Anxiety Disorders

13.1 Overview

Anxiety disorders are among the most prevalent mental disorders in the general population. Nearly 30 million persons are affected in the United States, with women affected nearly twice as frequently as men. 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 the following, as classified in the text revision of the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR): (1) panic disorder with or without agoraphobia; (2) agoraphobia with or without panic disorder; (3) specific phobia; (4) social phobia; (5) obsessive-compulsive disorder (OCD); (5) posttraumatic stress disorder (PTSD); (6) acute stress disorder; and (7) 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.

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 Sigmund Freud’s early translator mistranslated angst, the German word for “fear,” as anxiety, Freud 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.

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. Externally caused conflicts are usually interpersonal, whereas 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 necessarily to eliminate all anxiety, but rather 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.

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 him. 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, 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 used to study anxiety is the conflict test, in which an 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, whereas 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 or urinary levels of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol.

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 responses to corticotropin-releasing factor (CRF) have been reported in some studies and not in others.

CORTICOTROPIN-RELEASING HORMONE.

One of the most important mediators of the stress response, corticotropin-releasing hormone (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. 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 OCD. The effectiveness of buspirone (BuSpar), a serotonin 5-HT_1A 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 meta-chlorophenylpiperazine, 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; in addition, many anecdotal reports indicate that serotonergic hallucinogens and stimulants—for example, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine—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 controls. 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 (GABA_A) receptor, in the treatment of some types of anxiety disorders. Although low-potency 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 GABA_A 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 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 CRH and locus ceruleus-norepinephrine 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 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 brainimaging (fMRI) studies—for example, positron emission tomography, single photon emission computed tomography, and electroencephalography—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. 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 on anxiety disorders have not been reported, data from twin registers 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 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 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 exploring 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 brainimaging studies, these areas have become the focus of much hypothesis forming 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 GABA_A receptors. Ablation and stimulation studies in nonhuman primates have also implicated the limbic system in the generation of anxiety and fear responses. Increased activity in two areas of the limbic system has received special attention in the literature: 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.

13.2 Panic Disorder and Agoraphobia

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.

Agoraphobia 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. Researchers in other countries as well as some researchers and clinicians in the United States disagree with this theory, but the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) establishes panic disorder as the predominant disorder in the dyad. DSM-IV-TR includes diagnoses for panic disorder with and without agoraphobia and also for agoraphobia without a history of panic disorder. Panic attacks can also occur in many mental disorders (e.g., depressive disorders) and medical
conditions (e.g., substance withdrawal or intoxication), and the presence of a panic attack does not in itself necessitate a diagnosis of panic disorder.

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 U.S. 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. Freud’s acute anxiety neurosis was similar to panic disorder as defined in DSM-IV-TR, and Freud first noted the relation between panic attacks and agoraphobia. 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 panic disorder is in the 1 to 4 percent range; the 6-month prevalence is approximately 0.5 to 1.0 percent, and that for panic attacks is 3 to 5.6 percent. 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.

The lifetime prevalence of agoraphobia is somewhat more controversial, varying between 2 and 6 percent across studies. 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 of the patients have agoraphobia without panic disorder. The reasons for these divergent findings are unknown, but they probably involve differences in ascertainment techniques. In many cases, the onset of agoraphobia follows a traumatic event.

COMORBIDITY

Of patients with panic disorder, 91 percent have at least one other psychiatric disorder, as do 84 percent of those with agoraphobia. According to DSM-IV-TR, 10 to 15 percent of persons with panic disorder have comorbid major depressive disorder. About one third of persons with both disorders have major depressive disorder before the onset of panic disorder; about two thirds first experience panic disorder during or after the onset of major depression.

Anxiety disorders also commonly occur in persons with panic disorder and agoraphobia. Of persons with panic disorder, 15 to 30 percent also have social phobia, 2 to 20 percent have specific phobia, 15 to 30 percent have generalized anxiety disorder, 2 to 10 percent have posttraumatic stress disorder (PTSD), and up to 30 percent have obsessive-compulsive disorder (OCD). Other common comorbid conditions are hypochondriasis, 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 γ-aminobutyric acid (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, in particular, playing a significant role. Patients with panic disorder are sensitive to the anxiogenic effects of yohimbine in addition to having exaggerated plasma 3-methoxy-4-hydroxyphenylglycol, 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. (The use of panic-inducing substances is strictly limited to research settings; no clinically indicated reasons exist to stimulate panic attacks in patients.) So-called respiratory panic-inducing substances cause respiratory stimulation and a shift in the acidbase 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; meta-chlorophenylpiperazine, an agent with multiple serotonergic effects; GABA_B receptor inverse agonists; flumazenil (Romazicon), a GABA_B receptor antagonist; cholecystokinin; and caffeine. Isoproterenol (Isuprel) is also a panic-inducing 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 paragiganto-cellularis of the medulla. The hyperventilation in panic disorder patients may be caused by a hypersensitive suffocation alarm system whereby increasing partial pressure of carbon dioxide and brain lactate concentrations prematurely activates a physiological asphyxia monitor. The neurochemical panic-inducing substances are presumed primarily to affect the noradrenergic, serotonergic, and GABA receptors of the CNS directly.

Brain Imaging.

Structural brain-imaging studies, for example, magnetic resonance imaging (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 single photon emission computed tomography to assess the effects of the panic-inducing substance and the induced panic attack on cerebral blood flow.

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