiety disorders. Although lowpotency benzodiazepines are most effective for the symptoms of generalized anxiety
disorder, high-potency benzodiazepines, such as alprazolam (Xanax), and clonazepam
are effective in the treatment of panic disorder. Studies in primates have found that
autonomic nervous system symptoms of anxiety disorders are induced when a

benzodiazepine inverse agonist, β-carboline-3-carboxylic acid (BCCE), is administered.
BCCE also causes anxiety in normal control volunteers. A benzodiazepine antagonist,
flumazenil (Romazicon), causes frequent severe panic attacks in patients with panic
disorder. These data have led researchers to hypothesize that some patients with anxiety
disorders have abnormal functioning of their GABAA receptors, although this connection
has not been shown directly.
APLYSIA. A neurotransmitter model for anxiety disorders is based on the study of Aplysia
californica by Nobel Prize winner Eric Kandel, M.D. Aplysia is a sea snail that reacts to
danger by moving away, withdrawing into its shell, and decreasing its feeding behavior.
These behaviors can be classically conditioned, so that the snail responds to a neutral
stimulus as if it were a dangerous stimulus. The snail can also be sensitized by random
shocks, so that it exhibits a flight response in the absence of real danger. Parallels have
previously been drawn between classic conditioning and human phobic anxiety. The
classically conditioned Aplysia shows measurable changes in presynaptic facilitation,
resulting in the release of increased amounts of neurotransmitter. Although the sea snail
is a simple animal, this work shows an experimental approach to complex
neurochemical processes potentially involved in anxiety disorders in humans.
NEUROPEPTIDE Y. Neuropeptide Y (NPY) is a highly conserved 36–amino acid peptide,
which is among the most abundant peptides found in mammalian brain. Evidence
suggesting the involvement of the amygdala in the anxiolytic effects of NPY is robust,
and it probably occurs via the NPY-Y1 receptor. NPY has counterregulatory effects on
corticotropin-releasing hormone (CRH) and LC-NE systems at brain sites that are
important in the expression of anxiety, fear, and depression. Preliminary studies in
special operations soldiers under extreme training stress indicate that high NPY levels
are associated with better performance.
GALANIN. Galanin is a peptide that, in humans, contains 30 amino acids. It has been
demonstrated to be involved in a number of physiological and behavioral functions,
including learning and memory, pain control, food intake, neuroendocrine control,
cardiovascular regulation, and, most recently, anxiety. A dense galanin immunoreactive
fiber system originating in the LC innervates forebrain and midbrain structures,
including the hippocampus, hypothalamus, amygdala, and prefrontal cortex. Studies in
rats have shown that galanin administered centrally modulates anxiety-related
behaviors. Galanin and NPY receptor agonists may be novel targets for antianxiety drug
development.
Brain Imaging Studies.
 A range of brain imaging studies, almost always
conducted with a specific anxiety disorder, has produced several possible leads in the
understanding of anxiety disorders. Structural studies—for example, computed
tomography (CT) and magnetic resonance imaging (MRI)—occasionally show some
increase in the size of cerebral ventricles. In one study, the increase was correlated with
the length of time patients had been taking benzodiazepines. In one MRI study, a

specific defect in the right temporal lobe was noted in patients with panic disorder.
Several other brain imaging studies have reported abnormal findings in the right
hemisphere but not the left hemisphere; this finding suggests that some types of cerebral
asymmetries may be important in the development of anxiety disorder symptoms in
specific patients. Functional brain imaging (fMRI) studies—for example, positron
emission tomography (PET), single-photon emission computed tomography (SPECT),
and electroencephalography (EEG)—of patients with anxiety disorder have variously
reported abnormalities in the frontal cortex; the occipital and temporal areas; and, in a
study of panic disorder, the parahippocampal gyrus. Several functional neuroimaging
studies have implicated the caudate nucleus in the pathophysiology of OCD. In
posttraumatic stress disorder, fMRI studies have found increased activity in the
amygdala, a brain region associated with fear (see Color Plate 9.1-1). A conservative
interpretation of these data is that some patients with anxiety disorders have a
demonstrable functional cerebral pathological condition and that the condition may be
causally relevant to their anxiety disorder symptoms.
Genetic Studies.
 Genetic studies have produced solid evidence that at least some
genetic component contributes to the development of anxiety disorders. Heredity has
been recognized as a predisposing factor in the development of anxiety disorders.
Almost half of all patients with panic disorder have at least one affected relative. The
figures for other anxiety disorders, although not as high, also indicate a higher
frequency of the illness in first-degree relatives of affected patients than in the relatives
of nonaffected persons. Although adoption studies with anxiety disorders have not been
reported, data from twin registries also support the hypothesis that anxiety disorders are
at least partially genetically determined. Clearly, a linkage exists between genetics and
anxiety disorders, but no anxiety disorder is likely to result from a simple mendelian
abnormality. One report has attributed about 4 percent of the intrinsic variability of
anxiety within the general population to a polymorphic variant of the gene for the
serotonin transporter, which is the site of action of many serotonergic drugs. Persons
with the variant produce less transporter and have higher levels of anxiety.
In 2005, a scientific team, led by National Institute of Mental Health grantee and Noble Laureate Dr. Eric Kandel
demonstrated that knocking out a gene in the brain’s fear hub creates mice unperturbed by situations that would normally
trigger instinctive or learned fear responses. The gene codes for stathmin, a protein that is critical for the amygdala to form
fear memories. Stathmin knockout mice showed less anxiety when they heard a tone that had previously been associated
with a shock, indicating less learned fear. The knockout mice also were more susceptible to explore novel open space and
maze environments, a reflection of less innate fear. Kandel suggests that stathmin knockout mice can be used as a model of
anxiety states of mental disorders with innate and learned fear components: these animals could be used to develop new
antianxiety agents. Whether stathmin is similarly expressed and pivotal for anxiety in the human amygdala remains to be
confirmed.
Neuroanatomical Considerations.
 The locus ceruleus and the raphe nuclei
project primarily to the limbic system and the cerebral cortex. In combination with the

data from brain imaging studies, these areas have become the focus of much hypothesisforming about the neuroanatomical substrates of anxiety disorders.
LIMBIC SYSTEM. In addition to receiving noradrenergic and serotonergic innervation, the
limbic system also contains a high concentration of GABAA receptors. Ablation and
stimulation studies in nonhuman primates have also implicated the limbic system in the
generation of anxiety and fear responses. Two areas of the limbic system have received
special attention in the literature: increased activity in the septohippocampal pathway,
which may lead to anxiety; and the cingulate gyrus, which has been implicated
particularly in the pathophysiology of OCD.
CEREBRAL CORTEX. The frontal cerebral cortex is connected with the parahippocampal
region, the cingulate gyrus, and the hypothalamus and thus may be involved in the
production of anxiety disorders. The temporal cortex has also been implicated as a
pathophysiological site in anxiety disorders. This association is based in part on the
similarity in clinical presentation and electrophysiology between some patients with
temporal lobe epilepsy and patients with OCD.
REFERENCES
Bulbena A, Gago J, Pailhez G, Sperry L, Fullana MA, Vilarroya O. Joint hypermobility syndrome is a risk factor trait for
anxiety disorders: A 15-year follow-up cohort study. Gen Hosp Psychiatry. 2011;33:363.
Craske MG, Rauch SL, Ursano R, Prenoveau J, Pine DS, Zinbarg RE. What is an anxiety disorder? Depress Anxiety.
2009;26:1066.
Fergus TA, Valentiner DP, McGrath PB, Jencius S. Shame- and guilt-proneness: Relationships with anxiety disorder
symptoms in a clinical sample. J Anxiety Disord. 2010;24:811.
Goodwin RD, Stein DJ. Anxiety disorders and drug dependence: Evidence on sequence and specificity among adults. Psych
Clin Neurosci. 2013;67:167.
Kravitz HM, Schott LL, Joffe H, Cyranowski JM, Bromberger JT. Do anxiety symptoms predict major depressive disorder
in midlife women? The Study of Women’s Health Across the Nation (SWAN) Mental Health Study (MHS). Psychol Med.
2014:1–10.
McKay D, Storch EA, eds. Handbook of Treating Variants and Complications in Anxiety Disorders. New York: Springer
Science+Business Media; 2013.
McLean CP, Asnaani A, Litz BT, Hofmann SG. Gender differences in anxiety disorders: Prevalence, course of illness,
comorbidity and burden of illness. J Psychiatr Res. 2011;45:1027.
Naragon-Gainey K, Gallagher MW, Brown TA. A longitudinal examination of psychosocial impairment across the anxiety
disorders. Psycholog Med. 2013;43:1475.
Nebel-Schwalm MS, Davis III TE. Nature and etiological models of anxiety disorders. In: McKay D, Storch EA, eds.
Handbook of Treating Variants and Complications in Anxiety Disorders. New York: Springer Science+Business Media;
2013:3.
Pacheco-Unguetti AP, Acosta A, Marqués E, Lupiáñez J. Alterations of the attentional networks in patients with anxiety
disorders. J Anxiety Disord. 2011;25:888.
Pine DS. Anxiety disorders: Introduction and overview. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s
Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009:1839.

# 02 - 9.2 Panic Disorder

# 9.2 Panic Disorder

Schanche E. The transdiagnostic phenomenon of self-criticism. Psychotherapy. 2013;50:316.
Shin LM, Davis FC, Van Elzakker MB, Dahlgren MK, Dubois SJ. Neuroimaging predictors of treatment response in anxiety
disorders. Bio Mood Anxiety Dis. 2013;3:15.
Stein DJ, Hollander E, Rothbaum BO, eds. Textbook of Anxiety Disorders. 2nd edition. Arlington, VA: American Psychiatric
Publishing; 2009.
Stein DJ, Nesse RM. Threat detection, precautionary responses, and anxiety disorders. Neurosci Biobehav Rev.
2011;35:1075.
Taylor S, Abramowitz JS, McKay D. Non-adherence and non-response in the treatment of anxiety disorders. J Anxiety
Disord. 2012;26:583.
Uebelacker L, Weisberg R, Millman M, Yen S, Keller M. Prospective study of risk factors for suicidal behavior in
individuals with anxiety disorders. Psychological Med. 2013;43:1465.
 9.2 Panic Disorder
An acute intense attack of anxiety accompanied by feelings of impending doom is
known as panic disorder. The anxiety is characterized by discrete periods of intense fear
that can vary from several attacks during one day to only a few attacks during a year.
Patients with panic disorder present with a number of comorbid conditions, most
commonly agoraphobia, which refers to a fear of or anxiety regarding places from
which escape might be difficult.
HISTORY
The idea of panic disorder may have its roots in the concept of irritable heart syndrome,
which the physician Jacob Mendes DaCosta (1833–1900) noted in soldiers in the
American Civil War. DaCosta’s syndrome included many psychological and somatic
symptoms that have since been included among the diagnostic criteria for panic
disorder. In 1895, Sigmund Freud introduced the concept of anxiety neurosis, consisting
of acute and chronic psychological and somatic symptoms.
EPIDEMIOLOGY
The lifetime prevalence of panic disorder is in the 1 to 4 percent range, with 6-month
prevalence approximately 0.5 to 1.0 percent and 3 to 5.6 percent for panic attacks.
Women are two to three times more likely to be affected than men, although
underdiagnosis of panic disorder in men may contribute to the skewed distribution. The
differences among Hispanics, whites, and blacks are few. The only social factor
identified as contributing to the development of panic disorder is a recent history of
divorce or separation. Panic disorder most commonly develops in young adulthood—the
mean age of presentation is about 25 years—but both panic disorder and agoraphobia
can develop at any age. Panic disorder has been reported in children and adolescents,
and it is probably underdiagnosed in these age groups.

COMORBIDITY
Of patients with panic disorder, 91 percent have at least one other psychiatric disorder.
About one-third of persons with panic disorders have major depressive disorder before
onset; about two-thirds first experience panic disorder during or after the onset of major
depression.
Other disorders also commonly occur in persons with panic disorder. Of persons with
panic disorder, 15 to 30 percent also have social anxiety disorder or social phobia, 2 to
20 percent have specific phobia, 15 to 30 percent have generalized anxiety disorder, 2
to 10 percent have PTSD, and up to 30 percent have OCD. Other common comorbid
conditions are hypochondriasis or illness anxiety disorder, personality disorders, and
substance-related disorders.
ETIOLOGY
Biological Factors
Research on the biological basis of panic disorder has produced a range of findings; one
interpretation is that the symptoms of panic disorder are related to a range of biological
abnormalities in brain structure and function. Most work has used biological stimulants
to induce panic attacks in patients with panic disorder. Considerable evidence indicates
that abnormal regulation of brain noradrenergic systems is also involved in the
pathophysiology of panic disorder. These and other studies have produced hypotheses
implicating both peripheral and central nervous system (CNS) dysregulation in the
pathophysiology of panic disorder. The autonomic nervous systems of some patients
with panic disorder have been reported to exhibit increased sympathetic tone, to adapt
slowly to repeated stimuli, and to respond excessively to moderate stimuli. Studies of the
neuroendocrine status of these patients have shown several abnormalities, although the
studies have been inconsistent in their findings.
The major neurotransmitter systems that have been implicated are those for
norepinephrine, serotonin, and GABA. Serotonergic dysfunction is quite evident in panic
disorder, and various studies with mixed serotonin agonist–antagonist drugs have
demonstrated increased rates of anxiety. Such responses may be caused by postsynaptic
serotonin hypersensitivity in panic disorder. Preclinical evidence suggests that
attenuation of local inhibitory GABAergic transmission in the basolateral amygdala,
midbrain, and hypothalamus can elicit anxiety-like physiological responses. The
biological data have led to a focus on the brainstem (particularly the noradrenergic
neurons of the locus ceruleus and the serotonergic neurons of the median raphe
nucleus), the limbic system (possibly responsible for the generation of anticipatory
anxiety), and the prefrontal cortex (possibly responsible for the generation of phobic
avoidance). Among the various neurotransmitters involved, the noradrenergic system
has also attracted much attention, with the presynaptic α2-adrenergic receptors,
particularly, playing a significant role. Patients with panic disorder are sensitive to the

anxiogenic effects of yohimbine in addition to having exaggerated MHPG, cortisol, and
cardiovascular responses. They have been identified by pharmacological challenges with
the α2-receptor agonist clonidine (Catapres) and the α2-receptor antagonist yohimbine
(Yocon), which stimulates firing of the locus ceruleus and elicits high rates of panic-like
activity in those with panic disorder.
Panic-Inducing Substances.
 Panic-inducing substances (sometimes called
panicogens) induce panic attacks in most patients with panic disorder and in a much
smaller proportion of persons without panic disorder or a history of panic attacks. Socalled respiratory panic-inducing substances cause respiratory stimulation and a shift in
the acid–base balance. These substances include carbon dioxide (5 to 35 percent
mixtures), sodium lactate, and bicarbonate. Neurochemical panic-inducing substances
that act through specific neurotransmitter systems include yohimbine, an α2-adrenergic
receptor antagonist; mCPP, an agent with multiple serotonergic effects; m-Caroline
drugs; GABAB receptor inverse agonists; flumazenil (Romazicon), a GABAB receptor
antagonist; cholecystokinin; and caffeine. Isoproterenol (Isuprel) is also a panicinducing substance, although its mechanism of action in inducing panic attacks is poorly
understood. The respiratory panic-inducing substances may act initially at the
peripheral cardiovascular baroreceptors and relay their signal by vagal afferents to the
nucleus tractus solitarii and then on to the nucleus paragigantocellularis of the medulla.
The hyperventilation in patients with panic disorder may be caused by a hypersensitive
suffocation alarm system whereby increasing PCO2 and brain lactate concentrations
prematurely activate a physiological asphyxia monitor. The neurochemical panicinducing substances are presumed to primarily affect the noradrenergic, serotonergic,
and GABA receptors of the CNS directly.
Brain Imaging.
 Structural brain imaging studies, for example, MRI, in patients
with panic disorder have implicated pathological involvement in the temporal lobes,
particularly the hippocampus and the amygdala. One MRI study reported abnormalities,
especially cortical atrophy, in the right temporal lobe of these patients. Functional brain
imaging studies, for example, positron emission tomography (PET), have implicated
dysregulation of cerebral blood flow (smaller increase or an actual decrease in cerebral
blood flow). Specifically, anxiety disorders and panic attacks are associated with
cerebral vasoconstriction, which may result in CNS symptoms, such as dizziness, and in
peripheral nervous system symptoms that may be induced by hyperventilation and
hypocapnia. Most functional brain imaging studies have used a specific panic-inducing
substance (e.g., lactate, caffeine, or yohimbine) in combination with PET or SPECT to
assess the effects of the panic-inducing substance and the induced panic attack on
cerebral blood flow.
Mitral Valve Prolapse.
 Although great interest was formerly expressed in an
association between mitral valve prolapse and panic disorder, research has almost

