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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: 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 Figure 1. Agents used in pharmacotherapy
appears to be anxiogenic, depressogenic, for panic disorder.
and proinflammatory and leads to Checklist
increased pain perception.10 -Aminobu-
tyric acid (GABA) inhibits CRF release.6
Glucocorticoids activate the locus Selective Serotonin Reuptake
caeruleus, which sends a powerfully acti- Citalopram hydrobromide worry about the implications of the
vating projection back to the amygdala Fluoxetine attacks or their consequences (eg, losing
using the neurotransmitter norepineph- Fluvoxamine maleate control, having a heart attack, going
Paroxetine hydrochloride
rine. The amygdala then sends out more Sertraline hydrochloride
crazy); or
CRF, which leads to more secretion of glu- a significant change in behavior
cocorticoids, and a vicious circle of feed- Other Antidepressants related to the attacks.
back between the mind and the body Monoamine oxidase inhibitors In general, individuals with PD may
results.5 Repeated stimulation of the amyg- reuptake inhibitors
see up to ten practitioners before a correct
dala results in strenghtened communica- diagnosis is made, have continuous
tion across its synapses with other regions Benzodiazepines increases in health care utilization span-
of the brain (ie, long-term potentiation).5 Alprazolam ning 10 years before diagnosis, and have
Prolonged exposure of the CNS to a 5 to 8 times greater likelihood of being
glucocorticoid hormones eventually Tricyclic Antidepressants high users of health care.13-15
depletes norepinephrine levels in the Clomipramine Figure 1 summarizes pharma-
locus caeruleus. As norepinephrine is an Imipramine hydrochloride cotherapy for panic disorders.
important neurotransmitter involved in Anticonvulsants
attention, vigilance, motivation, and Valproate sodium Generalized Anxiety Disorder
activity, the onset of depression may sub- Gabapentin Generalized anxiety disorder (GAD) is
sequently occur. a chronic disorder that involves exces-
Serotonin appears to be involved in sive anxiety and worry about a number
the pathogenesis of anxiety disorders as of events for most days out of 6 months.
well. Agents that enhance serotonin neu- Difficulty controlling the worry is
rotransmission may stimulate hip- feeling of choking; paramount, with the individual mani-
pocampal 5-HT1A receptors, thus pro- chest pain or discomfort; festing physical and psychologic symp-
moting neuroprotection and nausea or abdominal distress; toms with the condition leading to sig-
neurogenesis and exerting an anxiolytic feeling dizzy, unsteady, lightheaded, nificant distress or impairment.
effect.11 or faint; In diagnosing GAD, physicians
GABA, the primary inhibitory neu- derealization (feelings of unreality) must rule out a general medical condition
rotransmitter in the CNS, is another neu- or depersonalization (being detached); or substance abuse. Common somatic
rotransmitter believed to be inherently fear of losing control or going crazy; complaints of patients with GAD include
involved in the pathophysiology of anx- fear of dying; muscle tension, cold or clammy hands,
iety disorders. Levels of GABA appear to paresthesias; dry mouth, sweating, nausea, diarrhea,
be decreased in the cortex of patients chills or hot flushes; and urinary frequency. Psychologic
with PD, compared with those in con- one or more unexpected panic attacks; symptoms include irritability, difficulty
trol subjects.12 Benzodiazepines facilitate at least 1 month of worry, including concentrating, and sleep disturbance.
GABA neurotransmission and therefore change in cognition or behavior; In many individuals, subsyndromal
can improve anxiety. presence or absence of agoraphobia; manifestations of GAD are noticed in
or childhood and adolescence. The disorder
Panic disorder attacks not accounted for by another manifests chronically with a pattern of
As discussed, panic attacks, defined as mental disorder, general medical condi- waxing and waning symptoms and
discrete periods of sudden symptom tion, or effect of a substance. ongoing impairment in social function,
onset usually peaking in 10 minutes, can Panic attacks must be differentiated potentially leading to the development of
occur with most anxiety disorders. from PD. Panic disorder as defined by other anxiety, depressive, and substance
The DSM-IV-TR criteria for panic the DSM-IV-TR includes: abuse disorders.16,17 Treatment of GAD to
attack are as follows1 recurrent unexpected panic attacks; remission is associated with a decreased
palpitations, pounding heart, or accel- and risk of relapse.18
erated heart rate; at least one of the attacks has been
sweating; followed by 1 month (or more) of one or Social Anxiety Disorder
trembling or shaking; more of the following: The DSM-IV-TR criteria for SAD include
sensations of shortness of breath or persistent concern about having addi- fear or avoidance of social and perfor-
smothering; tional attacks; mance situations or enduring such situ-

Shelton Diagnosis and Management of Anxiety Disorders JAOA Supplement 3 Vol 104 No 3 March 2004 S3

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Figure 2. Treatment options for anxiety be highly effective for treating patients
disorders. with the spectrum of anxiety disorders.
