stimulates the release of corticotropin,

leading to release of the stress hormones

(glucocorticoids and epinephrine) from
Diagnosis and Management the adrenal cortex. The glucocorticoids
of Anxiety Disorders typically exert negative feedback to the
hypothalamus, thus decreasing the
Charles I. Shelton, DO release of CRF.6
The stress response is hardwired
into the brain of the typical mammal and
is most often triggered when survival of
the organism is threatened. The primate
stress response, however, can be trig-
gered not only by a physical challenge,
but also by the mere anticipation of a
homeostatic challenge. As a result, when
Major anxiety disorders are more prevalent in women than in men. Although humans chronically and erroneously
the tendency toward anxiety disorders appears familial, other factors such as believe that a homeostatic challenge is
environmental influences can play a role in the risk for anxiety. This clinical about to occur, they enter the realm of
review focuses on the pathophysiologic basis for anxiety disorders. It provides neurosis, anxiety, and paranoia.5
brief overviews of panic disorder, generalized anxiety disorder, social anxiety The amygdala is the primary mod-
disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. It ulator of the response to fear- or anxiety-
also summarizes treatment options for patients with anxiety disorders. inducing stimuli. It is central to regis-
tering the emotional significance of
stressful stimuli and creating emotional
memories.7 The amygdala receives input
T he Diagnostic and Statistical Manual
of Mental Disorders, 4th ed. (Text
Revision) (DSM-IV-TR)1 defines the five
ders range between approximately 3%
(OCD) and 12% (SAD) and are approx-
imately two times greater among
from neurons in the cortex. This infor-
mation is mostly conscious and involves
major anxiety disorders as social anx- women than among men.2,3 abstract associations. Being stuck in
iety disorder (SAD), panic disorder (PD), traffic, in a crowded shopping mall, or on
obsessive-compulsive disorder (OCD), Pathophysiology of Anxiety an airplane that is full may serve to
generalized anxiety disorder (GAD), Disorders trigger the anxiety response in a suscep-
and posttraumatic stress disorder In the same way that behavioral traits tible individual via this mechanism.
(PTSD). Panic attacks, which represent are passed from parent to child, anxiety The amygdala also receives sensory
an extreme form of anxiety, can occur in disorders tend to run through family input that bypasses the cortex and thus
association with most of these anxiety structures. Studies comparing the risk of tends to be subconscious. An example is
disorders, though they are not typically psychiatric illness in identical twins (who that of a victim of sexual abuse who sud-
associated with GAD. Lifetime preva- share 100% of their DNA) have found denly finds herself acutely anxious when
lence rates of the major anxiety disor- that in general, if one identical twin has interacting with a number of friendly
a psychiatric condition, the risk that the people. It may take her a few moments to
other twin will have the same condition realize that characteristics of the indi-
Dr Shelton is an assistant professor of psychiatry at is approximately 50%. 4 It therefore viduals with whom she is interacting
the University of Kentucky in Lexington, and clin- appears that nongenetic factors, including remind her of the person who abused
ical professor of psychiatry at the Pikeville Col-
lege of Osteopathic Medicine, Pikeville, Ky. In
environmental influences occurring her.
addition, Dr Shelton practices psychology in a solo throughout the lifespan, must also con- When activated, the amygdala stim-
outpatient practice. tribute to the risk of developing an anx- ulates regions of the midbrain and brain
This article was developed from a lecture pre-
sented by Dr Shelton at a symposium sponsored by
iety disorder.2,3 stem, causing autonomic hyperactivity,
Wyeth Pharmaceuticals at the 108th Annual AOA The human body attempts to main- which can be correlated with the physical
Convention and Scientific Seminar on October 15, tain homeostasis at all times. Anything in symptoms of anxiety. Thus, the stress
2003, in New Orleans, La.
Dr Shelton is a national speaker on the vis-
the environment that disturbs home- response involves activation of the
iting speakers bureau of Wyeth Pharmaceuticals. ostasis is defined as a stressor. Homeo- hypothalamic-pituitary-adrenal axis. This
He is also on the speakers bureaus of Glaxo- static balance is then reestablished by axis is hyperactive in depression and in
SmithKline; Pfizer Inc; Cephalon, Inc; and Bristol-
Myers Squibb Company. Dr Shelton is also on the
physiologic adaptations that occur in anxiety disorders.8,9
CNS advisory panels of Pfizer Inc and Elan Phar- response to the stress response.5 Corticotropin-releasing factor, a
maceuticals. The stress response in humans 41 amino acid peptide, is a neurotrans-
Correspondence to Charles I. Shelton, DO,
1030 Monarch St No. 100, Lexington, KY 40513-
involves a cascade of hormonal events, mitter within the central nervous system
1843. including the release of corticotropin- (CNS) that acts as a key mediator of auto-
E-mail: cisdo123@alltel.net releasing factor (CRF), which, in turn, nomic, behavioral, immune, and

S2 JAOA Supplement 3 Vol 104 No 3 March 2004 Shelton Diagnosis and Management of Anxiety Disorders

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 endocrine stress responses. The peptide
appears to be anxiogenic, depressogenic,
and proinflammatory and leads to
increased pain perception.10 -Aminobu-
tyric acid (GABA) inhibits CRF release.6
Glucocorticoids activate the locus
caeruleus, which sends a powerfully acti-
vating projection back to the amygdala
using the neurotransmitter norepineph-
rine. The amygdala then sends out more
CRF, which leads to more secretion of glu-
cocorticoids, and a vicious circle of feed-
back between the mind and the body
results.5 Repeated stimulation of the amyg-
dala results in strenghtened communica-
tion across its synapses with other regions
of the brain (ie, long-term potentiation).5
Prolonged exposure of the CNS to
glucocorticoid hormones eventually
depletes norepinephrine levels in the
locus caeruleus. As norepinephrine is an
important neurotransmitter involved in
attention, vigilance, motivation, and
activity, the onset of depression may sub-
sequently occur.