completely erased any clinical significance or relevance to the association. Mitral valve
prolapse is a heterogeneous syndrome consisting of the prolapse of one of the mitral
valve leaflets, resulting in a midsystolic click on cardiac auscultation. Studies have found
that the prevalence of panic disorder in patients with mitral valve prolapse is the same
as the prevalence of panic disorder in patients without mitral valve prolapse.
Genetic Factors
Various studies have found that the first-degree relatives of patients with panic disorder
have a four- to eightfold higher risk for panic disorder than first-degree relatives of other
psychiatric patients. The twin studies conducted to date have generally reported that
monozygotic twins are more likely to be concordant for panic disorder than are
dizygotic twins. At this point, no data exist indicating an association between a specific
chromosomal location or mode of transmission and this disorder.
Psychosocial Factors
Psychoanalytic theories have been developed to explain the pathogenesis of panic
disorder. Psychoanalytic theories conceptualize panic attacks as arising from an
unsuccessful defense against anxiety-provoking impulses. What was previously a mild
signal anxiety becomes an overwhelming feeling of apprehension, complete with
somatic symptoms.
Many patients describe panic attacks as coming out of the blue, as though no
psychological factors were involved, but psychodynamic exploration frequently reveals
a clear psychological trigger for the panic attack. Although panic attacks are correlated
neurophysiologically with the locus ceruleus, the onset of panic is generally related to
environmental or psychological factors. Patients with panic disorder have a higher
incidence of stressful life events (particularly loss) than control subjects in the months
before the onset of panic disorder. Moreover, the patients typically experience greater
distress about life events than control subjects do.
The hypothesis that stressful psychological events produce neurophysiological changes
in panic disorder is supported by a study of female twins. Separation from the mother
early in life was clearly more likely to result in panic disorder than was paternal
separation in the cohort of 1,018 pairs of female twins. Another etiological factor in
adult female patients appears to be childhood physical and sexual abuse. Approximately
60 percent of women with panic disorder have a history of childhood sexual abuse
compared with 31 percent of women with other anxiety disorders. Further support for
psychological mechanisms in panic disorder can be inferred from a study of panic
disorder in which patients received successful treatment with cognitive therapy. Before
the therapy, the patients responded to panic attack induction with lactate. After
successful cognitive therapy, lactate infusion no longer produced a panic attack.
The research indicates that the cause of panic attacks is likely to involve the
unconscious meaning of stressful events and that the pathogenesis of the panic attacks
may be related to neurophysiological factors triggered by the psychological reactions.

Psychodynamic clinicians should always thoroughly investigate possible triggers
whenever assessing a patient with panic disorder. The psychodynamics of panic disorder
are summarized in Table 9.2-1.
Table 9.2-1
Psychodynamic Themes in Panic Disorder
DIAGNOSIS
Panic Attacks
A panic attack is a sudden period of intense fear or apprehension that may last from
minutes to hours. Panic attacks can occur in mental disorders other than panic disorder,
particularly in specific phobia, social phobia, and PTSD. Unexpected panic attacks occur
at any time and are not associated with any identifiable situational stimulus, but panic
attacks need not be unexpected. Attacks in patients with social and specific phobias are
usually expected or cued to a recognized or specific stimulus. Some panic attacks do not
fit easily into the distinction between unexpected and expected, and these attacks are
referred to as situationally predisposed panic attacks. They may or may not occur when a
patient is exposed to a specific trigger, or they may occur either immediately after
exposure or after a considerable delay.
Panic Disorder
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
diagnostic criteria for panic disorder are listed in Table 9.2-2. Some community surveys
have indicated that panic attacks are common, and a major issue in developing
diagnostic criteria for panic disorder was determining a threshold number or frequency
of panic attacks required to meet the diagnosis. Setting the threshold too low results in
the diagnosis of panic disorder in patients who do not have an impairment from an

occasional panic attack; setting the threshold too high results in a situation in which
patients who are impaired by their panic attacks do not meet the diagnostic criteria.
Table 9.2-2
DSM-5 Diagnostic Criteria for Panic Disorder

CLINICAL FEATURES
The first panic attack is often completely spontaneous, although panic attacks
occasionally follow excitement, physical exertion, sexual activity, or moderate

emotional trauma. Clinicians should attempt to ascertain any habit or situation that
commonly precedes a patient’s panic attacks. Such activities may include the use of
caffeine, alcohol, nicotine, or other substances; unusual patterns of sleeping or eating;
and specific environmental settings, such as harsh lighting at work.
The attack often begins with a 10-minute period of rapidly increasing symptoms. The
major mental symptoms are extreme fear and a sense of impending death and doom.
Patients usually cannot name the source of their fear; they may feel confused and have
trouble concentrating. The physical signs often include tachycardia, palpitations,
dyspnea, and sweating. Patients often try to leave whatever situation they are in to
seek help. The attack generally lasts 20 to 30 minutes and rarely more than an hour. A
formal mental status examination during a panic attack may reveal rumination,
difficulty speaking (e.g., stammering), and impaired memory. Patients may experience
depression or depersonalization during an attack. The symptoms can disappear quickly
or gradually. Between attacks, patients may have anticipatory anxiety about having
another attack. The differentiation between anticipatory anxiety and generalized
anxiety disorder can be difficult, although patients with pain disorder with anticipatory
anxiety can name the focus of their anxiety.
Somatic concerns of death from a cardiac or respiratory problem may be the major
focus of patients’ attention during panic attacks. Patients may believe that the
palpitations and chest pain indicate that they are about to die. As many as 20 percent of
such patients actually have syncopal episodes during a panic attack. The patients may
be seen in emergency departments as young (20s), physically healthy persons who
nevertheless insist that they are about to die from a heart attack. Rather than
immediately diagnosing hypochondriasis, the emergency department physician should
consider a diagnosis of panic disorder. Hyperventilation can produce respiratory
alkalosis and other symptoms. The age-old treatment of breathing into a paper bag
sometimes helps because it decreases alkalosis.
Mrs. K was a 35-year-old woman who initially presented for treatment at the
medical emergency department at a large university-based medical center. She
reported that while sitting at her desk at her job, she had suddenly experienced
difficulty breathing, dizziness, tachycardia, shakiness, and a feeling of terror that she
was going to die of a heart attack. A colleague drove her to the emergency
department, 
where 
she 
received 
a 
full 
medical 
evaluation, 
including
electrocardiography and routine blood work, which revealed no sign of
cardiovascular, pulmonary, or other illness. She was subsequently referred for
psychiatric evaluation, where she revealed that she had experienced two additional
episodes over the past month, once when driving home from work and once when
eating breakfast. However, she had not presented for medical treatment because the
symptoms had resolved relatively quickly each time, and she worried that if she went
to the hospital without ongoing symptoms, “people would think I’m crazy.” Mrs. K
reluctantly took the phone number of a local psychiatrist but did not call until she

experienced a fourth episode of a similar nature. (Courtesy of Erin B. McClure-Tone,
Ph.D., and Daniel S. Pine, M.D.)
Associated Symptoms
Depressive symptoms are often present in panic disorder, and in some patients, a
depressive disorder coexists with the panic disorder. Some studies have found that the
lifetime risk of suicide in persons with panic disorder is higher than it is in persons with
no mental disorder. Clinicians should be alert to the risk of suicide. In addition to
agoraphobia, other phobias and OCD can coexist with panic disorder. The psychosocial
consequences of panic disorder, in addition to marital discord, can include time lost
from work, financial difficulties related to the loss of work, and alcohol and other
substance abuse.
DIFFERENTIAL DIAGNOSIS
Panic Disorder
The differential diagnosis for a patient with panic disorder includes many medical
disorders (Table 9.2-3), as well as many mental disorders.
Table 9.2-3
Organic Differential Diagnosis for Panic Disorder

Medical Disorders
Panic disorder must be differentiated from a number of medical conditions that produce
similar symptomatology. Panic attacks are associated with a variety of endocrinological
disorders, including both hypo- and hyperthyroid states, hyperparathyroidism, and
pheochromocytomas. Episodic hypoglycemia associated with insulinomas can also
produce panic-like states, as can primary neuropathological processes. These include
seizure disorders, vestibular dysfunction, neoplasms, or the effects of both prescribed
and illicit substances on the CNS. Finally, disorders of the cardiac and pulmonary
systems, including arrhythmias, chronic obstructive pulmonary disease, and asthma, can
produce autonomic symptoms and accompanying crescendo anxiety that can be difficult

to distinguish from panic disorder. Clues of an underlying medical etiology to panic-like
symptoms include the presence of atypical features during panic attacks, such as ataxia,
alterations in consciousness, or bladder dyscontrol; onset of panic disorder relatively
late in life; and physical signs or symptoms indicative of a medical disorder.
Mental Disorders
Panic disorder also must be differentiated from a number of psychiatric disorders,
particularly other anxiety disorders. Panic attacks occur in many anxiety disorders,
including social and specific phobia, Panic may also occur in PTSD and OCD. The key to
correctly diagnosing panic disorder and differentiating the condition from other anxiety
disorders involves the documentation of recurrent spontaneous panic attacks at some
point in the illness. Differentiation from generalized anxiety disorder can also be
difficult. Classically, panic attacks are characterized by their rapid onset (within
minutes) and short duration (usually less than 10 to 15 minutes), in contrast to the
anxiety associated with generalized anxiety disorder, which emerges and dissipates more
slowly. Making this distinction can be difficult, however, because the anxiety
surrounding panic attacks can be more diffuse and slower to dissipate than is typical.
Because anxiety is a frequent concomitant of many other psychiatric disorders, including
the psychoses and affective disorders, discrimination between panic disorder and a
multitude of disorders can also be difficult.
Specific and Social Phobias
Sometimes it is difficult to distinguish between panic disorder, on the one hand, and
specific and social phobias, on the other hand. Some patients who experience a single
panic attack in a specific setting (e.g., an elevator) may go on to have long-lasting
avoidance of the specific setting, regardless of whether they ever have another panic
attack. These patients meet the diagnostic criteria for a specific phobia, and clinicians
must use their judgment about what is the most appropriate diagnosis. In another
example, a person who experiences one or more panic attacks may then fear speaking
in public. Although the clinical picture is almost identical to the clinical picture in social
phobia, a diagnosis of social phobia is excluded because the avoidance of the public
situation is based on fear of having a panic attack rather than on fear of the public
speaking itself.
COURSE AND PROGNOSIS
Panic disorder usually has its onset in late adolescence or early adulthood, although
onset during childhood, early adolescence, and midlife does occur. Some data implicate
increased psychosocial stressors with the onset of panic disorder, although no
psychosocial stressor can be definitely identified in most cases.
Panic disorder, in general, is a chronic disorder, although its course is variable, both
among patients and within a single patient. The available long-term follow-up studies of

panic disorder are difficult to interpret because they have not controlled for the effects
of treatment. Nevertheless, about 30 to 40 percent of patients seem to be symptom free
at long-term follow-up, about 50 percent have symptoms that are sufficiently mild not
to affect their lives significantly, and about 10 to 20 percent continue to have significant
symptoms.
After the first one or two panic attacks, patients may be relatively unconcerned about
their condition; with repeated attacks, however, the symptoms may become a major
concern. Patients may attempt to keep the panic attacks secret and thereby cause their
families and friends concern about unexplained changes in behavior. The frequency and
severity of the attacks can fluctuate. Panic attacks can occur several times in a day or
less than once a month. Excessive intake of caffeine or nicotine can exacerbate the
symptoms.
Depression can complicate the symptom picture in anywhere from 40 to 80 percent of
all patients, as estimated by various studies. Although the patients do not tend to talk
about suicidal ideation, they are at increased risk for committing suicide. Alcohol and
other substance dependence occurs in about 20 to 40 percent of all patients, and OCD
may also develop. Family interactions and performance in school and at work
commonly suffer. Patients with good premorbid functioning and symptoms of brief
duration tend to have good prognoses.
TREATMENT
With treatment, most patients exhibit dramatic improvement in the symptoms of panic
disorder and agoraphobia. The two most effective treatments are pharmacotherapy and
cognitive-behavioral therapy. Family and group therapy may help affected patients and
their families adjust to the patient’s disorder and to the psychosocial difficulties that the
disorder may have precipitated.
Pharmacotherapy
Overview.
 Alprazolam (Xanax) and paroxetine (Paxil) are the two drugs approved
by the US Food and Drug Administration (FDA) for the treatment of panic disorder. In
general, experience is showing superiority of the selective serotonin reuptake inhibitors
(SSRIs) and clomipramine (Anafranil) over the benzodiazepines, monoamine oxidase
inhibitors (MAOIs), and tricyclic and tetracyclic drugs in terms of effectiveness and
tolerance of adverse effects. Some reports have suggested a role for venlafaxine
(Effexor), and buspirone (BuSpar) has been suggested as an additive medication in some
cases. Venlafaxine is approved by the FDA for treatment of generalized anxiety disorder
and may be useful in panic disorder combined with depression. β-adrenergic receptor
antagonists have not been found to be particularly useful for panic disorder. A
conservative approach is to begin treatment with paroxetine, sertraline (Zoloft),
citalopram (Celexa), or fluvoxamine (Luvox) in isolated panic disorder. If rapid control
of severe symptoms is desired, a brief course of alprazolam should be initiated

concurrently with the SSRI followed by slowly tapering use of the benzodiazepine. In
long-term use, fluoxetine (Prozac) is an effective drug for panic with comorbid
depression, although its initial activating properties may mimic panic symptoms for the
first several weeks, and it may be poorly tolerated on this basis. Clonazepam (Klonopin)
can be prescribed for patients who anticipate a situation in which panic may occur (0.5
to 1 mg as required). Common dosages for antipanic drugs are listed in Table 9.2-4.
Table 9.2-4
Recommended Dosages for Antipanic Drugs (Daily Unless Indicated
Otherwise)

Selective Serotonin Reuptake Inhibitors.
 All SSRIs are effective for panic
disorder. Paroxetine and paroxetine CR have sedative effects and tend to calm patients
immediately, which leads to greater compliance and less discontinuation, but this must
be weighed against its weight gain potential. Citalopram, escitalopram (Lexapro),
fluvoxamine, and sertraline are the next best tolerated. Anecdotal reports suggest that
patients with panic disorder are particularly sensitive to the activating effects of SSRIs,
particularly fluoxetine, so they should be given initially at small dosages and titrated up
slowly. At therapeutic dosages—for example, 20 mg a day of paroxetine—some patients
may experience increased sedation. One approach for patients with panic disorder is to
give 5 or 10 mg a day of paroxetine or 12.5 to 25 mg of paroxetine CR for 1 to 2 weeks
and then increase the dosage by 10 mg of paroxetine or 12.5 mg of paroxetine CR a day
every 1 to 2 weeks to a maximum of 60 mg of paroxetine or 62.5 mg of paroxetine CR.
If sedation becomes intolerable, then taper the paroxetine dosage down to 10 mg a day
of paroxetine or 12.5 mg of paroxetine CR and switch to fluoxetine at 10 mg a day and
titrate upward slowly. Other strategies can be used based on the experience of the
clinician.
Benzodiazepines.
 Benzodiazepines have the most rapid onset of action against
panic, often within the first week, and they can be used for long periods without the
development of tolerance to the antipanic effects. Alprazolam has been the most widely
used benzodiazepine for panic disorder, but controlled studies have demonstrated equal
efficacy for lorazepam (Ativan), and case reports have also indicated that clonazepam
may be effective. Some patients use benzodiazepines as needed when faced with a
phobic stimulus. Benzodiazepines can reasonably be used as the first agent for treatment
of panic disorder while a serotonergic drug is being slowly titrated to a therapeutic dose.
After 4 to 12 weeks, benzodiazepine use can be slowly tapered (over 4 to 10 weeks)
while the serotonergic drug is continued. The major reservation among clinicians
regarding the use of benzodiazepines for panic disorder is the potential for dependence,
cognitive impairment, and abuse, especially after long-term use. Patients should be
instructed not to drive, abstain from alcohol or other CNS depressant medications, and
avoid operating dangerous equipment while taking benzodiazepines. Whereas
benzodiazepines elicit a sense of well-being, discontinuation of benzodiazepines
produces a well-documented and unpleasant withdrawal syndrome. Anecdotal reports
and small case series have indicated that addiction to alprazolam is one of the most
difficult to overcome, and it may require a comprehensive program of detoxification.
Benzodiazepine dosage should be tapered slowly, and all anticipated withdrawal effects
should be thoroughly explained to the patient.
Tricyclic and Tetracyclic Drugs.
 At the present time, SSRIs are considered the
first-line agents for the treatment of panic disorder. Data, however, show that among
tricyclic drugs, clomipramine and imipramine (Tofranil) are the most effective in the
treatment of panic disorder. Clinical experience indicates that the dosages must be
titrated slowly upward to avoid overstimulation and that the full clinical benefit