Checklist The benzodiazepines (eg, alpra-
zolam and clonazepam) can provide
immediate relief, especially in individ-
Psychosocial Treatment
Cognitive behavioral therapy
uals with acute panic attacks. These
ations with anxiety or notable distress. Other modes of therapy, agents work by facilitating GABA neu-
Patients recognize SAD symptoms as such as: rotransmission. Of particular interest is
being excessive or unreasonable; the con- individual the compound tiagabine hydrochloride,
dition is highly distressing or disabling. group
which is a GABA reuptake inhibitor.
Common fears expressed by patients Anticonvulsants can be particularly
with SAD include participating in small Pharmacotherapy useful. Use of -blockers can be helpful
groups; eating, drinking, or writing in Selective serotonin reuptake in performance anxiety, and buspirone
public; talking to authority figures; per- Tricyclic antidepressants hydrochloride can be effective for GAD.
forming or giving a talk; attending social Benzodiazepines Several agents have proved ineffec-
events; working while being observed; Buspirone hydrochloride tive in treating panic attacks. These
meeting strangers or dating; using a Other antidepressants: agents include bupropion hydrochloride,
venlafazine hydrochloride
public bathroom, and being the center extended release trazodone hydrochloride, buspirone
of attention. Common somatic com- nefazodone hydrochloride, antipsychotics, (eg, olan-
plaints presented by patients with SAD mirtazapine zapine, risperidone) and -blockers (eg,
include trembling, shaking, blushing, propranolol hydrochloride, atenolol).19
sweating, stuttering, abdominal distress, Use of MAOIs, tricyclic antidepres-
and palpitations. sants, and benzodiazepines requires close
monitoring and patient education, as
Obsessive-compulsive disorder lence (eg, combat, rape, spousal abuse); there is a heightened risk of dietary and
The DSM-IV-TR criteria for obsessions other injury or shocking experience (eg, drug-drug interactions, lethality in over-
include unwanted thoughts, impulses, involvement in a fire, flood, or earth- dose, and abuse or dependence.
or images that cause great anxiety. These quake); and learning about trauma to a
thoughts are not simply excessive worries loved one.19 Comment
about real life problems. Persons with Anxiety disorders, though ubiquitous,
obsessions attempt to ignore, suppress, or Treatment Options for Patients are responsive to treatment. By using
neutralize these thoughts, which are rec- With Anxiety Disorders knowledge of the pathophysiology, an
ognized as the product of their minds. Figure 2 summarizes treatment options astute clinician can implement pharma-
The DSM-IV-TR criteria for com- for patients with anxiety disorder. cologic regimens with various mecha-
pulsions include repetitive behaviors or Psychosocial treatment modalities nisms of action, leading to a positive out-
mental acts that those affected feel driven may include cognitive behavioral therapy come. Anxiety disorders that are
to perform. Compulsions are aimed at in which the individual is trained to iden- untreated or undertreated can chroni-
preventing or reducing distress or pre- tify recurrent negative, irrational thoughts cally expose the CNS to long-term
venting a dreaded event, though the that are correlated with the anxiety. Other increased glucocorticoid levels, which
behavior is not realistically connected to treatment modalities involve desensiti- can lead to functional changes in the
the dreaded event and is clearly exces- zation modes of therapy, as well as sup- CNS. Use of a multimodal approach in
sive. portive and interpersonal psychotherapy. terms of pharmacologic mechanism of
Pharmacotherapy of anxiety disorders action will help in achieving and sus-
Posttraumatic Stress Disorder involves consideration of the known taining remission.
Criteria for the diagnosis of posttrau- pharmacologic anxiolytic mechanisms
matic stress disorder (PTSD), as defined of action. References
by the DSM-IV-TR,1 include exposure to Selective serotonin reuptake
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