51 - Early-Onset Schizophrenia

Authors: Sadock, Benjamin James; Sadock, Virginia Alcott

Title: Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > 16 - Anxiety Disorders > 16.1 - Overview

16.1

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. For an overview of the features of all the anxiety disorders, see Table 16.1-1.

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 16.1-2).

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 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.

P.580


Table 16.1-1 Key Phenomenological Features of Major Anxiety Disorders As Defined by DSM-IV-TR

Panic disorder
   Recurrent unexpected panic attacks characterized by four or more of the following:
      Palpitations
      Sweating
      Trembling or shaking
      Shortness of breath
      Feeling of choking (also known as air hunger)
      Chest pain or discomfort
      Nausea or abdominal distress
      Feeling dizzy, lightheaded, or faint
      Derealization or depersonalization
      Fear of losing control or going crazy
      Fear of dying
      Numbness or tingling
      Chills or hot flashes
   Persistent concern of future attacks
   Worry about the meaning of or consequences of the attacks (e.g., heart attack or stroke)
   Significant change in behavior related to the attacks (e.g., avoiding places at which panic attacks have occurred)
   ± Presence of agoraphobia
Agoraphobia
   Fear of being in places or situations from which escape might be difficult, embarrassing, or in which help may be unavailable in the event of having a panic attack
   Often results in avoidance of the feared places or situations, for example:
      Crowds
      Stores
      Bridges
      Tunnels
      Traveling on a bus, train, or airplane
      Theaters
      Standing in a line
      Small enclosed rooms
Social phobia
   Marked and persistent fear of one or more social or performance situations in which the person is concerned about negative evaluation or scrutiny by others, for example:
      Public speaking
      Writing, eating, or drinking in public
      Initiating or maintaining conversations
   Fears humiliation or embarrassment, perhaps by manifesting anxiety symptoms (e.g., blushing or sweating)
   Feared social or performance situations are avoided or endured with intense anxiety or distress
Specific phobia
   Marked and persistent fear that is excessive, unreasonable, cued by the presence or anticipation of a specific object or situation, for example:
      Flying
      Enclosed spaces
      Heights
      Storms
      Animals (e.g., snakes or spiders)
      Receiving an injection
      Blood
   Provokes an immediate anxiety response
   Recognition that the fear is excessive or unreasonable
   Avoidance, anticipatory anxiety, or distress is significantly impairing
Obsessive-compulsive disorder
   Has obsessions or compulsions
      Obsessions are defined as recurrent and persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate, for example:
         Contamination
         Repeated doubts
         Order
         Impulses
         Sexual images
      Compulsions are defined as repetitive behaviors or mental acts whose goal is to prevent or to reduce anxiety or distress, for example:
         Hand washing
         Ordering
         Checking
         Praying
         Counting
         Repeating words
   Recognition that the fear is excessive or unreasonable
   Obsessions cause marked distress, are time-consuming (more than 1 hour per day), or cause significant impairment in social, occupational or other daily functioning
Generalized anxiety disorder or overanxious disorder
   Excessive anxiety and worry about a number of events or activities (future oriented), occurring more days than not for at least 6 months
   Worry is difficult to control
   Worry is associated with at least three of the following symptoms:
      Restlessness or feeling keyed up or on edge
      Easily fatigued
      Difficulty concentrating
      Irritability
      Muscle tension
      Sleep disturbance
   Anxiety and worry cause significant distress and impairment in social, occupational, or other daily functioning
Separation anxiety disorder
   Developmentally inappropriate and excessive anxiety concerning separation from home or to an attachment figure. Characterized by three or more of the following:
      Recurrent and excessive distress when separation from home or major attachment figure occurs or is anticipated
      Persistent and excessive worry that major attachment figure will be lost or harmed
      Persistent and excessive worry that an event will lead to separation from major attachment figure (e.g., getting kidnapped)
      Persistent and recurring fear of being alone or without attachment figure at home
      Reluctance or refusal to sleep away from home or without being near major attachment figure
      Duration of at least 4 weeks
      Age of onset before 18 years of age
      Causes distress or impairment in functioning
      Physical symptoms (e.g., headaches, stomachaches, nausea, and vomiting) when separation occurs or is anticipated
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

P.581


Table 16.1-2 Peripheral Manifestations of Anxiety

Diarrhea
Dizziness, light-headedness
Hyperhidrosis
Hyperreflexia
Hypertension
Palpitations
Pupillary mydriasis
Restlessness (e.g., pacing)
Syncope
Tachycardia
Tingling in the extremities
Tremors
Upset stomach (“butterflies”)
Urinary frequency, hesitancy, urgency

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. 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 (Table 16.1-2), 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

P.582


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 the 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. (See Section 6.1 for a discussion of Freud's theories.) 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, 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

P.583


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 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 meta-chlorophenylpiperazine (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 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 (GABAA) 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 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 counter regulatory effects on 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

P.584


P.585


P.586


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 Fig. 16.1-1 on p. 494). 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.