requires full dosages and may not be achieved for 8 to 12 weeks. Some data support the
efficacy of desipramine (Norpramin), and less evidence suggests a role for maprotiline
(Ludiomil), trazodone (Desyrel), nortriptyline (Pamelor), amitriptyline (Elavil), and
doxepin (Adapin). Tricyclic drugs are less widely used than SSRIs because the tricyclic
drugs generally have more severe adverse effects at the higher dosages required for
effective treatment of panic disorder.
Monoamine Oxidase Inhibitors.
 The most robust data support the effectiveness
of phenelzine (Nardil), and some data also support the use of tranylcypromine
(Parnate). MAOIs appear less likely to cause overstimulation than either SSRIs or
tricyclic drugs, but they may require full dosages for at least 8 to 12 weeks to be
effective. The need for dietary restrictions has limited the use of MAOIs, particularly
since the appearance of the SSRIs.
Treatment Nonresponse.
 If patients fail to respond to one class of drugs, another
should be tried. Recent data support the effectiveness of venlafaxine. The combination
of an SSRI or a tricyclic drug and a benzodiazepine or of an SSRI and lithium or a
tricyclic drug can be tried. Case reports have suggested the effectiveness of
carbamazepine (Tegretol), valproate (Depakene), and calcium channel inhibitors.
Buspirone may have a role in the augmentation of other medications but has little
effectiveness by itself. Clinicians should reassess the patient, particularly to establish the
presence of comorbid conditions such as depression, alcohol use, or other substance use.
Duration of Pharmacotherapy.
 When it becomes effective, pharmacological
treatment should generally continue for 8 to 12 months. Data indicate that panic
disorder is a chronic, perhaps lifelong, condition that recurs when treatment is
discontinued. Studies have reported that 30 to 90 percent of patients with panic disorder
who have had successful treatment have a relapse when their medication is
discontinued. Patients may be likely to relapse if they have been given benzodiazepines
and the benzodiazepine therapy is terminated in a way that causes withdrawal
symptoms.
Cognitive and Behavior Therapies
Cognitive and behavior therapies are effective treatments for panic disorder. Various
reports have concluded that cognitive and behavior therapies are superior to
pharmacotherapy alone; other reports have concluded the opposite. Several studies and
reports have found that the combination of cognitive or behavior therapy with
pharmacotherapy is more effective than either approach alone. Several studies that
included long-term follow-up of patients who received cognitive or behavior therapy
indicate that the therapies are effective in producing long-lasting remission of
symptoms.

Cognitive Therapy.
 The two major foci of cognitive therapy for panic disorder are
instruction about a patient’s false beliefs and information about panic attacks. The
instruction about false beliefs centers on the patient’s tendency to misinterpret mild
bodily sensations as indicating impending panic attacks, doom, or death. The
information about panic attacks includes explanations that when panic attacks occur,
they are time limited and not life threatening.
REFERENCES
Cougle JR, Feldner MT, Keough ME, Hawkins KA, Fitch KE. Comorbid panic attacks among individuals with posttraumatic
stress disorder: Associations with traumatic event exposure history, symptoms, and impairment. J Anxiety Disord.
2010;24:183.
Fentz HN, Hoffart A, Jensen MB, Arendt M, O’Toole MS, Rosenberg NK, Hougaard E. Mechanisms of change in cognitive
behaviour therapy for panic disorder: the role of panic self-efficacy and catastrophic misinterpretations. Behav Res
Ther. 2013;51:579–587.
Funayama T, Furukawa TA, Nakano Y, Noda Y, Ogawa S, Watanabe N, Chen J, Noguchi Y. In-situation safety behaviors
among patients with panic disorder: descriptive and correlational study. Psych Clin Neurosci. 2013;67:332–339.
Hodges LM, Fyer AJ, Weissman MM, Logue MW, Haghighi F, Evgrafov O, Rotondo A, Knowles JA, Hamilton SP. Evidence
for Linkage and Association of GABRB3 and GABRA5 to Panic Disorder. Neuropsychopharmacology. 2014.
McClure-Tone EB, Pine DS. Clinical features of the anxiety disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan &
Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009:1844.
McTeague LM, Lang PJ, Laplante MC, Bradley MM. Aversive imagery in panic disorder: Agoraphobia severity, comorbidity,
and defensive physiology. Biol Psychiatry. 2011;70:415.
Nardi AE, Valença AM, Freire RC, Amrein R, Sardinha A, Levitan MN, Nascimento I, de-Melo-Neto VL, King AL, de O. e
Silva AC, Veras AB, Dias GP, Soares-Filho GL, da Costa RT, Mezzasalma MA, de Carvalho MR, de Cerqueira AC, Hallak
JE, Crippa JA, Versiani M. Randomized, open naturalistic, acute treatment of panic disorder with clonazepam or
paroxetine. J Clin Psychopharmacol. 2011;31:259.
Noel JM, Curtis JL. The pharmacological management of stress reactions. In: Everly GS Jr, Lating JM. A Clinical Guide to
the Treatment of the Human Stress Response. New York: Springer Science+Business Media; 2013:317.
Onur E, Alkın T, Sheridan MJ, Wise TN. Alexithymia and emotional intelligence in patients with panic disorder,
generalized anxiety disorder and major depressive disorder. Psych Quart. 2013;84:303.
Otto MW, Tolin DF, Simon NM, Pearlson GD, Basden S, Meunier SA, Hofmann SG, Eisenmenger K, Krystal JH, Pollack MH.
Efficacy of D-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder. Biol Psychiatry.
2010;67:365.
Pilecki B, Arentoft A, McKay D. An evidence-based causal model of panic disorder. J Anxiety Disord. 2011;25:381.
Spatola CAM, Scaini S, Pesenti-Gritti P, Medland SE, Moruzzi S, Ogliari A, Tambs K, Battaglia M. Gene–environment
interactions in panic disorder and CO2 sensitivity: Effects of events occurring early in life. Am J Med Gen. 2011;156:79.
Thorpe GL, Sigmon ST, Yoon KL. Agoraphobia and panic disorder. In: Ramachandran VS, ed. Encyclopedia of Human
Behavior. 2nd edition. Burlington, MA: Academic Press; 2012:68.
Wuyek LA, Antony MM, McCabe RE. Psychometric properties of the panic disorder severity scale: Clinician-administered
and self-report versions. Clin Psychol Psychother. 2011;18:234.

# 03 - 9.3 Agoraphobia

# 9.3 Agoraphobia

9.3 Agoraphobia
Agoraphobia refers to a fear of or anxiety regarding places from which escape might be
difficult. It can be the most disabling of the phobias because it can significantly interfere
with a person’s ability to function in work and social situations outside the home. In the
United States, most researchers of panic disorder believe that agoraphobia almost
always develops as a complication in patients with panic disorder. That is, the fear of
having a panic attack in a public place from which escape would be formidable is
thought to cause the agoraphobia. Although agoraphobia often coexists with panic
disorder, DSM-5 classifies agoraphobia as a separate condition that may or may not be
comorbid with panic disorder.
HISTORY
The term agoraphobia was coined in 1871 to describe the condition of patients who were
afraid to venture alone into public places. The term is derived from the Greek words
agora and phobos, meaning “fear of the marketplace.”
EPIDEMIOLOGY
The lifetime prevalence of agoraphobia is somewhat controversial, varying between 2 to
6 percent across studies. According to the DSM-5, persons older than age 65 years have
a 0.4 percent prevalence rate of agoraphobia, but this may be a low estimate. The
major factor leading to this wide range of estimates relates to disagreement about the
conceptualization of agoraphobia’s relationship to panic disorder. Although studies of
agoraphobia in psychiatric settings have reported that at least three fourths of the
affected patients have panic disorder as well, studies of agoraphobia in community
samples have found that as many as half the patients have agoraphobia without panic
disorder. The reasons for these divergent findings are unknown but probably involve
differences in ascertainment techniques. In many cases, the onset of agoraphobia
follows a traumatic event.
DIAGNOSIS AND CLINICAL FEATURES
The DSM-5 diagnostic criteria for agoraphobia stipulates marked fear or anxiety about
at least one situation from two or more of five situation groups: (1) using public
transportation (e.g., bus, train, cars, planes), (2) in an open space (e.g., park, shopping
center, parking lot), (3) in an enclosed space (e.g., stores, elevators, theaters), (4) in a
crowd or standing in line, or (5) alone outside of the home. The fear or anxiety must be
persistent and last at least 6 months (Table 9.3-1).
Table 9.3-1
DSM-5 Diagnostic Criteria for Agoraphobia

Patients with agoraphobia rigidly avoid situations in which it would be difficult to
obtain help. They prefer to be accompanied by a friend or a family member in busy
streets, crowded stores, closed-in spaces (e.g., tunnels, bridges, and elevators), and
closed-in vehicles (e.g., subways, buses, and airplanes). Patients may insist that they be
accompanied every time they leave the house. The behavior can result in marital

discord, which may be misdiagnosed as the primary problem. Severely affected patients
may simply refuse to leave the house. Particularly before a correct diagnosis is made,
patients may be terrified that they are going crazy.
Mrs. W was a 33-year-old married woman. She visited an anxiety clinic reporting
that she felt like she was having a heart attack whenever she left her home. Her
disorder began 8 years earlier while attending a yoga class when she suddenly noticed
a dramatic increase in her heartbeat, felt stabbing pains in her chest, and had
difficulty breathing. She began sweating and trembling and felt dizzy. She
immediately went to the emergency department, where an electrocardiogram was
performed. No abnormalities were detected. Over the next few months, Mrs. W
experienced similar attacks of 15 to 30 minutes’ duration about four times per month.
She often sought medical advice after each episode, and each time no physical
abnormalities were detected. After experiencing a few of these attacks, Mrs. W
became afraid of having an attack away from home and would not leave her home
unless absolutely necessary, in which case she needed to have her cell phone or be
accompanied by someone. Even so, she avoided crowded places such as malls, movie
theaters, and banks, where rapid escape is sometimes blocked. Her symptoms and
avoidance dominated her life, although she was aware that they were irrational and
excessive. She experienced mild depression and restlessness and had difficulty
sleeping.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for agoraphobia includes all the medical disorders that can
cause anxiety or depression. The psychiatric differential diagnosis includes major
depressive disorder, schizophrenia, paranoid personality disorder, avoidance personality
disorder, and dependent personality disorder.
COURSE AND PROGNOSIS
Most cases of agoraphobia are thought to be caused by panic disorder. When the panic
disorder is treated, the agoraphobia often improves with time. For rapid and complete
reduction of agoraphobia, behavior therapy is sometimes indicated. Agoraphobia
without a history of panic disorder is often incapacitating and chronic, and depressive
disorders and alcohol dependence often complicate its course.
TREATMENT
Pharmacotherapy
Benzodiazepines.
 Benzodiazepines have the most rapid onset of action against

panic. Some patients use them as needed when faced with a phobic stimulus.
Alprazolam (Xanax) and lorazepam (Ativan) are the most commonly prescribed
benzodiazepines. Clonazepam (Klonopin) has also been shown to be effective. The
major reservations among clinicians regarding the use of benzodiazepines are the
potential for dependence, cognitive impairment, and abuse, particularly with long-term
use. However, when used appropriately under medical supervision, benzodiazepines are
efficacious and generally well tolerated. The most common side effects are mild
dizziness and sedation, both of which are generally attenuated by time or change of
dose. Caution must be exercised when using heavy or dangerous machinery or when
driving, especially when first starting the medication or when the dose is changed.
Benzodiazepines should not be used in combination with alcohol because they can
intensify its effects. Benzodiazepines are also best avoided in individuals with histories
of alcohol or substance abuse unless there are compelling reasons, such as failure to
respond to other classes of medications.
Selective Serotonin Reuptake Inhibitors.
 SSRIs have been shown to help
reduce or prevent relapse from various forms of anxiety, including agoraphobia.
Effective doses are essentially the same as for the treatment of depression, although it is
customary to start with lower initial doses than in depression to minimize an initial
anxiolytic effect, which is almost always short lived, and to titrate upward somewhat
slower toward a therapeutic dose. The main advantages of SSRIs antidepressants include
their improved safety profile in overdose and more tolerable side-effect burden.
Common side effects of most SSRIs are sleep disturbance, drowsiness, lightheadedness,
nausea, and diarrhea; many of these adverse effects improve with continued use.
Another commonly reported side effect of SSRIs is sexual dysfunction (i.e., decreased
libido, delayed ejaculation in men, delayed orgasm in women), which rarely improves
with time or switching among SSRIs (or from an SSRI to a serotonin-norepinephrine
reuptake inhibitor [SNRI]). Proposed strategies to combat sexual dysfunction in patients
taking SSRIs include adjunctive use of yohimbine (Yocon), bupropion (Wellbutrin), or
mirtazapine (Remeron); dose reduction; or adjunctive use of sildenafil (Viagra). Another
issue to be considered when prescribing an SSRI is the possibility of a discontinuation
syndrome if these medications are stopped abruptly. Commonly reported symptoms of
this condition, which tend to occur 2 to 4 days after medication cessation, include
increased anxiety, irritability, tearfulness, dizziness or lightheadedness, malaise, sleep
disturbance, and concentration difficulties. This discontinuation syndrome is most
common among SSRIs with shorter half-lives (e.g., paroxetine [Paxil]).
Tricyclic and Tetracyclic Drugs.
 Although SSRIs are considered the first-line
agents for treatment of panic disorders with or without agoraphobia, the tricyclic drugs
clomipramine (Anafranil) and imipramine (Tofranil) are the most effective in the
treatment of these disorders. Dosages must be titrated slowly upward to avoid
overstimulation (e.g., “jitteriness” syndrome), and the full clinical benefit requires full
dosages and may not be achieved for 8 to 12 weeks. Therapeutic drug monitoring

(TDM) may be useful to ensure that the patient is on an adequate dose of medication
while avoiding issues of toxicity. The other adverse effects to these antidepressants are
related to their effects on seizure threshold, as well as anticholinergic and potentially
harmful cardiac effects, particularly in overdose.
Psychotherapy
Supportive Psychotherapy.
 Supportive psychotherapy involves the use of
psychodynamic concepts and a therapeutic alliance to promote adaptive coping.
Adaptive defenses are encouraged and strengthened, and maladaptive ones are
discouraged. The therapist assists in reality testing and may offer advice regarding
behavior.
Insight-Oriented Psychotherapy.
 In insight-oriented psychotherapy, the goal is
to increase the patient’s development of insight into psychological conflicts that, if
unresolved, can manifest as symptomatic behavior.
Behavior Therapy.
 In behavior therapy, the basic assumption is that change can
occur without the development of psychological insight into underlying causes.
Techniques include positive and negative reinforcement, systematic desensitization,
flooding, implosion, graded exposure, response prevention, stop thought, relaxation
techniques, panic control therapy, self-monitoring, and hypnosis.
Cognitive Therapy.
 This is based on the premise that maladaptive behavior is
secondary to distortions in how people perceive themselves and in how other perceive
them. Treatment is short term and interactive, with assigned homework and tasks to be
performed between sessions that focus on correcting distorted assumptions and
cognitions. The emphasis is on confronting and examining situations that elicit
interpersonal anxiety and associated mild depression.
Virtual Therapy.
 Computer programs have been developed that allow patients to
see themselves as avatars who are then placed in open or crowded spaces (e.g., a
supermarket). As they identify with the avatars in repeated computer sessions, they are
able to master their anxiety through deconditioning.
REFERENCES
Chambless DL, Sharpless BA, Rodriguez D, McCarthy KS, Milrod BL, Khalsa SR, Barber JP. Psychometric properties of the
mobility inventory for agoraphobia: Convergent, discriminant, and criterion-related validity. Behav Therapy.
2011;42:689.
Croft A, Hackmann A. Agoraphobia: An outreach treatment programme. Behav Cogn Psychother. 2013;41:359.
Huppert JD, Kivity Y, Barlow DH, Gorman JM, Shear MK, Woods SW. Therapist effects and the outcome–alliance
correlation in cognitive behavioral therapy for panic disorder with agoraphobia. Behav Res Ther. 2014;52:26–34.
McCabe RE, Gifford S. Psychological treatment of panic disorder and agoraphobia. In: Anthony MM, Stein MB, eds. Oxford

