ANXIETY

Anna Schwartz, M.D. and Adriana Feder, M.D.

Anxiety is a state of fear or a subjective feeling of apprehension, dread or foreboding. This

psychological state is often accompanied by signs of autonomic activation or other physical
symptoms. Anxiety is a universal human emotion that may serve adaptive purposes, but may
also be a symptom or syndrome causing suffering and disability. The task of the clinician is to
determine whether an anxious patient has an anxiety disorder, whether the anxiety is a
symptom of an underlying medical condition or is due to the effects of a medication or drug, or
if the anxiety is an expectable reaction to a life event.

Anxiety disorders are common in primary care settings; prevalence rates of all DSM-IV anxiety
disorders in primary care settings range from five percent to 21 percent, with panic disorder
and generalized anxiety disorder accounting for a majority of cases.,,, A survey administered to a
systematic sample of 1007 patients with scheduled appointments at the Associates in Internal
Medicine (AIM) practice found prevalences of 14.8 percent for generalized anxiety disorder and
8.3 percent for panic disorder. Patients with panic disorder have higher rates of utilization of
general medical services than patients with any other psychiatric diagnosis, and have a high
likelihood of having multiple medically explained symptoms. The level of overall functioning and
well-being is significantly lower for patients with anxiety symptoms compared with controls,
and comparable to that of patients with chronic physical disease.

Etiology

The pathophysiology of anxiety disorders is not well fully understood. Animal studies have
demonstrated the existence of a "fear network" involving the amygdala and its interactions
with the hippocampus and the medial prefrontal cortex, thought to be important in generating
conditioned fear responses. The noradrenergic, serotonergic and gamma-aminobutyric acid
(GABA) neurotransmitter systems have all been implicated in the biology of anxiety.
Noradrenergic neurons that originate in the locus coeruleus (LC) terminate in cortical and
subcortical regions involved in the mediation of fearful behavior. In animal studies, stimulation
of these LC neurons results in behaviors that mimic fear responses, while LC lesions can
eliminate these fear responses. In humans, drugs that activate noradrenergic neurons (such as
yohimbine) are anxiogenic, while drugs that decrease activity of LC cells (such as the tricyclic
antidepressants) are anxiolytic. GABA is the major inhibitory neurotransmitter in the brain.
Benzodiazepines, which are potent anxiolytic agents, bind to the GABA receptor and cause
increased affinity of GABA to its receptor, leading to enhanced neuronal inhibition. The role of
serotonin in anxiety is complex. Serotonergic neurons connecting the dorsal raphe and the
amygdala are thought to be important in regulating anxiety. Buspirone, an anxiolytic effective in
generalized anxiety disorder, has multiple effects at serotonin receptors, with an overall effect
of causing a decrease in serotonin neurotransmission, while the selective serotonin reuptake
inhibitors, also effective in treating anxiety disorders, cause an increase in serotonin in the
synaptic cleft after chronic use. Finally, alterations in hypothalamic-pituitary-adrenal axis
function are present in some anxiety disorders, such as post-traumatic stress disorder.