Table 16.1-3 ICD-10 Diagnostic Criteria for Phobic Anxiety Disorders

Agoraphobia
  1. There is marked and consistently manifest fear in, or avoidance of, at least two of the following situations:
    1. crowds;
    2. public places;
    3. traveling alone;
    4. traveling away from home.
  2. At least two symptoms of anxiety in the feared situation must have been present together, on at least one occasion since the onset of the disorder, and one of the symptoms must have been from items (1) to (4) listed below.
    Autonomic arousal symptoms
    1. palpitations or pounding heart, or accelerated heart rate;
    2. sweating;
    3. trembling or shaking;
    4. dry mouth (not due to medication or dehydration);
    Symptoms involving chest and abdomen
    1. difficulty in breathing;
    2. feeling of choking;
    3. chest pain or discomfort;
    4. nausea or abdominal distress (e.g., churning in stomach);
    Symptoms involving mental state
    1. feeling dizzy, unsteady, faint, or light-headed;
    2. feelings that objects are unreal (derealization), or that the self is distant or “not really here” (depersonalization);
    3. fear of losing control, “going crazy,” or passing out;
    4. fear of dying
    General symptoms
    1. hot flushes or cold chills;
    2. numbness or tingling sensations.
  3. Significant emotional distress is caused by the avoidance or by the anxiety symptoms, and the individual recognizes that these are excessive or unreasonable.
  4. Symptoms are restricted to, or predominate in, the feared situations or contemplation of the feared situations.
  5. Most commonly used exclusion clause. Fear or avoidance of situations (Criterion A) is not the result of delusions, hallucinations, or other disorders such as organic mental disorders, schizophrenia and related disorders, mood [affective] disorders, or obsessive-compulsive disorder, and is not secondary to cultural beliefs.
    The presence or absence of panic disorder in a majority of agoraphobic situations may be specified by using a fifth character.
    Without panic disorder
    With panic disorder
    Options for rating severity
    Severity in agoraphobia may be rated by indicating the degree of avoidance, taking into account the specific cultural setting. Severity in social phobias may be rated by counting the number of panic attacks.
Social phobias
  1. Either of the following must be present.
    1. marked fear of being the focus of attention, or fear of behaving in a way that will be embarrassing or humiliating;
    2. marked avoidance of being the focus of attention, or of situations in which there is fear of behaving in an embarrassing or humiliating way.
    These fears are manifested in social situations, such as eating or speaking in public, encountering known individuals in public or entering or enduring small group situations (e.g., parties, meetings, classrooms).
  2. At least two symptoms of anxiety in the feared situation as defined in agoraphobia, Criterion B, must have been manifest at some time since the onset of the disorder, together with at least one of the following symptoms:
    1. blushing or shaking;
    2. fear of vomiting;
    3. urgency or fear of micturition or defecation.
  3. Significant emotional distress is caused by the symptoms or by the avoidance, and the individual recognizes that these are excessive or unreasonable.
  4. Symptoms are restricted to, or predominate in, the feared situations or contemplation of the feared situations.
  5. Most commonly used exclusion clause. The symptoms listed in Criteria A and B are not the result of delusions, hallucinations, or other disorders such as organic mental disorders, schizophrenia and related disorders, mood [affective] disorders, or obsessive-compulsive disorder, and are not secondary to cultural beliefs.
Specific (isolated) phobias.
  1. Either of the following must be present:
    1. marked fear of a specific object or situation not included in agoraphobia or social phobia;
    2. marked avoidance of a specific object or situation not included in agoraphobia or social phobia.
      Among the most common objects and situations are animals, birds, insects, heights, thunder, flying, small enclosed spaces the sight of blood or injury, injections, dentists, and hospitals.
  2. Symptoms of anxiety in the feared situation as defined in agoraphobia, Criterion B, must have been manifest at some time since the onset of the disorder.
  3. Significant emotional distress is caused by the symptoms or by the avoidance, and the individual recognizes that these are excessive or unreasonable.
  4. Symptoms are restricted to the feared situation or contemplation of the feared situation. If desired, the specific phobias may be subdivided as follows. —animal type (e.g., insects, dogs)
    —nature-forces type (e.g., storms, water)
    —blood, injection, and injury type.
    —situation type (e.g., elevators, tunnels)
    —other type
Other phobic anxiety disorders
Phobic anxiety disorder, unspecified
(From World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Copyright, World Health Organization, Geneva, 1993, with permission.)