# 04 - 9.4 Specific Phobia

# 9.4 Specific Phobia

Handbook of Anxiety and Related Disorders. New York: Oxford University Press; 2009:308.
McClure-Tone EB, Pine DS. Clinical features of the anxiety disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan &
Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009:1844.
Meyerbroker K, Morina N, Kerkhof G, Emmelkamp PM. Virtual reality exposure treatment of agoraphobia: a comparison
of computer automatic virtual environment and head-mounted display. Stud Health Technol Inform. 2011;167:51.
Nay W, Brown R, Roberson-Nay R. Longitudinal course of panic disorder with and without agoraphobia using the National
Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Psych Res. 2013;208:54.
Perna G, Daccò S, Menotti R, Caldirola D. Antianxiety medications for the treatment of complex agoraphobia:
Pharmacological interventions for a behavioral condition. Neuropsychiatr Dis Treat. 2011;7:621.
Pollack MH, Simon NM. Pharmacotherapy for panic disorder and agoraphobia. In: Anthony MM, Stein MB, eds. Oxford
Handbook of Anxiety and Related Disorders. New York: Oxford University Press; 2009:295.
Ritchie K, Norton J, Mann A, Carriere I, Ancelin M-L. Late-onset agoraphobia: General population incidence and evidence
for clinical subtype. Am J Psych. 2013;170:790.
Vögele C, Ehlers A, Meyer AH, Frank M, Hahlweg K, Margraf J. Cognitive mediation of clinical improvement after intensive
exposure therapy of agoraphobia and social phobia. Depress Anxiety. 2010;27:294.
Wittchen HU, Gloster AT, Beesdo-Baum K, Fava GA, Craske MG. Agoraphobia: A review of the diagnostic classificatory
position and criteria. Depress Anxiety. 2010;27:113.
 9.4 Specific Phobia
The term phobia refers to an excessive fear of a specific object, circumstance, or
situation. A specific phobia is a strong, persisting fear of an object or situation. The
diagnosis of specific phobia requires the development of intense anxiety, even to the
point of panic, when exposed to the feared object. Persons with specific phobias may
anticipate harm, such as being bitten by a dog, or may panic at the thought of losing
control; for instance, if they fear being in an elevator, they may also worry about
fainting after the door closes.
EPIDEMIOLOGY
Phobias are one of the most common mental disorders in the United States, where
approximately 5 to 10 percent of the population is estimated to have these troubling
and sometimes disabling disorders. The lifetime prevalence of specific phobia is about
10 percent. Specific phobia is the most common mental disorder among women and the
second most common among men, second only to substance-related disorders. The 6month prevalence of specific phobia is about 5 to 10 per 100 persons (Table 9.4-1). The
rates of specific phobias in women (14 to 16 percent) were double those of men (5 to 7
percent), although the ratio is closer to 1 to 1 for the fear of blood, injection, or injury
type. (Types of phobias are discussed below in this section.) The peak age of onset for
the natural environment type and the blood-injection-injury type is in the range of 5 to
9 years, although onset also occurs at older ages. In contrast, the peak age of onset for
the situational type (except fear of heights) is higher, in the mid-20s, which is closer to
the age of onset for agoraphobia. The feared objects and situations in specific phobias

(listed in descending frequency of appearance) are animals, storms, heights, illness,
injury, and death.
Table 9.4-1
Lifetime Prevalence Rates of Specific Phobia
COMORBIDITY
Reports of comorbidity in specific phobia range from 50 to 80 percent. Common
comorbid disorders with specific phobia include anxiety, mood, and substance-related
disorders.
ETIOLOGY
General Principles of Phobias
Behavioral Factors.
 In 1920, John B. Watson wrote an article called “Conditioned
Emotional Reactions,” in which he recounted his experiences with Little Albert, an
infant with a fear of rats and rabbits. Unlike Sigmund Freud’s case of Little Hans, who
had phobic symptoms (of horses) in the natural course of his maturation, Little Albert’s
difficulties were the direct result of the scientific experiments of two psychologists who
used techniques that had successfully induced conditioned responses in laboratory
animals.
Watson’s hypothesis invoked the traditional pavlovian stimulus–response model of the
conditioned reflex to account for the creation of the phobia: Anxiety is aroused by a
naturally frightening stimulus that occurs in contiguity with a second inherently neutral
stimulus. As a result of the contiguity, especially when the two stimuli are paired on
several successive occasions, the originally neutral stimulus becomes capable of arousing
anxiety by itself. The neutral stimulus, therefore, becomes a conditioned stimulus for
anxiety production.
In the classic stimulus–response theory, the conditioned stimulus gradually loses its

potency to arouse a response if it is not reinforced by periodic repetition of the
unconditioned stimulus. In phobias, attenuation of the response to the stimulus does not
occur; the symptom may last for years without any apparent external reinforcement.
Operant conditioning theory provides a model to explain this phenomenon: Anxiety is a
drive that motivates the organism to do whatever it can to obviate a painful affect. In
the course of its random behavior, the organism learns that certain actions enable it to
avoid the anxiety-provoking stimulus. These avoidance patterns remain stable for long
periods as a result of the reinforcement they receive from their capacity to diminish
anxiety. This model is readily applicable to phobias in that avoidance of the anxietyprovoking object or situation plays a central part. Such avoidance behavior becomes
fixed as a stable symptom because of its effectiveness in protecting the person from the
phobic anxiety.
Learning theory, which is particularly relevant to phobias, provides simple and
intelligible explanations for many aspects of phobic symptoms. Critics contend,
however, that learning theory deals mostly with surface mechanisms of symptom
formation and is less useful than psychoanalytic theories in clarifying some of the
complex underlying psychic processes involved.
Psychoanalytic Factors.
 Sigmund Freud’s formulation of phobic neurosis is still
the analytic explanation of specific phobia and social phobia. Freud hypothesized that
the major function of anxiety is to signal the ego that a forbidden unconscious drive is
pushing for conscious expression and to alert the ego to strengthen and marshal its
defenses against the threatening instinctual force. Freud viewed the phobia—anxiety
hysteria, as he continued to call it—as a result of conflicts centered on an unresolved
childhood oedipal situation. Because sex drives continue to have a strong incestuous
coloring in adults, sexual arousal can kindle an anxiety that is characteristically a fear
of castration. When repression fails to be entirely successful, the ego must call on
auxiliary defenses. In patients with phobias, the primary defense involved is
displacement; that is, the sexual conflict is displaced from the person who evokes the
conflict to a seemingly unimportant, irrelevant object or situation, which then has the
power to arouse a constellation of affects, one of which is called signal anxiety. The
phobic object or situation may have a direct associative connection with the primary
source of the conflict and thus symbolizes it (the defense mechanism of symbolization).
Furthermore, the situation or the object is usually one that the person can avoid; with
the additional defense mechanism of avoidance, the person can escape suffering serious
anxiety. The end result is that the three combined defenses (repression, displacement,
and symbolization) may eliminate the anxiety. The anxiety is controlled at the cost of
creating a phobic neurosis, however. Freud first discussed the theoretical formulation of
phobia formation in his famous case history of Little Hans, a 5-year-old boy who feared
horses.
Although psychiatrists followed Freud’s thought that phobias resulted from castration
anxiety, recent psychoanalytic theorists have suggested that other types of anxiety may
be involved. In agoraphobia, for example, separation anxiety clearly plays a leading

role, and in erythrophobia (a fear of red that can be manifested as a fear of blushing),
the element of shame implies the involvement of superego anxiety. Clinical observations
have led to the view that anxiety associated with phobias has a variety of sources and
colorings.
Phobias illustrate the interaction between a genetic constitutional diathesis and
environmental stressors. Longitudinal studies suggest that certain children are
constitutionally predisposed to phobias because they are born with a specific
temperament known as behavioral inhibition to the unfamiliar, but a chronic
environmental stress must act on a child’s temperamental disposition to create a fullblown phobia. Stressors, such as the death of a parent, separation from a parent,
criticism or humiliation by an older sibling, and violence in the household, may activate
the latent diathesis within the child, who then becomes symptomatic. An overview of
psychodynamic aspects of phobias is summarized in Table 9.4-2.
Table 9.4-2
Psychodynamic Themes in Phobias
COUNTERPHOBIC ATTITUDE. Otto Fenichel called attention to the fact that phobic anxiety
can be hidden behind attitudes and behavior patterns that represent a denial, either that
the dreaded object or situation is dangerous or that the person is afraid of it. Instead of
being a passive victim of external circumstances, a person reverses the situation and
actively attempts to confront and master whatever is feared. Persons with
counterphobic attitudes seek out situations of danger and rush enthusiastically toward
them. Devotees of potentially dangerous sports, such as parachute jumping and rock
climbing, may be exhibiting counterphobic behavior. Such patterns may be secondary to
phobic anxiety or may be normal means of dealing with a realistically dangerous
situation. Children’s play may exhibit counterphobic elements, as when children play
doctor and give a doll the shot they received earlier that day in the pediatrician’s office.
This pattern of behavior may involve the related defense mechanism of identifying with
the aggressor.

Specific Phobia
The development of specific phobia may result from the pairing of a specific object or
situation with the emotions of fear and panic. Various mechanisms for the pairing have
been postulated. In general, a nonspecific tendency to experience fear or anxiety forms
the backdrop; when a specific event (e.g., driving) is paired with an emotional
experience (e.g., an accident), the person is susceptible to a permanent emotional
association between driving or cars and fear or anxiety. The emotional experience itself
can be in response to an external incident, as a traffic accident, or to an internal
incident, most commonly a panic attack. Although a person may never again experience
a panic attack and may not meet the diagnostic criteria for panic disorder, he or she
may have a generalized fear of driving, not an expressed fear of having a panic attack
while driving. Other mechanisms of association between the phobic object and the
phobic emotions include modeling, in which a person observes the reaction in another
(e.g., a parent), and information transfer, in which a person is taught or warned about
the dangers of specific objects (e.g., venomous snakes).
Genetic Factors.
 Specific phobia tends to run in families. The blood-injectioninjury type has a particularly high familial tendency. Studies have reported that twothirds to three-fourths of affected probands have at least one first-degree relative with
specific phobia of the same type, but the necessary twin and adoption studies have not
been conducted to rule out a significant contribution by nongenetic transmission of
specific phobia.
DIAGNOSIS
The DSM-5 includes distinctive types of specific phobia: animal type, natural
environment type (e.g., storms), blood-injection-injury type (e.g., needles), situational
type (e.g., cars, elevators, planes), and other type (for specific phobias that do not fit
into the previous four types). The key feature of each type of phobia is that fear
symptoms occur only in the presence of a specific object (Table 9.4-3). The bloodinjection-injury type is differentiated from the others in that bradycardia and
hypotension often follow the initial tachycardia that is common to all phobias. The
blood-injection-injury type of specific phobia is particularly likely to affect many
members and generations of a family. One type of phobia of recently reported phobia is
space phobia, in which persons fear falling when there is no nearby support, such as a
wall or a chair. Some data indicate that affected persons may have abnormal right
hemisphere function, possibly resulting in visual-spatial impairment. Balance disorders
should be ruled out in such patients.
Table 9.4-3
DSM-5 Diagnostic Criteria for Specific Phobia

Phobias have traditionally been classified according to specific fear by means of Greek
or Latin prefixes, as indicated in Table 9.4-4. Other phobias that are related to changes
in the society are the fear of electromagnetic fields, of microwaves, and of society as a

whole (amaxophobia).
Table 9.4-4
Phobias
Mr. S was a successful lawyer who presented for treatment after his firm, to which
he had previously been able to walk from home, moved to a new location that he
could only reach by driving. Mr. S reported that he was “terrified” of driving,
particularly on highways. Even the thought of getting into a car led him to worry that
he would die in a fiery crash. His thoughts were associated with intense fear and
numerous somatic symptoms, including a racing heart, nausea, and sweating.
Although the thought of driving was terrifying in and of itself, Mr. S became nearly
incapacitated when he drove on busy roads, often having to pull over to vomit.
(Courtesy of Erin B. McClure-Tone, Ph.D., and Daniel S. Pine, M.D.)
CLINICAL FEATURES
Phobias are characterized by the arousal of severe anxiety when patients are exposed to
specific situations or objects or when patients even anticipate exposure to the situations
or objects. Exposure to the phobic stimulus or anticipation of it almost invariably results
in a panic attack in a person who is susceptible to them.
Persons with phobias, by definition, try to avoid the phobic stimulus; some go to great
trouble to avoid anxiety-provoking situations. For example, a patient with a phobia may
take a bus across the United States, rather than fly, to avoid contact with the object of
the patient’s phobia, an airplane. Perhaps as another way to avoid the stress of the
phobic stimulus, many patients have substance-related disorders, particularly alcohol
use disorders. Moreover, an estimated one-third of patients with social phobia have
major depressive disorder.
The major finding on the mental status examination is the presence of an irrational
and ego-dystonic fear of a specific situation, activity, or object; patients are able to
describe how they avoid contact with the phobia. Depression is commonly found on the
mental status examination and may be present in as many as one-third of all patients

with phobia.
Differential Diagnosis
Nonpsychiatric medical conditions that can result in the development of a phobia
include the use of substances (particularly hallucinogens and sympathomimetics), CNS
tumors, and cerebrovascular diseases. Phobic symptoms in these instances are unlikely
in the absence of additional suggestive findings on physical, neurological, and mental
status examinations. Schizophrenia is also in the differential diagnosis of specific phobia
because patients with schizophrenia can have phobic symptoms as part of their
psychoses. Unlike patients with schizophrenia, however, patients with phobia have
insight into the irrationality of their fears and lack the bizarre quality and other
psychotic symptoms that accompany schizophrenia.
In the differential diagnosis of specific phobia, clinicians must consider panic disorder,
agoraphobia, and avoidant personality disorder. Differentiation among panic disorder,
agoraphobia, social phobia, and specific phobia can be difficult in individual cases. In
general, however, patients with specific phobia tend to experience anxiety immediately
when presented with the phobic stimulus. Furthermore, the anxiety or panic is limited to
the identified situation; patients are not abnormally anxious when they are neither
confronted with the phobic stimulus nor caused to anticipate the stimulus.
Other diagnoses to consider in the differential diagnosis of specific phobia are
hypochondriasis, OCD, and paranoid personality disorder. Whereas hypochondriasis is
the fear of having a disease, specific phobia of the illness type is the fear of contracting
the disease. Some patients with OCD manifest behavior indistinguishable from that of a
patient with specific phobia. For example, whereas patients with OCD may avoid knives
because they have compulsive thoughts about killing their children, patients with
specific phobia about knives may avoid them for fear of cutting themselves. Patients
with paranoid personality disorder have generalized fear that distinguishes them from
those with specific phobia.
COURSE AND PROGNOSIS
Specific phobia exhibits a bimodal age of onset, with a childhood peak for animal
phobia, natural environment phobia, and blood-injection-injury phobia and an early
adulthood peak for other phobias, such as situational phobia. Limited prospective
epidemiological data are available that chart the natural course of specific phobia.
Because patients with isolated specific phobia rarely present for treatment, there is also
little research on the course of the disorder in the clinic. The limited information that is
available suggests that most specific phobias that begin in childhood and persist into
adulthood will continue to persist for many years. The severity of the condition is
believed to remain relatively constant, which contrasts with the waxing and waning
course seen in other anxiety disorders.