The biologic basis of anxiety has been most extensively studied in panic disorder. Several
theoretical models exist. One theory posits that patients with panic disorder have a faulty
central "suffocation alarm" mechanism, and respond to slight rises in CO2 blood levels with a
sensation of suffocation, and hence, panic. Evidence supporting this model includes the
observation , confirmed infrom several studies, that panic attacks can be induced in susceptible
individuals (though not in normal controls) by the intravenous infusion of sodium lactate or the
inhalation of five percent CO2. However, not all investigators have found evidence of CO2
hypersensitivity..7 A psychological theory of panic disorder postulates that panic attacks are the
result of "catastrophizing" misinterpretations of bodily sensations, which can be corrected by
cognitive-behavioral therapy, a form of psychotherapy whose efficacy in treating panic disorder
has been documented in controlled studies. An overarching hypothesis based on recent
research developments proposes that patients with panic disorder, a highly familial condition,
may inherit an especially sensitive central nervous system fear mechanism, centered in the
amygdala and involving the hippocampus and other areas of the brain. Medications and
cognitive-behavioral therapy may act at different levels of this mechanism, both producing
clinical improvement.
The neurocircuitry of anxiety has been postulated to arise from the amygdala, the brain area
that registers the emotional significance of environmental stimuli and stores emotional
memories. The efferent pathways from the central nucleus of the amygdala travel to a
multiplicity of critical brain structures, including the parabrachial nucleus (resulting in dyspnea
and hyperventilation), the dorsomedial nucleus of the vagus nerve and nucleus ambiguous
(activating the parasympathetic nervous system), and the lateral hypothalamus (resulting in
SNS activation). Through reciprocal neuronal pathways connecting the amygdala to the medial
prefrontal cortex, cognitive experience of the specific anxiety disorder differs, although fear
symptoms may overlap. During panic attacks the fear is of imminent death; in social phobia, the
fear is of embarassment; in postraumatic stress disorder, the traumatic memory is remembered
or reexperienced; in obsessive-compulsive disorder, obsessional ideas recur and intrude; and in
generalized anxiety disorder, anxiety is “free-floating” (i.e., not conditioned to specific
situations or triggers).

Described in the past with terms such as cardiac neurosis, irritable heart syndrome, battle
fatigue, and soldier’s heart, panic disorder is the anxiety disorder most often associated with
cardiovascular symptoms of chest pain, Tachycardia, and dyspnea. Discrete panic attacks can be
induced in the laboratory setting, especially in patients with panic disorder, by a variety of
stimuli: sodium lactate, caffeine, isoproterenol, serotonin receptor agonist m-
chlorophenylpiperazine (m-CPP), cholecystokinin tetrapeptide (CCK4), inhalation of CO2-
enriched air, and voluntary acute hyperventilation of room air. The common element among
these disparate inducers may be their ability to stimulate the respiratory rate with the
induction of an accompanying subjective sense of breathlessness.

Although some researchers have proposed that patients with panic disorder have only a
heightened sensitivity to and develop a learned intolerance of tachypnea, the higher
concordance rate of panic disorder observed in monozygotic as compared with dizygotic twins
and evidence of altered respiratory rhythym during sleep provide proof of a genetic diathesis
and a biological abnormality, respectively, underlying the phenotype of panic disorder.
Hurst's The Heart, 12e

Pathophysiology of Anxiety

Sections: Pathophysiology of Anxiety, A Focus on the Cardiovascular System, Treatment of

Major Depression and Anxiety Disorders in Patients with Cardiovascular Disease.

Topics Discussed: anxiety; anxiety disorder; depression; mood disorder.

Excerpt: "The neurocircuitry of anxiety has been postulated to arise from the amygdala, the
brain area that registers the emotional significance of environmental stimuli and stores
emotional memories. The efferent pathways from the central nucleus of the amygdala travel to
a multitude of critical brain structures, including the parabrachial nucleus (resulting in dyspnea
and hyperventilation), the dorsomedial nucleus of the vagus nerve and nucleus ambiguous
(activating the parasympathetic nervous system), and the lateral hypothalamus (resulting in
SNS activation).115 Through reciprocal neuronal pathways connecting the amygdala to the
medial prefrontal cortex, cognitive experience of the specific anxiety disorder differs, although
fear symptoms can overlap. During panic attacks, the fear is of imminent death; in social
phobia, the fear is of embarrassment; in posttraumatic stress disorder, the traumatic memory is
remembered or reexperienced; in obsessive-compulsive disorder, obsessional ideas recur and
intrude; and in generalized anxiety disorder, anxiety is free-floating (i.e., not conditioned to
specific situations or triggers).116Although the neurobiology of specific anxiety disorders has..."