Serotonin appears to be involved in
the pathogenesis of anxiety disorders as
well. Agents that enhance serotonin neu-
rotransmission may stimulate hip-
pocampal 5-HT1A receptors, thus pro-
moting neuroprotection and
neurogenesis and exerting an anxiolytic
effect.11
GABA, the primary inhibitory neu-
rotransmitter in the CNS, is another neu-
rotransmitter believed to be inherently
involved in the pathophysiology of anx-
iety disorders. Levels of GABA appear to
be decreased in the cortex of patients
with PD, compared with those in con-
trol subjects.12 Benzodiazepines facilitate
GABA neurotransmission and therefore
can improve anxiety.
Panic disorder
As discussed, panic attacks, defined as
discrete periods of sudden symptom
onset usually peaking in 10 minutes, can
occur with most anxiety disorders.
The DSM-IV-TR criteria for panic
attack are as follows1
palpitations, pounding heart, or accel-
erated heart rate;
sweating;
trembling or shaking;
sensations of shortness of breath or
smothering;
Shelton Diagnosis and Management of Anxiety Disorders
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Checklist
Selective Serotonin Reuptake
Inhibitors
Citalopram hydrobromide
Fluoxetine
Fluvoxamine maleate
Paroxetine hydrochloride
Sertraline hydrochloride
Other Antidepressants
Monoamine oxidase inhibitors
Serotonin-norepinephrine
reuptake inhibitors
Benzodiazepines
Alprazolam
Clonazepam
Tricyclic Antidepressants
Clomipramine
Imipramine hydrochloride
Anticonvulsants
Valproate sodium
Gabapentin
feeling of choking;
chest pain or discomfort;
nausea or abdominal distress;
feeling dizzy, unsteady, lightheaded,
or faint;
derealization (feelings of unreality)
or depersonalization (being detached);
fear of losing control or going crazy;
fear of dying;
paresthesias;
chills or hot flushes;
one or more unexpected panic attacks;
at least 1 month of worry, including
change in cognition or behavior;
presence or absence of agoraphobia;
or
attacks not accounted for by another
mental disorder, general medical condi-
tion, or effect of a substance.
Panic attacks must be differentiated
from PD. Panic disorder as defined by
the DSM-IV-TR includes:
recurrent unexpected panic attacks;
and
at least one of the attacks has been
followed by 1 month (or more) of one or
more of the following:
persistent concern about having addi-
tional attacks;
JAOA Supplement 3 Vol 104 No 3 March 2004 S3
Figure 1. Agents used in pharmacotherapy
for panic disorder.
worry about the implications of the
attacks or their consequences (eg, losing
control, having a heart attack, going
crazy); or
a significant change in behavior
related to the attacks.
In general, individuals with PD may
see up to ten practitioners before a correct
diagnosis is made, have continuous
increases in health care utilization span-
ning 10 years before diagnosis, and have
a 5 to 8 times greater likelihood of being
high users of health care.13-15
Figure 1 summarizes pharma-
cotherapy for panic disorders.
Generalized Anxiety Disorder
Generalized anxiety disorder (GAD) is
a chronic disorder that involves exces-
sive anxiety and worry about a number
of events for most days out of 6 months.
Difficulty controlling the worry is
paramount, with the individual mani-
festing physical and psychologic symp-
toms with the condition leading to sig-
nificant distress or impairment.
In diagnosing GAD, physicians
must rule out a general medical condition
or substance abuse. Common somatic
complaints of patients with GAD include
muscle tension, cold or clammy hands,
dry mouth, sweating, nausea, diarrhea,
and urinary frequency. Psychologic
symptoms include irritability, difficulty
concentrating, and sleep disturbance.
In many individuals, subsyndromal
manifestations of GAD are noticed in
childhood and adolescence. The disorder
manifests chronically with a pattern of
waxing and waning symptoms and
ongoing impairment in social function,
potentially leading to the development of
other anxiety, depressive, and substance
abuse disorders.16,17 Treatment of GAD to
remission is associated with a decreased
risk of relapse.18
Social Anxiety Disorder
The DSM-IV-TR criteria for SAD include
fear or avoidance of social and perfor-
mance situations or enduring such situ-
 Figure 2. Treatment options for anxiety
disorders.
ations with anxiety or notable distress.