TREATMENT
Phobias
Behavior Therapy.
 The most studied and most effective treatment for phobias is
probably behavior therapy. The key aspects of successful treatment are (1) the patient’s
commitment to treatment; (2) clearly identified problems and objectives; and (3)
available alternative strategies for coping with the feelings. A variety of behavioral
treatment techniques have been used, the most common being systematic
desensitization, a method pioneered by Joseph Wolpe. In this method, the patient is
exposed serially to a predetermined list of anxiety-provoking stimuli graded in a
hierarchy from the least to the most frightening. Through the use of antianxiety drugs,
hypnosis, and instruction in muscle relaxation, patients are taught how to induce in
themselves both mental and physical repose. After they have mastered the techniques,
patients are taught to use them to induce relaxation in the face of each anxietyprovoking stimulus. As they become desensitized to each stimulus in the scale, the
patients move up to the next stimulus until, ultimately, what previously produced the
most anxiety no longer elicits the painful affect.
Other behavioral techniques that have been used more recently involve intensive
exposure to the phobic stimulus through either imagery or desensitization in vivo. In
imaginal flooding, patients are exposed to the phobic stimulus for as long as they can
tolerate the fear until they reach a point at which they can no longer feel it. Flooding
(also known as implosion) in vivo requires patients to experience similar anxiety
through exposure to the actual phobic stimulus.
Insight-Oriented Psychotherapy.
 Early in the development of psychoanalysis
and the dynamically oriented psychotherapies, theorists believed that these methods
were the treatments of choice for phobic neurosis, which was then thought to stem from
oedipal-genital conflicts. Soon, however, therapists recognized that, despite progress in
uncovering and analyzing unconscious conflicts, patients frequently failed to lose their
phobic symptoms. Moreover, by continuing to avoid phobic situations, patients excluded
a significant degree of anxiety and its related associations from the analytic process.
Both Freud and his pupil Sandor Ferenczi recognized that if progress in analyzing these
symptoms was to be made, therapists had to go beyond their analytic roles and actively
urge patients with phobia to seek the phobic situation and experience the anxiety and
resultant insight. Since then, psychiatrists have generally agreed that a measure of
activity on the therapist’s part is often required to treat phobic anxiety successfully. The
decision to apply the techniques of psychodynamic insight-oriented therapy should be
based not on the presence of phobic symptoms alone but on positive indications from
the patient’s ego structure and life patterns for the use of this method of treatment.
Insight-oriented therapy enables patients to understand the origin of the phobia, the
phenomenon of secondary gain, and the role of resistance and enables them to seek

healthy ways of dealing with anxiety-provoking stimuli.
Virtual Therapy.
 A number of computer-generated simulations of phobic disorders
have been developed. Patients are exposed to or interact with the phobic object or
situation on the computer screen. Countless numbers of such programs are available,
and others are in continual development. Variable success rates have been reported, but
virtual therapy for phobic disorder is on the cutting edge of using computers to treat
mental illness.
Other Therapeutic Modalities.
 Hypnosis, supportive therapy, and family
therapy may be useful in the treatment of phobic disorders. Hypnosis is used to enhance
the therapist’s suggestion that the phobic object is not dangerous, and self-hypnosis can
be taught to the patient as a method of relaxation when confronted with the phobic
object. Supportive psychotherapy and family therapy are often useful in helping the
patient actively confront the phobic object during treatment. Not only can family
therapy enlist the aid of the family in treating the patient, but it may also help the
family understand the nature of the patient’s problem.
Specific Phobia
A common treatment for specific phobia is exposure therapy. In this method, therapists
desensitize patients by using a series of gradual, self-paced exposures to the phobic
stimuli, and they teach patients various techniques to deal with anxiety, including
relaxation, breathing control, and cognitive approaches. The cognitive-behavioral
approaches include reinforcing the realization that the phobic situation is, in fact, safe.
The key aspects of successful behavior therapy are the patient’s commitment to
treatment, clearly identified problems and objectives, and alternative strategies for
coping with the patient’s feelings. In the special situation of blood-injection-injury
phobia, some therapists recommend that patients tense their bodies and remain seated
during the exposure to help avoid the possibility of fainting from a vasovagal reaction
to the phobic stimulation. β-adrenergic receptor antagonists may be useful in the
treatment of specific phobia, especially when the phobia is associated with panic
attacks. Pharmacotherapy (e.g., benzodiazepines), psychotherapy, or combined therapy
directed to the attacks may also be of benefit.
REFERENCES
Britton JC, Gold AL, Deckersbach T, Rauch SL. Functional MRI study of specific animal phobia using an event-related
emotional counting stroop paradigm. Depress Anxiety. 2009;26:796.
Coelho CM, Purkis H. The origins of specific phobias: Influential theories and current perspectives. Rev Gen Psychology.
2009;13:335.
Gamble AL, Harvey AG, Rapee RM. Specific phobia. In: Stein DJ, Hollander E, Rothbaum BO, eds. Textbook of Anxiety
Disorders. 2nd Edition. Arlington, VA: American Psychiatric Publishing; 2009:525.
Hamm AO. Specific phobias. Psychiatr Clin North Am. 2009;32(3):577.

# 05 - 9.5 Social Anxiety Disorder (Social Phobia)

# 9.5 Social Anxiety Disorder (Social Phobia)

Ipser JC, Singh L, Stein DJ. Meta-analysis of functional brain imaging in specific phobia. Psych Clin Neurosci. 2013;67:311.
Lipka J, Miltner WR, Straube T. Vigilance for threat interacts with amygdala responses to subliminal threat cues in specific
phobia. Biol Psychiatry. 2011;70:472.
McClure-Tone EB, Pine DS. Clinical features of the anxiety disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan &
Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009;1844.
McTeague LM, Lang PJ, Wangelin BC, Laplante MC, Bradley MM. Defensive mobilization in specific phobia: Fear
specificity, negative affectivity, and diagnostic prominence. Biol Psychiatry. 2012;72:8.
Podina˘a IR, Kosterb EHW, Philippotc P, Dethierc V, David DO. Optimal attentional focus during exposure in specific
phobia: A meta-analysis. Clin Psychol Rev. 2013;33:1172.
Price K, Veale D, Brewin CR. Intrusive imagery in people with a specific phobia of vomiting. J Behav Ther Exp Psychiatry.
2012;43:672.
Salas MM, Brooks AJ, Rowe JE. The immediate effect of a brief energy psychology intervention (Emotional Freedom
Techniques) on specific phobias: A pilot study. Exposure. 2011;7:155.
Simos G, Hofmann SG, Öst L-G, Reuterskiöld L. Specific phobias. In: Simos G, Hofmann SG, eds. CBT For Anxiety
Disorders: A Practitioner Book. Malden, MA: Wiley-Blackwell;2013:107.
Trumpf J, Margraf J, Vriends N, Meyer AH, Becker ES. Predictors of specific phobia in young women: A prospective
community study. J Anxiety Disord. 2010;24:87.
Van Houtm C, Laine M, BoomsmA D, Ligthart L, van Wijk A, De Jongh A. A review and meta-analysis of the heritability of
specific phobia subtypes and corresponding fears. J Anxiety Disord. 2013;27:379.
Waters AM, Bradley BP, Mogg K. Biased attention to threat in paediatric anxiety disorders (generalized anxiety disorder,
social phobia, specific phobia, separation anxiety disorder) as a function of ‘distress’ versus ‘fear’ diagnostic
categorization. Psychol Med. 2014;1–10.
Zimmerman M, Dalrymple K, Chelminski I, Young D, Galione JN. Recognition of irrationality of fear and the diagnosis of
social anxiety disorder and specific phobia in adults: Implications for criteria revision in DSM-5. Depress Anxiety.
2010;27:1044.
 9.5 Social Anxiety Disorder (Social Phobia)
Social anxiety disorder (also referred to as social phobia) involves the fear of social
situations, including situations that involve scrutiny or contact with strangers. The term
social anxiety reflects the distinct differentiation of social anxiety disorder from specific
phobia, which is the intense and persistent fear of an object or situation. Persons with
social anxiety disorder are fearful of embarrassing themselves in social situations (i.e.,
social gatherings, oral presentations, meeting new people). They may have specific
fears about performing specific activities such as eating or speaking in front of others,
or they may experience a vague, nonspecific fear of “embarrassing oneself.” In either
case, the fear in social anxiety disorder is of the embarrassment that may occur in the
situation, not of the situation itself.
EPIDEMIOLOGY
Various studies have reported a lifetime prevalence ranging from 3 to 13 percent for
social anxiety disorder. The 6-month prevalence is about 2 to 3 per 100 persons (Table

9.5-1). In epidemiological studies, females are affected more often than males, but in
clinical samples, the reverse is often true. The reasons for these varying observations are
unknown. The peak age of onset for social anxiety disorder is in the teens, although
onset is common as young as 5 years of age and as old as 35 years.
Table 9.5-1
Lifetime Prevalence Rates of Social Anxiety Disorder
COMORBIDITY
Persons with social anxiety disorder may have a history of other anxiety disorders, mood
disorders, substance-related disorders, and bulimia nervosa.
ETIOLOGY
Several studies have reported that some children possibly have a trait characterized by a
consistent pattern of behavioral inhibition. This trait may be particularly common in the
children of parents who are affected with panic disorder, and it may develop into severe
shyness as the children grow older. At least some persons with social anxiety disorder
may have exhibited behavioral inhibition during childhood. Perhaps associated with this
trait, which is thought to be biologically based, are the psychologically based data
indicating that the parents of persons with social anxiety disorder, as a group, were less
caring, more rejecting, and more overprotective of their children than were other
parents. Some social anxiety disorder research has referred to the spectrum from
dominance to submission observed in the animal kingdom. For example, whereas
dominant humans may tend to walk with their chins in the air and to make eye contact,
submissive humans may tend to walk with their chins down and to avoid eye contact.
Neurochemical Factors

The success of pharmacotherapies in treating social anxiety disorder has generated two
specific neurochemical hypotheses about two types of social anxiety disorder.
Specifically, the use of β-adrenergic receptor antagonists—for example, propranolol
(Inderal)—for performance phobias (e.g., public speaking) has led to the development
of an adrenergic theory for these phobias. Patients with performance phobias may
release more norepinephrine or epinephrine, both centrally and peripherally, than do
nonphobic persons, or such patients may be sensitive to a normal level of adrenergic
stimulation. The observation that MAOIs may be more effective than tricyclic drugs in
the treatment of generalized social anxiety disorder, in combination with preclinical
data, has led some investigators to hypothesize that dopaminergic activity is related to
the pathogenesis of the disorder. One study has shown significantly lower homovanillic
acid concentrations. Another study using SPECT demonstrated decreased striatal
dopamine reuptake site density. Thus, some evidence suggests dopaminergic dysfunction
in social anxiety disorder.
Genetic Factors
First-degree relatives of persons with social anxiety disorder are about three times more
likely to be affected with social anxiety disorder than are first-degree relatives of those
without mental disorders. And some preliminary data indicate that monozygotic twins
are more often concordant than are dizygotic twins, although in social anxiety disorder,
it is particularly important to study twins reared apart to help control for
environmental factors.
DIAGNOSIS AND CLINICAL FEATURES
The DSM-5 diagnostic criteria for social anxiety disorder is listed in Table 9.5-2. The
clinician should recognize that at least some degree of social anxiety or selfconsciousness is common in the general population. Community studies suggest that
roughly one-third of all persons consider themselves to be far more anxious than other
people in social situations. Moreover, such concerns may appear particularly heightened
during certain developmental stages, such as adolescence, or after life transitions, such
as marriage or occupation changes, associated with new demands for social interaction.
Such anxiety only becomes social anxiety disorder when the anxiety either prevents an
individual from participating in desired activities or causes marked distress during such
activities. DSM-5 also includes a performance only diagnostic specifier for persons who
have extreme social phobia specifically about speaking or performing in public.
Table 9.5-2
DSM-5 Diagnostic Criteria for Social Anxiety Disorder

Ms. B was a 29-year-old computer programmer who presented for treatment after
she was offered promotion to a managerial position at her firm. Although she wanted
the raise and the increased responsibility that would come with the new job, which
she had agreed to try on a probationary basis, Ms. B reported that she was reluctant
to accept the position because it required frequent interactions with employees from
other divisions of the company, as well as occasional public speaking. She stated that
she had always felt nervous around new people, whom she worried would ridicule her

for “saying stupid things” or committing social faux pas. She also reported feeling
“terrified” to speak before groups. These fears had not previously interfered with her
social life and job performance. However, since starting her probationary job, Ms. B
reported that they had become problematic. She noted that when she had to interact
with others, her heart started racing, her mouth became dry, and she felt sweaty. At
meetings, she had sudden thoughts that she would say something very foolish or
commit a terrible social gaffe that would cause people to laugh. As a consequence, she
had skipped several important meetings and left others early. (Courtesy of Erin B.
McClure-Tone, Ph.D., and Daniel S. Pine, M.D.)
DIFFERENTIAL DIAGNOSIS
Social anxiety disorder needs to be differentiated from appropriate fear and normal
shyness, respectively. Differential diagnostic considerations for social anxiety disorder
are agoraphobia, panic disorder, avoidant personality disorder, major depressive
disorder, and schizoid personality disorder. A patient with agoraphobia is often
comforted by the presence of another person in an anxiety-provoking situation, but a
patient with social anxiety disorder is made more anxious by the presence of other
people. Whereas breathlessness, dizziness, a sense of suffocation, and a fear of dying are
common in panic disorder and agoraphobia, the symptoms associated with social
anxiety disorder usually involve blushing, muscle twitching, and anxiety about scrutiny.
Differentiation between social anxiety disorder and avoidant personality disorder can be
difficult and can require extensive interviews and psychiatric histories.
The avoidance of social situations can often be a symptom in depression, but a
psychiatric interview with the patient is likely to elicit a broad constellation of
depressive symptoms. In patients with schizoid personality disorder, the lack of interest
in socializing, not the fear of socializing, leads to the avoidant social behavior.
COURSE AND PROGNOSIS
Social anxiety disorder tends to have its onset in late childhood or early adolescence.
Existing prospective epidemiological findings indicate that social anxiety disorder is
typically chronic, although patients whose symptoms do remit tend to stay well. Both
retrospective epidemiological studies and prospective clinical studies suggest that the
disorder can profoundly disrupt the life of an individual over many years. This can
include disruption in school or academic achievement and interference with job
performance and social development.
TREATMENT
Both psychotherapy and pharmacotherapy are useful in treating social anxiety disorder.
Some studies indicate that the use of both pharmacotherapy and psychotherapy
produces better results than either therapy alone, although the finding may not be

applicable to all situations and patients.
Effective drugs for the treatment of social anxiety disorder include (1) SSRIs, (2) the
benzodiazepines, (3) venlafaxine (Effexor), and (4) buspirone (BuSpar). Most clinicians
consider SSRIs the first-line treatment choice for patients with more generalized forms of
social anxiety disorder. The benzodiazepines alprazolam (Xanax) and clonazepam
(Klonopin) are also efficacious in social anxiety disorder. Buspirone has shown additive
effects when used to augment treatment with SSRIs.
In severe cases, successful treatment of social anxiety disorder with both irreversible
MAOIs such as phenelzine (Nardil) and reversible inhibitors of monoamine oxidase such
as moclobemide (Aurorix) and brofaromine (Consonar), which are not available in the
United States, has been reported. Therapeutic dosages of phenelzine range from 45 to
90 mg a day, with response rates ranging from 50 to 70 percent; approximately 5 to 6
weeks is needed to assess the efficacy.
The treatment of social anxiety disorder associated with performance situations
frequently involves the use of β-adrenergic receptor antagonists shortly before exposure
to a phobic stimulus. The two compounds most widely used are atenolol (Tenormin) 50
to 100 mg taken about 1 hour before the performance, or propranolol, 20 to 40 mg.
Another option to help with performance anxiety is a relatively short- or intermediateacting benzodiazepine, such as lorazepam or alprazolam. Cognitive, behavioral, and
exposure techniques are also useful in performance situations.
Psychotherapy for social anxiety disorder usually involves a combination of
behavioral and cognitive methods, including cognitive retraining, desensitization,
rehearsal during sessions, and a range of homework assignments.
REFERENCES
Baillie AJ, Sannibale C, Stapinski LA, Teesson M, Rapee RM, Haber PS. An investigator-blinded, randomized study to
compare the efficacy of combined CBT for alcohol use disorders and social anxiety disorder versus CBT focused on
alcohol alone in adults with comorbid disorders: The Combined Alcohol Social Phobia (CASP) trial protocol. BMC
Psychiatry. 2013;13:199.
Blanco C, Schneier FR, Vesga-Lopez O, Liebowitz MR. Pharmacotherapy for social anxiety disorder. In: Stein DJ, Hollander
E, Rothbaum BO, eds. Textbook of Anxiety Disorders. 2nd edition. Arlington, VA: American Psychiatric Publishing;
2009:471.
Doehrmann O, Ghosh SS, Polli FE, Reynolds GO, Horn F, Keshavan A, Triantafyllou C, Saygin ZM, Whitfield-Gabrieli S,
Hofmann SG, Pollack M, Gabriel JD. Treatment response in social anxiety disorder from functional magnetic resonance
imaging. JAMA Psych. 2013;70:87.
Essex MJ, Klein MH, Slattery MJ, Goldsmith HH, Kalin NH. Early risk factors and developmental pathways to chronic high
inhibition and social anxiety disorder in adolescence. Am J Psychiatry. 2010;167:40.
Goldin PR, Ziv M, Jazaieri H, Hahn K, Heimberg R, Gross JJ. Impact of cognitive behavioral therapy for social anxiety
disorder on the neural dynamics of cognitive reappraisal of negative self-beliefs: Randomized clinical trial. JAMA.
2013;70:1048.
Hofmann SG, Asnaani A, Hinton DE. Cultural aspects in social anxiety and social anxiety disorder. Depress Anxiety.
2010;27:1117.

# 06 - 9.6 Generalized Anxiety Disorder

# 9.6 Generalized Anxiety Disorder

Hofmann SG, DiBartolo PM. Social Anxiety: Clinical, Developmental, and Social Perspectives. 2nd edition. San Diego:
Academic Press; 2010.
Hofmann SG, Smits JAJ, Rosenfield D, Simon N, Otto MW, Meuret AE, Marques L, Fang A, Tart C, Pollack MH. DCycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. Am J Psych.
2013;170:751.
Leichsenring F, Salzer S, Beutel ME, Herpertz S. Psychodynamic therapy and cognitive-behavioral therapy in social anxiety
disorder: A multicenter randomized controlled trial. Am J Psych. 2013;170:759.
McClure-Tone EB, Pine DS. Clinical features of the anxiety disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan &
Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009:1844.
Morreale M, Tancer ME, Uhde TW. Pathogenesis of social anxiety disorder. In: Stein DJ, Hollander E, Rothbaum BO, eds.
Textbook of Anxiety Disorders. 2nd edition. Arlington, VA: American Psychiatric Publishing; 2009:453.
Penttinen H, Wahlström J. Progress in assimilation of problematic experience in group therapy for social phobia: A
subgroup analysis. J Contemp Psychother. 2013;43:123.
Pollack MH, Van Ameringen M, Simon NM, Worthington JW, Hoge EA, Keshaviah A, Stein, MB. A double-blind
randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry.
2014; 171(1):44–53.
Teo AR, Lerrigo R, Rogers MA. The role of social isolation in social anxiety disorder: A systematic review and metaanalysis. J Anxiety Disorders. 2013;27:353.
Yuen EK, Herbert JD, Forman EM, Goetter EM, Juarascio AS, Rabin S, Goodwin C, Bouchard S. Acceptance based behavior
therapy for social anxiety disorder through videoconferencing. J Anxiety Disorders. 2013;27:389.
 9.6 Generalized Anxiety Disorder
Anxiety can be conceptualized as a normal and adaptive response to threat that
prepares the organism for flight or fight. Persons who seem to be anxious about almost
everything, however, are likely to be classified as having generalized anxiety disorder.
Generalized anxiety disorder is defined as excessive anxiety and worry about several
events or activities for most days during at least a 6-month period. The worry is difficult
to control and is associated with somatic symptoms, such as muscle tension, irritability,
difficulty sleeping, and restlessness. The anxiety is not focused on features of another
disorder, is not caused by substance use or a general medical condition, and does not
occur only during a mood or psychiatric disorder. The anxiety is difficult to control, is
subjectively distressing, and produces impairment in important areas of a person’s life.
EPIDEMIOLOGY
Generalized anxiety disorder is a common condition; reasonable estimates for its 1-year
prevalence range from 3 to 8 percent. The ratio of women to men with the disorder is
about 2 to 1, but the ratio of women to men who are receiving inpatient treatment for
the disorder is about 1 to 1. A lifetime prevalence is close to 5 percent with the
Epidemiological Catchment Area (ECA) study suggesting a lifetime prevalence as high as
8 percent. In anxiety disorder clinics, about 25 percent of patients have generalized

anxiety disorder. The disorder usually has its onset in late adolescence or early
adulthood, although cases are commonly seen in older adults. Also, some evidence
suggests that the prevalence of generalized anxiety disorder is particularly high in
primary care settings.
COMORBIDITY
Generalized anxiety disorder is probably the disorder that most often coexists with
another mental disorder, usually social phobia, specific phobia, panic disorder, or a
depressive disorder. Perhaps 50 to 90 percent of patients with generalized anxiety
disorder have another mental disorder. As many as 25 percent of patients eventually
experience panic disorder. Generalized anxiety disorder is differentiated from panic
disorder by the absence of spontaneous panic attacks. An additional high percentage of
patients are likely to have major depressive disorder. Other common disorders
associated with generalized anxiety disorder are dysthymic disorder and substancerelated disorders.
ETIOLOGY
The cause of generalized anxiety disorder is not known. As currently defined,
generalized anxiety disorder probably affects a heterogeneous group of persons. Perhaps
because a certain degree of anxiety is normal and adaptive, differentiating normal
anxiety from pathological anxiety and differentiating biological causative factors from
psychosocial factors are difficult. Biological and psychological factors probably work
together.
Biological Factors
The therapeutic efficacies of benzodiazepines and the azaspirones (e.g., buspirone
[BuSpar]) have focused biological research efforts on the γ-aminobutyric acid and
serotonin 
neurotransmitter 
systems. 
Whereas 
benzodiazepines 
(which 
are
benzodiazepine receptor agonists) are known to reduce anxiety, flumazenil (Romazicon)
(a benzodiazepine receptor antagonist) and the β-carbolines (benzodiazepine receptor
reverse agonists) are known to induce anxiety. Although no convincing data indicate
that the benzodiazepine receptors are abnormal in patients with generalized anxiety
disorder, some researchers have focused on the occipital lobe, which has the highest
concentrations of benzodiazepine receptors in the brain. Other brain areas hypothesized
to be involved in generalized anxiety disorder are the basal ganglia, the limbic system,
and the frontal cortex. Because buspirone is an agonist at the serotonin 5-HT1A receptor,
there is the hypothesis that the regulation of the serotonergic system in generalized
anxiety disorder is abnormal. Other neurotransmitter systems that have been the subject
of research in generalized anxiety disorder include the norepinephrine, glutamate, and
cholecystokinin systems. Some evidence indicates that patients with generalized anxiety
disorder may have subsensitivity of their α2-adrenergic receptors, as indicated by a

blunted release of growth hormone after clonidine (Catapres) infusion.
Brain imaging studies of patients with generalized anxiety disorder have revealed
significant findings. One PET study reported a lower metabolic rate in basal ganglia and
white matter in patients with generalized anxiety disorder than in normal control
subjects. A few genetic studies have also been conducted in the field. One study found
that a genetic relation might exist between generalized anxiety disorder and major
depressive disorder in women. Another study showed a distinct, but difficult-toquantitate, genetic component in generalized anxiety disorder. About 25 percent of firstdegree relatives of patients with generalized anxiety disorder are also affected. Male
relatives are likely to have an alcohol use disorder. Some twin studies report a
concordance rate of 50 percent in monozygotic twins and 15 percent in dizygotic twins.
Table 9.6-1 lists relative genetic risks in selected anxiety disorders.
Table 9.6-1
Familial Relative Risks in Selected Anxiety Disorders
A variety of electroencephalogram (EEG) abnormalities has been noted in alpha
rhythm and evoked potentials. Sleep EEG studies have reported increased sleep
discontinuity, decreased delta sleep, decreased stage 1 sleep, and reduced rapid eye
movement sleep. These changes in sleep architecture differ from the changes seen in
depressive disorders.
Psychosocial Factors
The two major schools of thought about psychosocial factors leading to the development
of generalized anxiety disorder are the cognitive-behavioral school and the
psychoanalytic school. According to the cognitive-behavioral school, patients with
generalized anxiety disorder respond to incorrectly and inaccurately perceived dangers.
The inaccuracy is generated by selective attention to negative details in the
environment, by distortions in information processing, and by an overly negative view
of the person’s own ability to cope. The psychoanalytic school hypothesizes that anxiety
is a symptom of unresolved, unconscious conflicts. Sigmund Freud first presented this
psychological theory in 1909 with his description of Little Hans; before then, Freud had
conceptualized anxiety as having a physiological basis. An example of Freudian theory
as applied to general anxiety can be seen in the following case:

Mrs. B, a 26-year-old married woman, was admitted to the hospital for the
evaluation of persistent anxiety that had begun 8 months earlier and was becoming
increasingly disabling. Especially disturbing to the patient was the spontaneous
intrusion of intermittent images in her mind’s eye of her father and herself locked in a
naked sexual embrace. The images were not only frightening, but they puzzled her
greatly because she had always disliked her father intensely. Not only was he “poison”
to her, but she tried to avoid any contact with him and found it difficult to talk to him
if she was forced to be in his company.
As the patient described the difficulty of her relationship with her father, she
suddenly recalled that her anxiety had begun at a time when her father was seemingly
being more intrusive than ever as he tried to help her and her husband over a period
of financial difficulty.
As the patient continued to revile her father, she suddenly commented that her
mother had told her that her father “had been good to me when I was little and he
used to sing songs to me and take me on his lap, but I don’t remember. I only
remember when he was mean to me. I just am glad when he keeps on talking mean to
me the way he always has. I just wouldn’t know what to do if he was nice to me.”
When asked by the interviewer if there might have been a time when she had wanted
him to be nice to her, the patient replied, “When I was little, I just wanted to know
that he did love me a little. I guess I always wanted him to be nice to me. But when I
stop to think about it, I guess I didn’t want him to be nice to me.” The doctor then
commented, “It sounds as if a part of you wants to be close to your father.” In
response, the patient burst into agitated sobs and blurted out, “I don’t know how to be
close to my father! I am too old to care about my father now!”
When the patient regained her composure, she recalled the memory of an event she
had not thought of since it had occurred 15 years earlier. When she was 11 years old,
she reported, while in the living room with her father, she had suddenly had the
mental image of being in a sexual embrace with him. Terrified, she had run into the
kitchen to find her mother. There had been no recurrence of that image until the onset
of the current illness, and the incident had remained forgotten until its recall during
the interview. Its emergence into consciousness amplified the history of the patient’s
illness and disclosed an earlier transient outbreak of the same symptoms she had
experienced as an adult. After the patient had recovered her composure, she recalled
further hitherto forgotten memories. She had slept in her parents’ bedroom until she
was 6, during which period her father, on one occasion, had taken her into bed and
told her stories and, on another, had yelled at her very angrily as she lay in her crib.
During a clinical interview the next day, the patient revealed a fact that she had
forgotten in her earlier account of her illness: At the end of the period during which
her father had been making the friendly overtures that had so deeply troubled her,
and the night before the sudden onset of her symptoms, she had had a nightmare. She
was, she dreamed, at a zoo. It was night, and she heard strange noises in the
darkness. She asked an attendant standing next to her what the noises were. “Oh,” the

attendant replied casually, “that’s only the animals mating.” She then noticed a large,
gray elephant lying on its right side in the grass in front of her. As she watched, she
noticed the creature moving its left hind leg up and down as if it were trying to get to
its feet. At that point she awoke from the dream with a feeling of terror and,
afterward, during the morning, experienced the first episode of the frightening
imagery of sexual activity with her father.
In direct association to the dream, the patient recalled a long-forgotten childhood
memory of an incident that had occurred during her fourth or fifth year. She had
awoken one night while in her crib in her parents’ bedroom to observe her parents
having sexual intercourse. They suddenly became aware of her watching them and
sprang apart. The patient remembered seeing her mother hastily pulling up the
bedclothes around her to cover her nakedness. Her father, meanwhile, rolled over half
on his back, half on his left side. The patient noticed his erection and then saw him lift
up his left leg as he sat up and yelled at her angrily to go to sleep.
It was not easy for the patient to communicate these memories. She spoke haltingly
in a low voice and was visibly ashamed and anxious throughout the whole recital of
the dream and its associations. She discharged a great quantity of affect, but after
doing so, appeared considerably relaxed, relieved, and composed. On her return to
the psychiatric ward, she was observed to be cheerful and outgoing with the ward
personnel and other patients. Of particular note was that she no longer experienced
any anxiety and had no recurrence of the sexual images involving her father that had
previously been so deeply distressing. The patient was discharged a short while later
after a further series of psychotherapeutic interviews, and when seen for a follow-up
visit 2 months later, she reported continued emotional calm and comfort, without
recurrence of psychiatric symptoms.
DIAGNOSIS
Generalized anxiety disorder is characterized by a pattern of frequent, persistent worry
and anxiety that is out of proportion to the impact of the event or circumstance that is
the focus of the worry. The distinction between generalized anxiety disorder and normal
anxiety is emphasized by the use of the word “excessive” in the criteria and by the
specification that the symptoms cause significant impairment or distress. DSM-5
diagnostic criteria for generalized anxiety disorder are listed in Table 9.6-2.
Table 9.6-2
DSM-5 Diagnostic Criteria for Generalized Anxiety Disorder

CLINICAL FEATURES
The essential characteristics of generalized anxiety disorder are sustained and excessive
anxiety and worry accompanied by either motor tension or restlessness. The anxiety is
excessive and interferes with other aspects of a person’s life. This pattern must occur
more days than not for at least 3 months. The motor tension is most commonly
manifested as shakiness, restlessness, and headaches.
Patients with generalized anxiety disorder usually seek out a general practitioner or
internist for help with a somatic symptom. Alternatively, the patients go to a specialist
for a specific symptom (e.g., chronic diarrhea). A specific nonpsychiatric medical
disorder is rarely found, and patients vary in their doctor-seeking behavior. Some
patients accept a diagnosis of generalized anxiety disorder and the appropriate

treatment; others seek additional medical consultations for their problems.
Mr. G was a successful, married, 28-year-old teacher who presented for a psychiatric
evaluation to treat mounting symptoms of worry and anxiety. Mr. G noted that for
the preceding year, he had become more and more worried about his job
performance. For example, although he had always been a respected and popular
lecturer, he found himself worrying more and more about his ability to engage
students and convey material effectively. Similarly, although he had always been
financially secure, he increasingly worried that he was going to lose his wealth due to
unexpected expenses. Mr. G noted frequent somatic symptoms that accompanied his
worries. For example, he often felt tense and irritable while he worked and spent time
with his family, and he had difficulty distracting himself from worries about the
upcoming challenges for the next day. He reported feeling increasingly restless,
especially at night, when his worries kept him from falling asleep. (Courtesy of Erin
B. McClure-Tone, Ph.D., and Daniel S. Pine, M.D.)
DIFFERENTIAL DIAGNOSIS
As with other anxiety disorders, generalized anxiety disorder must be differentiated from
both medical and psychiatric disorders. Neurological, endocrinological, metabolic, and
medication-related disorders similar to those considered in the differential diagnosis of
panic disorder must be considered in the differential diagnosis of generalized anxiety
disorder. Common co-occurring anxiety disorders also must be considered, including
panic disorder, phobias, OCD, and PTSD. To meet criteria for generalized anxiety
disorder, patients must both exhibit the full syndrome, and their symptoms also cannot
be explained by the presence of a comorbid anxiety disorder. To diagnose generalized
anxiety disorder in the context of other anxiety disorders, it is most important to
document anxiety or worry related to circumstances or topics that are either unrelated,
or only minimally related, to other disorders. Proper diagnosis involves both definitively
establishing the presence of generalized anxiety disorder and properly diagnosing other
anxiety disorders. Patients with generalized anxiety disorder frequently develop major
depressive disorder. As a result, this condition must also be recognized and
distinguished. The key to making a correct diagnosis is documenting anxiety or worry
that is unrelated to the depressive disorder.
COURSE AND PROGNOSIS
The age of onset is difficult to specify; most patients with the disorder report that they
have been anxious for as long as they can remember. Patients usually come to a
clinician’s attention in their 20s, although the first contact with a clinician can occur at
virtually any age. Only one-third of patients who have generalized anxiety disorder seek
psychiatric treatment. Many go to general practitioners, internists, cardiologists,

pulmonary specialists, or gastroenterologists, seeking treatment for the somatic
component of the disorder. Because of the high incidence of comorbid mental disorders
in patients with generalized anxiety disorder, the clinical course and prognosis of the
disorder are difficult to predict. Nonetheless, some data indicate that life events are
associated with the onset of generalized anxiety disorder: The occurrence of several
negative life events greatly increases the likelihood that the disorder will develop. By
definition, generalized anxiety disorder is a chronic condition that may well be lifelong.
TREATMENT
The most effective treatment of generalized anxiety disorder is probably one that
combines psychotherapeutic, pharmacotherapeutic, and supportive approaches. The
treatment may take a significant amount of time for the involved clinician, whether the
clinician is a psychiatrist, a family practitioner, or another specialist.
Psychotherapy
The major psychotherapeutic approaches to generalized anxiety disorder are cognitivebehavioral, supportive, and insight oriented. Data are still limited on the relative merits
of those approaches, although the most sophisticated studies have examined cognitivebehavioral techniques, which seem to have both short-term and long-term efficacy.
Cognitive approaches address patients’ hypothesized cognitive distortions directly, and
behavioral approaches address somatic symptoms directly. The major techniques used in
behavioral approaches are relaxation and biofeedback. Some preliminary data indicate
that the combination of cognitive and behavioral approaches is more effective than
either technique used alone. Supportive therapy offers patients reassurance and comfort,
although its long-term efficacy is doubtful. Insight-oriented psychotherapy focuses on
uncovering unconscious conflicts and identifying ego strengths. The efficacy of insightoriented psychotherapy for generalized anxiety disorder is found in many anecdotal
case reports, but large controlled studies are lacking.
Most patients experience a marked lessening of anxiety when given the opportunity
to discuss their difficulties with a concerned and sympathetic physician. If clinicians
discover external situations that are anxiety provoking, they may be able—alone or
with the help of the patients or their families—to change the environment and thus
reduce the stressful pressures. A reduction in symptoms often allows patients to function
effectively in their daily work and relationships and thus gain new rewards and
gratification that are themselves therapeutic.
In the psychoanalytic perspective, anxiety sometimes signals unconscious turmoil that
deserves investigation. The anxiety can be normal, adaptive, maladaptive, too intense,
or too mild, depending on the circumstances. Anxiety appears in numerous situations
over the course of the life cycle; in many cases, symptom relief is not the most
appropriate course of action.
For patients who are psychologically minded and motivated to understand the sources
of their anxiety, psychotherapy may be the treatment of choice. Psychodynamic therapy