Patients recognize SAD symptoms as
being excessive or unreasonable; the con-
dition is highly distressing or disabling.
Common fears expressed by patients
with SAD include participating in small
groups; eating, drinking, or writing in
public; talking to authority figures; per-
forming or giving a talk; attending social
events; working while being observed;
meeting strangers or dating; using a
public bathroom, and being the center
of attention. Common somatic com-
plaints presented by patients with SAD
include trembling, shaking, blushing,
sweating, stuttering, abdominal distress,
and palpitations.
Obsessive-compulsive disorder
The DSM-IV-TR criteria for obsessions
include unwanted thoughts, impulses,
or images that cause great anxiety. These
thoughts are not simply excessive worries
about real life problems. Persons with
obsessions attempt to ignore, suppress, or
neutralize these thoughts, which are rec-
ognized as the product of their minds.
The DSM-IV-TR criteria for com-
pulsions include repetitive behaviors or
mental acts that those affected feel driven
to perform. Compulsions are aimed at
preventing or reducing distress or pre-
venting a dreaded event, though the
behavior is not realistically connected to
the dreaded event and is clearly exces-
sive.
Posttraumatic Stress Disorder
Criteria for the diagnosis of posttrau-
matic stress disorder (PTSD), as defined
by the DSM-IV-TR,1 include exposure to
a life-threatening or traumatic event that
is persistently reexperienced. Individ-
uals with PTSD avoid stimuli associated
with the trauma, and they appear to have
a numbing of general responsiveness
and increased arousal. Posttraumatic
stress disorder can also occur in indi-
viduals who witness another persons
traumatic event. Common stressors
leading to PTSD include assaultive vio-
S4 JAOA Supplement 3 Vol 104 No 3 March 2004
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Checklist
Psychosocial Treatment
Cognitive behavioral therapy
Other modes of therapy,
such as:
individual
family
group
Pharmacotherapy
Selective serotonin reuptake
inhibitors
Tricyclic antidepressants
Benzodiazepines
Buspirone hydrochloride
Other antidepressants:
venlafazine hydrochloride
extended release
nefazodone
mirtazapine
lence (eg, combat, rape, spousal abuse);
other injury or shocking experience (eg,
involvement in a fire, flood, or earth-
quake); and learning about trauma to a
loved one.19
Treatment Options for Patients
With Anxiety Disorders
Figure 2 summarizes treatment options
for patients with anxiety disorder.
Psychosocial treatment modalities
may include cognitive behavioral therapy
in which the individual is trained to iden-
tify recurrent negative, irrational thoughts
that are correlated with the anxiety. Other
treatment modalities involve desensiti-
zation modes of therapy, as well as sup-
portive and interpersonal psychotherapy.
Pharmacotherapy of anxiety disorders
involves consideration of the known
pharmacologic anxiolytic mechanisms
of action.
Selective serotonin reuptake
inhibitors include sertraline hydrochlo-
ride, paroxetine hydrochloride, fluvox-
amine maleate, fluoxetine, citalopram
hydrobromide, and escitalopram oxalate.
Dual-acting antidepressants, such as ven-
lafaxine (serotonin-norepinephrine reup-
take inhibitor), mirtazapine (2-antago-
nist/5-HT2 and 5-HT3 antagonists),
monoamine oxidase (MAO) inhibitors,
and the tricyclic antidepressants can also
Shelton Diagnosis and Management of Anxiety Disorders
be highly effective for treating patients
with the spectrum of anxiety disorders.
The benzodiazepines (eg, alpra-
zolam and clonazepam) can provide
immediate relief, especially in individ-
uals with acute panic attacks. These
agents work by facilitating GABA neu-
rotransmission. Of particular interest is
the compound tiagabine hydrochloride,
which is a GABA reuptake inhibitor.
Anticonvulsants can be particularly
useful. Use of -blockers can be helpful
in performance anxiety, and buspirone
hydrochloride can be effective for GAD.
Several agents have proved ineffec-
tive in treating panic attacks. These
agents include bupropion hydrochloride,
trazodone hydrochloride, buspirone
hydrochloride, antipsychotics, (eg, olan-
zapine, risperidone) and -blockers (eg,
propranolol hydrochloride, atenolol).19
Use of MAOIs, tricyclic antidepres-
sants, and benzodiazepines requires close
monitoring and patient education, as
there is a heightened risk of dietary and
drug-drug interactions, lethality in over-
dose, and abuse or dependence.
Comment
Anxiety disorders, though ubiquitous,
are responsive to treatment. By using
knowledge of the pathophysiology, an
astute clinician can implement pharma-
cologic regimens with various mecha-
nisms of action, leading to a positive out-
come. Anxiety disorders that are
untreated or undertreated can chroni-
cally expose the CNS to long-term
increased glucocorticoid levels, which
can lead to functional changes in the
CNS. Use of a multimodal approach in
terms of pharmacologic mechanism of
action will help in achieving and sus-
taining remission.
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