proceeds with the assumption that anxiety can increase with effective treatment. The
goal of the dynamic approach may be to increase the patient’s anxiety tolerance (a
capacity to experience anxiety without having to discharge it), rather than to eliminate
anxiety. Empirical research indicates that many patients who have successful
psychotherapeutic treatment may continue to experience anxiety after termination of
the psychotherapy, but their increased ego mastery allows them to use the anxiety
symptoms as a signal to reflect on internal struggles and to expand their insight and
understanding. A psychodynamic approach to patients with generalized anxiety disorder
involves a search for the patient’s underlying fears.
B, a 28-year-old man with a history of a generalized anxiety disorder, was a former
adolescent alcohol abuser now involved in Alcoholics Anonymous (AA). Because of
sexual side effects, he was unwilling to take SSRI antidepressants, buspirone (BuSpar)
had been ineffective, and gabapentin (Neurontin) was too sedating. Clonazepam
(Klonopin) was effective, but B’s continued participation in AA led to pressures from
AA peers to give up benzodiazepines. Partly because of these pressures, B sought
psychodynamic therapy with a psychiatrist. When the psychiatrist suggested that he
begin tapering clonazepam, B balked, worried that he would become more anxious.
The therapist suggested that it might be useful to bring his anxiety to sessions if their
task really was going to be to learn more about his anxiety.
On a tapering dose of clonazepam B’s anxiety increased. He complained that his
male therapist was unempathic, making B suffer with anxiety while the therapist
watched and did nothing. As the treatment unfolded, the therapist learned B had been
especially close to his mother, who, with B, had been the target of criticism from his
often absent, short-tempered, mean-spirited alcoholic father. B’s mother had surgery
and chemotherapy for breast cancer when B was 10 years old. It was shortly after this
that B’s anxiety symptoms began.
When clonazepam was discontinued, there was an outburst of anger at the therapist
for making B suffer so much. The therapist quietly accepted B’s anger at him, noting
that he had asked B to endure more anxiety, while leaving him alone and on his own
most of the week. When he suggested that B had found in the therapist his absent and
sadistic father, B thought this made sense, and he began to trust the therapist more. B
said he realized that the therapist could endure and understand his anger without
needing to retaliate and that he was sticking to a treatment plan they had agreed to
from the outset. As the alliance deepened, B struggled to put words to his experience
of anxiety. B spoke more of his attachment to his mother and to the way he would
cling to her to support her, pressing himself against her ample bosom, while his father
would rage at them both while drunk, sometimes suggesting that B’s clinging to her
was unnatural and inspired by lust.
B reported a dream in one session in which he watched passively, frozen with fear
and guilt and unable to move, as a man murdered and dismembered a naked woman.
B’s associations to the dream led to painful memories of his mother’s disfiguring

surgery and to his guilt about not having been able to stop his father from angrily
criticizing her both before and after the surgery. B then added there was another part
of the dream he had left out because of shame. He had been sexually aroused during
the dream. B suddenly reported an intrusive thought that upset him—a thought that
the breast cancer had come because he had been unable to protect his mother—and
because he had been aroused by her breasts. B wept for the first time in the therapy.
Over time the therapist and patient explored the dream and his intrusive thoughts,
learning that B felt guilty about having caused his mother’s illness and disfiguring
surgery not only because he could not protect her from father’s rages but also because
he felt guilty and ashamed about his attraction to his mother’s breasts. He spoke of the
way his father’s drunken accusation of lust toward his mother was right. He feared,
too, that he would be disfigured because of a disease or accident, perhaps by
castration, for what he had done to his mother. It was not easy for B to explore these
feelings, but as he did, his anxiety diminished. (Courtesy of Eric M. Plakun, M.D.)
Pharmacotherapy
The decision to prescribe an anxiolytic to patients with generalized anxiety disorder
should rarely be made on the first visit. Because of the long-term nature of the disorder,
a treatment plan must be carefully thought out. The three major drugs to be considered
for the treatment of generalized anxiety disorder are benzodiazepines, the SSRIs,
buspirone (BuSpar), and venlafaxine (Effexor). Other drugs that may be useful are the
tricyclic drugs (e.g., imipramine [Tofranil]), antihistamines, and the β-adrenergic
antagonists (e.g., propranolol [Inderal]) (Table 9.6-3).
Table 9.6-3
Common Medications for the Treatment of Recurrent Anxiety

Although drug treatment of generalized anxiety disorder is sometimes seen as a 6- to
12-month treatment, some evidence indicates that treatment should be long term,
perhaps lifelong. About 25 percent of patients relapse in the first month after the
discontinuation of therapy, and 60 to 80 percent relapse over the course of the next
year. Although some patients become dependent on the benzodiazepines, tolerance
rarely develops to the therapeutic effects of the benzodiazepines, buspirone,
venlafaxine, or the SSRIs.
Benzodiazepines.
 Benzodiazepines have been the drugs of choice for generalized
anxiety disorder. They can be prescribed on an as-needed basis, so that patients take a
rapidly acting benzodiazepine when they feel particularly anxious. The alternative
approach is to prescribe benzodiazepines for a limited period, during which psychosocial
therapeutic approaches are implemented.
Several problems are associated with the use of benzodiazepines in generalized
anxiety disorder. About 25 to 30 percent of all patients fail to respond, and tolerance

and dependence can occur. Some patients also experience impaired alertness while
taking the drugs and therefore are at risk for accidents involving automobiles and
machinery.
The clinical decision to initiate treatment with a benzodiazepine should be considered
and specific. The patient’s diagnosis, the specific target symptoms, and the duration of
treatment should all be defined, and the information should be shared with the patient.
Treatment for most anxiety conditions lasts for 2 to 6 weeks followed by 1 or 2 weeks of
tapering drug use before it is discontinued. The most common clinical mistake with
benzodiazepine treatment is to continue treatment indefinitely.
For the treatment of anxiety, it is usual to begin giving a drug at the low end of its
therapeutic range and to increase the dosage to achieve a therapeutic response. The use
of a benzodiazepine with an intermediate half-life (8 to 15 hours) will likely avoid some
of the adverse effects associated with the use of benzodiazepines with long half-lives,
and the use of divided doses prevents the development of adverse effects associated with
high peak plasma levels. The improvement produced by benzodiazepines may go
beyond a simple antianxiety effect. For example, the drugs may cause patients to regard
various occurrences in a positive light. The drugs can also have a mild disinhibiting
action, similar to that observed after ingesting modest amounts of alcohol.
Buspirone.
 Buspirone is a 5-HT1A receptor partial agonist and is most likely
effective in 60 to 80 percent of patients with generalized anxiety disorder. Data indicate
that buspirone is more effective in reducing the cognitive symptoms of generalized
anxiety disorder than in reducing the somatic symptoms. Evidence also indicates that
patients who have previously had treatment with benzodiazepines are not likely to
respond to treatment with buspirone. The lack of response may be caused by the
absence, with buspirone treatment, of some of the nonanxiolytic effects of
benzodiazepines (e.g., muscle relaxation and the additional sense of well-being). The
major disadvantage of buspirone is that its effects take 2 to 3 weeks to become evident,
in contrast to the almost immediate anxiolytic effects of the benzodiazepines. One
approach is to initiate benzodiazepine and buspirone use simultaneously and then taper
off the benzodiazepine use after 2 to 3 weeks, at which point the buspirone should have
reached its maximal effects. Some studies have also reported that long-term combined
treatment with benzodiazepine and buspirone may be more effective than either drug
alone. Buspirone is not an effective treatment for benzodiazepine withdrawal.
Venlafaxine.
 Venlafaxine is effective in treating the insomnia, poor concentration,
restlessness, irritability, and excessive muscle tension associated with generalized
anxiety disorder. Venlafaxine is a nonselective inhibitor of the reuptake of three
biogenic amines—serotonin; norepinephrine; and, to a lesser extent, dopamine.
Selective Serotonin Reuptake Inhibitors.
 SSRIs may be effective, especially
for patients with comorbid depression. The prominent disadvantage of SSRIs, especially

fluoxetine (Prozac), is that they can transiently increase anxiety and cause agitated
states. For this reason, the SSRIs sertraline (Zoloft), citalopram (Celexa), or paroxetine
(Paxil) are better choices in patients with high anxiety disorder. It is reasonable to begin
treatment with sertraline, citalopram, or paroxetine plus a benzodiazepine and then to
taper benzodiazepine use after 2 to 3 weeks. Further studies are needed to determine
whether SSRIs are as effective for generalized anxiety disorder as they are for panic
disorder and OCD.
Other Drugs.
 If conventional pharmacological treatment (e.g., with buspirone or a
benzodiazepine) is ineffective or not completely effective, then a clinical reassessment is
indicated to rule out comorbid conditions, such as depression, or to better understand
the patient’s environmental stresses. Other drugs that have proved useful for generalized
anxiety disorder include the tricyclic and tetracyclic drugs. The β-adrenergic receptor
antagonists may reduce the somatic manifestations of anxiety but not the underlying
condition, and their use is usually limited to situational anxieties, such as performance
anxiety.
REFERENCES
Cuijpers, P., Sijbrandij, M., Koole, S., Huibers, M., Berking, M., & Andersson, G. Psychological treatment of generalized
anxiety disorder: A meta-analysis. Clin Psychol Rev. 2014.
Etkin A, Prater KE, Hoeft F, Menon V, Schatzberg AF. Failure of anterior cingulate activation and connectivity with the
amygdala during implicit regulation of emotional processing in generalized anxiety disorder. Am J Psychiatry.
2010;167:545.
Goodwin RD, Stein DJ. Anxiety disorders and drug dependence: Evidence on sequence and specificity among adults. Psych
Clin Neurosci. 2013;67:167.
Hill N, Joubert L, Epstein I. Encouraging self-management in chronically ill patients with comorbid symptoms of
depression and anxiety: An emergency department study and response. Soc Work Health Care. 2013;52:207.
Lenze EJ, Mantella RC, Shi P, Goate AM, Nowotny P, Butters MA, Andreescu C, Thompson PA, Rollman BL. Elevated
cortisol in older adults with generalized anxiety disorder is reduced by treatment: A placebo-controlled evaluation of
escitalopram. Am J Geriatric Psychiatry. 2011;19:482.
Lorenz RA, Jackson CW, Saltz M. Adjunctive use of atypical antipsychotics for treatment-resistant generalized anxiety
disorder. Pharmacotherapy. 2010;30:942.
Maslowsky J, Mogg K, Bradley BP, McClure-Tone E, Ernst M, Pine DS, Monk CS. A preliminary investigation of neural
correlates of treatment in adolescents with generalized anxiety disorder. J Child Adolescent Psychcopharm. 2010;20:105.
McClure-Tone EB, Pine DS. Clinical features of the anxiety disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan &
Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009:1844.
Newman MG, Castonguay LG, Borkovec TD, Fisher AJ, Boswell JF, Szkodny LE, Nordberg SS. A randomized controlled trial
of cognitive-behavioral therapy for generalized anxiety disorder with integrated techniques from emotion-focused and
interpersonal therapies. J Consult Clin Psychol. 2011;79:171.
Newman MG, Przeworski A, Fisher AJ, Borkovec TD. Diagnostic comorbidity in adults with generalized anxiety disorder:
Impact of comorbidity on psychotherapy outcome and impact of psychotherapy on comorbid diagnoses. Behav Ther.
2010;41:59.
Ouimet AJ, Covin R, Dozois DJA. Generalized anxiety disorder. In: Sturmey P, Hersen M, eds. Handbook of Evidence-Based

# 07 - 9.7 Other Anxiety Disorders

# 9.7 Other Anxiety Disorders

Practice in Clinical Psychology. Vol 2: Adult Disorders. Hoboken: John Wiley & Sons; 2012:651.
Ritter MR, Blackmore MA, Heimberg RG. Generalized anxiety disorder. In: McKay D, Abramowitz JS, Taylor S, eds.
Cognitive Behavioral Therapy for Refractory Cases: Turing Failure Into Success. Washington, DC: American Psychological
Association; 2010.
Uebelacker L, Weisberg R, Millman M, Yen S, Keller M. Prospective study on risk factors for suicidal behavior in
individuals with anxiety disorders. Psychol Med. 2013;43:1465.
 9.7 Other Anxiety Disorders
ANXIETY DISORDER ATTRIBUTABLE TO ANOTHER MEDICAL
CONDITION
Many medical disorders are associated with anxiety. Symptoms can include panic
attacks, generalized anxiety, and other signs of distress. In all cases, the signs and
symptoms will be due to the direct physiological effects of the medical condition.
Epidemiology
The occurrence of anxiety symptoms related to general medical conditions is common,
although the incidence of the disorder varies for each specific general medical condition.
Etiology
A wide range of medical conditions can cause symptoms similar to those of anxiety
disorders (Table 9.7-1). Hyperthyroidism, hypothyroidism, hypoparathyroidism, and
vitamin B12 deficiency are frequently associated with anxiety symptoms. A
pheochromocytoma produces epinephrine, which can cause paroxysmal episodes of
anxiety symptoms. Other medical conditions, such as cardiac arrhythmia, can produce
physiological symptoms of panic disorder. Hypoglycemia can also mimic the symptoms
of an anxiety disorder. The diverse medical conditions that can cause symptoms of
anxiety disorder may do so through a common mechanism that involves both the
noradrenergic system and the serotonergic system. Each of these conditions is
characterized by prominent anxiety that arises as the direct result of some underlying
physiological perturbation.
Table 9.7-1
Disorders Associated with Anxiety

Diagnosis
The diagnosis of anxiety disorder attributable to another medical condition requires the
presence of symptoms of an anxiety disorder caused by one or more medical illnesses.
The DSM-5 suggests that clinicians to specify whether the disorder is characterized by
symptoms of generalized anxiety or panic attacks.
Clinicians should have an increased level of suspicion for the diagnosis when chronic
or paroxysmal anxiety is associated with a physical disease known to cause such
symptoms in some patients. Paroxysmal bouts of hypertension in an anxious patient
may indicate that a workup for a pheochromocytoma is appropriate. A general medical
workup may reveal diabetes, an adrenal tumor, thyroid disease, or a neurological
condition. For example, some patients with complex partial epilepsy have extreme

episodes of anxiety or fear as their only manifestation of the epileptic activity.
Clinical Features
The symptoms of anxiety disorder due to a general medical condition can be identical to
those of the primary anxiety disorders. A syndrome similar to panic disorder is the most
common clinical picture, and a syndrome similar to a phobia is the least common.
Panic Attacks.
 Patients who have cardiomyopathy may have the highest incidence
of panic disorder secondary to a general medical condition. One study reported that 83
percent of patients with cardiomyopathy awaiting cardiac transplantation had panic
disorder symptoms. Increased noradrenergic tone in these patients may be the
provoking stimulus for the panic attacks. In some studies, about 25 percent of patients
with Parkinson’s disease and chronic obstructive pulmonary disease have symptoms of
panic disorder. Other medical disorders associated with panic disorder include chronic
pain, primary biliary cirrhosis, and epilepsy, particularly when the focus is in the right
parahippocampal gyrus.
Generalized Anxiety.
 A high prevalence of generalized anxiety disorder
symptoms has been reported in patients with Sjögren’s syndrome, and this rate may be
related to the effects of Sjögren’s syndrome on cortical and subcortical functions and
thyroid function. The highest prevalence of generalized anxiety disorder symptoms in a
medical disorder seems to be in Graves’ disease (hyperthyroidism), in which as many as
two-thirds of all patients meet the criteria for generalized anxiety disorder.
A 86-year-old retired chemical engineer sought help for the onset of a series of
attacks over the preceding 4 months in which he experienced marked apprehension,
restlessness, a sense that the “walls were caving in,” and the need to “get air” to
relieve his sense of discomfort. These events typically occurred during the night and
awakened him from sound sleep. To feel better, he would need to stick his head out of
an open window, regardless of how cold it was outside. His symptoms would
gradually improve over 15 to 20 minutes, but complete resolution of these symptoms
took a full day. In response to pointed questioning, the patient reported sweating,
dizziness, and shortness of breath during these episodes. He imagined that he would
die if he could not open the window. He denied palpitations, choking sensations,
paresthesia, and nausea. The patient recalled a similar series of attacks almost 30
years earlier during a period of time in which he frequently needed to travel and
hence was away from home because of work obligations. The patient denied
depressed mood, anhedonia, recent sleep dysfunctions, change in appetite or weight,
decreased energy, and feelings of worthlessness. His medical history was notable for a
right basal ganglia stroke 6 months earlier. He had a history of hypertension,
borderline diabetes, and benign prostatic hypertrophy. Laboratory study results were
unremarkable.

A diagnosis of anxiety disorder due to stroke, with panic attacks, was made. The
patient was prescribed alprazolam (Xanax), 0.5 mg orally twice a day as needed for
panic attacks, and started on escitalopram (Lexapro), 10 mg per day. At a follow-up
visit, the patient reported complete resolution of his anxiety symptoms. He remained
taking the escitalopram but no longer required the alprazolam. (Courtesy of LL
Lavery, M.D., and EM Whyte, M.D.)
Phobias.
 Symptoms of phobias appear to be uncommon, although one study
reported a 17 percent prevalence of symptoms of social phobia in patients with
Parkinson’s disease. Older persons with balance difficulties often complain of a fear of
falling, which may express itself by their being unwilling or fearful of walking.
Laboratory Examination
A targeted work-up is required when an anxiety disorder due to another medical
condition is being considered as part of the differential diagnosis. If possible, tests
should be selected to rule in specific diagnoses suggested by the patient’s somatic
symptoms (if present).
Test to consider include complete book count, electrolytes, glucose, blood urea
nitrogen, creatinine, liver function tests, calcium, magnesium, phosphorus, thyroid
function tests, and urine toxicology. Occasionally, additional studies may be indicated to
rule out a pheochromocytoma (e.g., urinary catecholamines), a seizure disorder (e.g.,
EEG), cardiac arrhythmia (e.g., Holter monitoring), and pulmonary disease (pulse
oximetry, arterial blood gases). Brain imaging may be useful in ruling out
demyelinating disorder, tumor, stroke, or hydrocephalus and is especially important if
the anxious individual reports neurological symptoms (e.g., headache, motor or sensory
changes, and dizziness), although such complaints may represent somatic manifestations
of primary anxiety disorders. Lumbar puncture may be appropriate if an inflammatory
or infectious cause is suspected.
Differential Diagnosis
Anxiety, as a symptom, can be associated with many psychiatric disorders in addition to
the anxiety disorders themselves. A mental status examination is necessary to determine
the presence of mood symptoms or psychotic symptoms that may suggest another
psychiatric diagnosis. For a clinician to conclude that a patient has an anxiety disorder
caused by a general medical condition, the patient should clearly have anxiety as the
predominant symptom and should have a specific causative nonpsychiatric medical
disorder. To ascertain the degree to which a general medical condition is causative for
the anxiety, the clinician should evaluate the timeline between the medical condition
and the anxiety symptoms, the age of onset (primary anxiety disorders usually have
their onset before age 35 years), and the patient’s family history of both anxiety
disorders and relevant general medical conditions (e.g., hyperthyroidism). A diagnosis

of adjustment disorder with anxiety must also be considered in the differential diagnosis.
Course and Prognosis
The unremitting experience of anxiety can be disabling and can interfere with every
aspect of life, including social, occupational, and psychological functioning. A sudden
increase in anxiety level may prompt an affected person to seek medical or psychiatric
help more quickly than when the onset is insidious. The treatment or the removal of the
primary medical cause of the anxiety usually initiates a clear course of improvement in
the anxiety disorder symptoms. In some cases, however, the anxiety disorder symptoms
continue even after the primary medical condition is treated (e.g., after an episode of
encephalitis). Some symptoms linger for a longer time than other anxiety disorder
symptoms. When anxiety disorder symptoms are present for a significant period after
the medical disorder has been treated, the remaining symptoms should probably be
treated as if they were primary—that is, with psychotherapy, pharmacotherapy, or both.
Treatment
The primary treatment for anxiety disorder due to a general medical condition is to
treat the underlying medical condition. If a patient also has an alcohol or other
substance use disorder, this disorder must also be addressed therapeutically to gain
control of the anxiety disorder symptoms. If the removal of the primary medical
condition does not reverse the anxiety disorder symptoms, treatment of these symptoms
should follow the treatment guidelines for the specific mental disorder. In general,
behavioral modification techniques, anxiolytic agents, and serotonergic antidepressants
have been the most effective treatment modalities.
SUBSTANCE-INDUCED ANXIETY DISORDER
Substance-induced disorder is the direct result of a toxic substance, including drugs of
abuse, medication, poison, and alcohol, among others.
Epidemiology
Substance-induced anxiety disorder is common, both as the result of the ingestion of socalled recreational drugs and as the result of prescription drug use.
Etiology
A wide range of substances can cause symptoms of anxiety that can mimic any of the
DSM-5 anxiety disorders. Although sympathomimetics, such as amphetamine, cocaine,
and caffeine, have been most associated with the production of anxiety disorder
symptoms, many serotonergic drugs (e.g., LSD and MDMA) can also cause both acute
and chronic anxiety syndromes in users. A wide range of prescription medications is also
associated with the production of anxiety disorder symptoms in susceptible persons.

Diagnosis
The diagnostic criteria for substance-induced anxiety disorder require the presence of
prominent anxiety or panic attacks. The DSM-5 guidelines state that the symptoms
should have developed during the use of the substance or within 1 month of the
cessation of substance use; however, clinicians may have difficulty determining the
relation between substance exposure and anxiety symptoms. The structure of the
diagnosis includes specification of (1) the substance (e.g., cocaine), (2) the appropriate
state during the onset (e.g., intoxication), and (3) the specific symptom pattern (e.g.,
panic attacks).
Clinical Features
The associated clinical features of substance-induced anxiety disorder vary with the
particular substance involved. Even infrequent use of psychostimulants can result in
anxiety disorder symptoms in some persons. Cognitive impairments in comprehension,
calculation, and memory can be associated with anxiety disorder symptoms. These
cognitive deficits are usually reversible when the substance use is stopped.
Virtually everyone who drinks alcohol, on at least a few occasions, has used it to
reduce anxiety, most often social anxiety. In contrast, carefully controlled studies have
found that the effects of alcohol on anxiety are variable and can be significantly
affected by gender, the amount of alcohol ingested, and cultural attitudes. Nevertheless,
alcohol use disorders and other substance-related disorders are commonly associated
with anxiety disorders. Alcohol use disorders are about four times more common among
patients with panic disorder than among the general population and about two and a
half times more common among patients with phobias. Several studies have reported
data indicating that genetic diatheses for both anxiety disorders and alcohol use
disorders can exist in some families.
Differential Diagnosis
The differential diagnosis for substance-induced anxiety disorder includes the primary
anxiety disorders; anxiety disorder due to a general medical condition (for which the
patient may be receiving an implicated drug); and mood disorders, which are frequently
accompanied by symptoms of anxiety disorders. Personality disorders and malingering
must be considered in the differential diagnosis, particularly in some urban emergency
departments.
Course and Prognosis
The course and prognosis generally depend on removal of the causally involved
substance and the long-term ability of the affected person to limit use of the substance.
The anxiogenic effects of most drugs are reversible. When the anxiety does not reverse
with cessation of the drug, clinicians should reconsider the diagnosis of substance-

induced anxiety disorder or consider the possibility that the substance caused irreversible
brain damage.
Treatment
The primary treatment for substance-induced anxiety disorder is the removal of the
causally involved substance. Treatment then must focus on finding an alternative
treatment if the substance was a medically indicated drug, on limiting the patient’s
exposure if the substance was introduced through environmental exposure, or on
treating the underlying substance-related disorder. If anxiety disorder symptoms
continue even after stopping substance use, treatment of the anxiety disorder symptoms
with appropriate psychotherapeutic or pharmacotherapeutic modalities may be
appropriate.
MIXED ANXIETY-DEPRESSIVE DISORDER
Mixed anxiety-depressive disorder describes patients with both anxiety and depressive
symptoms who do not meet the diagnostic criteria for either an anxiety disorder or a
mood disorder. The combination of depressive and anxiety symptoms results in
significant functional impairment for the affected person. The condition may be
particularly prevalent in primary care practices and outpatient mental health clinics.
Opponents have argued that the availability of the diagnosis may discourage clinicians
from taking the necessary time to obtain a complete psychiatric history to differentiate
true depressive disorders from true anxiety disorders. In Europe and especially in China,
many of these patients are given a diagnosis of neurasthenia.
Epidemiology
The coexistence of major depressive disorder and panic disorder is common. As many as
two-thirds of all patients with depressive symptoms have prominent anxiety symptoms,
and one-third may meet the diagnostic criteria for panic disorder. Researchers have
reported that 20 to 90 percent of all patients with panic disorder have episodes of major
depressive disorder. These data suggest that the coexistence of depressive and anxiety
symptoms, neither of which meets the diagnostic criteria for other depressive or anxiety
disorders, may be common. Presently, however, formal epidemiological data on mixed
anxiety-depressive disorder are not available. Nevertheless, some clinicians and
researchers have estimated that the prevalence of the disorder in the general population
is as high as 10 percent and as high as 50 percent in primary care clinics, although
conservative estimates suggest a prevalence of about 1 percent in the general
population.
Etiology
Four principal lines of evidence suggest that anxiety symptoms and depressive
symptoms are causally linked in some affected patients. First, several investigators have

reported similar neuroendocrine findings in depressive disorders and anxiety disorders,
particularly panic disorder, including blunted cortisol response to adrenocorticotropic
hormone, blunted growth hormone response to clonidine (Catapres), and blunted
thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone.
Second, several investigators have reported data indicating that hyperactivity of the
noradrenergic system is causally relevant to some patients with depressive disorders and
with panic disorder. Specifically, these studies have found elevated concentrations of the
norepinephrine metabolite (MHPG) in the urine, the plasma, or the CSF of depressed
patients and patients with panic disorder who were actively experiencing a panic
attack. As with other anxiety and depressive disorders, serotonin and GABA may also be
causally involved in mixed anxiety-depressive disorder. Third, many studies have found
that serotonergic drugs, such as fluoxetine (Prozac) and clomipramine (Anafranil), are
useful in treating both depressive and anxiety disorders. Fourth, a number of family
studies have reported data indicating that anxiety and depressive symptoms are
genetically linked in at least some families.
Diagnosis
The diagnostic criteria for mixed anxiety-depressive disorder require the presence of
subsyndromal symptoms of both anxiety and depression and the presence of some
autonomic symptoms, such as tremor, palpitations, dry mouth, and the sensation of a
churning stomach. Some preliminary studies have indicated that the sensitivity of
general practitioners to a syndrome of mixed anxiety-depressive disorder is low,
although this lack of recognition may reflect the lack of an appropriate diagnostic label
for the patients.
Clinical Features
The clinical features of mixed anxiety-depressive disorder combine symptoms of anxiety
disorders and some symptoms of depressive disorders. In addition, symptoms of
autonomic nervous system hyperactivity, such as gastrointestinal complaints, are
common and contribute to the high frequency with which the patients are seen in
outpatient medical clinics.
Differential Diagnosis
The differential diagnosis includes other anxiety and depressive disorders and
personality disorders. Among the anxiety disorders, generalized anxiety disorder is most
likely to overlap with mixed anxiety-depressive disorder. Among the mood disorders,
dysthymic disorder and minor depressive disorder are most likely to overlap with mixed
anxiety-depressive disorder. Among the personality disorders, avoidant, dependent, and
obsessive-compulsive personality disorders may have symptoms that resemble those of
mixed anxiety-depressive disorder. A diagnosis of a somatoform disorder should also be
considered. Only a psychiatric history, a mental status examination, and a working

knowledge of the specific criteria can help clinicians differentiate among these
conditions. The prodromal signs of schizophrenia may show itself as a mixed picture of
mounting anxiety and depression with eventual onset of psychotic symptoms.
Course and Prognosis
On the basis of clinical data to date, patients seem to be equally likely to have
prominent anxiety symptoms, prominent depressive symptoms, or an equal mixture of
the two symptoms at onset. During the course of the illness, anxiety or depressive
symptoms may alternate in their predominance. The prognosis is not known.
Treatment
Because adequate studies comparing treatment modalities for mixed anxiety-depressive
disorder are not available, clinicians are probably most likely to provide treatment
based on the symptoms present, their severity, and the clinician’s own level of
experience with various treatment modalities. Psychotherapeutic approaches may
involve time-limited approaches, such as cognitive therapy or behavior modification,
although some clinicians use a less structured psychotherapeutic approach, such as
insight-oriented psychotherapy. Pharmacotherapy for mixed anxiety-depressive disorder
can include antianxiety drugs, antidepressant drugs, or both. Among the anxiolytic
drugs, some data indicate that the use of triazolobenzodiazepines (e.g., alprazolam
[Xanax]) may be indicated because of their effectiveness in treating depression
associated with anxiety. A drug that affects the serotonin 5-HT1A receptor, such as
buspirone (BuSpar), may also be indicated. Among the antidepressants, despite the
noradrenergic theories linking anxiety disorders and depressive disorders, the
serotonergic antidepressants may be most effective in treating mixed anxiety-depressive
disorder. Venlafaxine (Effexor) is an effective antidepressant that has been approved by
the FDA for the treatment of depression as well as generalized anxiety disorder and is a
drug of choice in the combined disorder.
REFERENCES
Algeria AA, Hasin DS, Nunes EV, Liu SM, Davies C, Grand BF, Blanco C. Comorbidity of generalized anxiety disorder and
substance use disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin
Psychiatry. 2010;71:1187.
Beard C, Weisberg RB, Keller MB. Health-related quality of life across the anxiety disorders: Findings from a sample of
primary care patients. J Anxiety Disord. 2010;24:559.
Campbell-Sills L, Stein MB, Sherbourne CD, Craske MG, Sullivan G, Golinelli D, Lang AJ, Chavira DA, Bystritsky A, Rose
RD, Welch SS, Kallenberg GA, Roy-Byrne P. Effects of medical comorbidity on anxiety treatment outcomes in primary
care. Psychosom Med. 2013; 75:713.
Comer JS, Blanco C, Hasin DS, Liu SM, Grant BF, Turner JB, Olfson M. Health-related quality of life across the anxiety
disorders. J Clin Psych. 2011;72:43.
Galbraith, T., Heimberg, RG, Wang, S., Schneier, FR, & Blanco, C. Comorbidity of social anxiety disorder and antisocial

personality disorder in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). J Anxiety
Disord. 2014;28(1):57–66.
Goodwin RD, Stein DJ. Anxiety disorders and drug dependence: Evidence on sequence and specificity among adults. Psych
Clin Neurosci. 2013;67:167.
Hill N, Joubert L, Epstein I. Encouraging self-management in chronically ill patients with comorbid symptoms of
depression and anxiety: An emergency department study and response. Soc Work Health Care. 2013;52:207.
Kroenke K, Outcalt S, Krebs E, Bair MJ, Wu J, Chumbler N, Yu Z. Association between anxiety, health-related quality of
life and functional impairment in primary care patients with chronic pain. Gen Hosp Psych. 2013; 35:359.
McClure-Tone EB, Pine DS. Clinical features of anxiety disorders. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s
Comprehensive Textbook of Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009:1844.
Pao M, Bosk A. Anxiety in medically ill children/adolescents. Depress Anxiety. 2011;28:40.
Pontone GM, Williams JR, Anderson K, Chase G, Goldstein S, Grill S, Hirsch ES, Lehmann S, Little JT, Margolis RL, Rabins
PV, Weiss H, Marsh L. Prevalence of anxiety disorders and anxiety subtypes in patients with Parkinson’s disease. Mov
Disord. 2009;24:1333.
Roy-Byrne P, Craske MG, Sullivan G, Rose RD, Edlund MJ, Lang AJ, Bystritsky A, Welch SS, Chavira DA, Golinelli D,
Campbell-Sills L, Sherbourne CD, Stein MB. Delivery of evidence-based treatment for multiple anxiety disorders in
primary care: A randomized controlled trial. JAMA. 2010;303:1921.