Table 16.1-4 ICD-10 Diagnostic Criteria for Other Anxiety Disorders

Panic disorder [episodic paroxysmal anxiety]
  1. The individual experiences recurrent panic attacks that are not consistently associated with a specific situation or object and that often occur spontaneously (i.e., the episodes are unpredictable). The panic attacks are not associated with marked exertion or with exposure to dangerous or life-threatening situations.
  2. A panic attack is characterized by all of the following:
    1. it is a discrete episode of intense fear of discomfort;
    2. it starts abruptly;
    3. it reaches a maximum within a few minutes and lasts at least some minutes;
    4. at least four of the symptoms listed below must be present, one of which must be from items (a) to (d):
         Autonomic arousal symptoms
      1. palpitations or pounding heart, or accelerated heart rate;
      2. sweating;
      3. trembling or shaking;
      4. dry mouth (not due to medication or dehydration);
      Symptoms involving chest and abdomen
      1. difficulty in breathing;
      2. feeling of choking;
      3. chest pain or discomfort;
      4. nausea or abdominal distress (e.g., churning in stomach);
      Symptoms involving mental state
      1. feeling dizzy, unsteady, faint, or light-headed;
      2. feeling that objects are unreal (derealization), or that the self is distant or “not really here” (depersonalization);
      3. fear of losing control, “going crazy,” or passing out;
      4. fear of dying;
      General symptoms
      1. hot flushes or cold chills;
      2. numbness or tingling sensations.
  3. Most commonly used exclusion clause. Panic attccks are not due to a physical disorder, organic mental disorder, or other mental disorders, such as schizophrenia and related disorders, mood [affective] disorders, or somatoform disorders.
The range of individual variation in both content and severity is so great that two grades, moderate and severe, may be specified, if desired, with a fifth character.
Panic disorder, moderate
   At least four panic attacks in a 4-week period.
Panic disorder, severe
   At least four panic attacks per week over a 4-week period.
Generalized anxiety disorder
Note. In children and adolescents the range of complaints by which the general anxiety is manifest is often more limited than in adults, and the specific symptoms of autonomic arousal are often less prominent. For these individuals, an alternative set of criteria is provided for use (in generalized anxiety disorder of childhood) if preferred.
  1. There must have been a period of at least 6 months with prominent tension, worry, and feelings of apprehension about everyday events and problems.
  2. At least four of the symptoms listed below must be present, at least one of which must be from items (1) to (4):
       Autonomic arousal symptoms
    1. palpitations or pounding heart, or accelerated heart rate;
    2. sweating;
    3. trembling or shaking;
    4. dry mouth (not due to medication or dehydration);
    Symptoms involving chest and abdomen
    1. difficulty in breathing;
    2. feeling of choking;
    3. chest pain or discomfort;
    4. nausea or abdominal distress (e.g., churning in stomach);
    Symptoms involving mental state
    1. feeling dizzy, unsteady, faint, or light-headed;
    2. feelings that objects are unreal (derealization), or that the self is distant or “not really here” (depersonalization);
    3. fear of losing control, “going crazy,” or passing out;
    4. fear of dying;
    General symptoms
    1. hot flushes or cold chills;
    2. numbness or tingling sensations;
    Symptoms of tension
    1. muscle tension or aches and pains;
    2. restlessness and inability to relax;
    3. feeling keyed up, on edge, or mentally tense;
    4. a sensation of a lump in the throat, or difficulty in swallowing;
    Other nonspecific symptoms
    1. exaggerated response to minor surprise or being startled;
    2. difficulty in concentrating, or mind “going blank,” because of worrying or anxiety;
    3. persistent irritability;
    4. difficulty in getting to sleep because of worrying.
  3. The disorder does not meet the criteria for panic disorder, phobic anxiety disorders, obsessive-compulsive disorder, or hypochondriacal disorder.
  4. Most commonly used exclusion clause. The anxiety disorder is not due to a physical disorder, such as hyperthyroidism, an organic mental disorder, or a psychoactive substance-related disorder, such as excess consumption of amphetaminelike substances or withdrawal from benzodiazepines.
Mixed anxiety and depressive disorder
There are so many possible combinations of comparatively mild symptoms for these disorders that specific criteria are not given other than those already in Clinical Descriptions and Diagnostic Guidelines. It is suggested that researchers wishing to study patients with these disorders should arrive at their own criteria within the guidelines, depending upon the setting and purpose of their studies.
Other mixed anxiety disorders
Other specified anxiety disorders
Anxiety disorder, unspecified
(From World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Copyright, World Health Organization, Geneva, 1993, with permission.)

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 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 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 (NIMH) 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 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 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.

ICD-10

In the 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10), neurotic (anxiety) disorders are grouped with stress-related and somatoform disorders because of “their historical association with the concept of neurosis and the association of a substantial (although uncertain) proportion of these disorders with psychological causation.” In ICD-10, mixtures of symptoms are described

P.587


as common, especially in less-severe varieties of these disorders, and a category for cases that cannot be based on a single main syndrome is provided. Although the idea of neurosis is no longer the organizing principle, “care has been taken to allow the easy identification of disorders that some users still might wish to regard as neurotic in their own usage of the term.”

Table 16.1-5 ICD-10 Diagnostic Criteria for Obsessive-Compulsive Disorder

  1. Either obsessions or compulsions (or both) are present on most days for a period of at least 2 weeks.
  2. Obsessions (thoughts, ideas, or images) and compulsions (acts) share the following features, all of which must be present:
    1. They are acknowledged as originating in the mind of the patient and are not imposed by outside persons or influences.
    2. They are repetitive and unpleasant, and at least one obsession or compulsion that is acknowledged as excessive or unreasonable must be present.
    3. The patient tries to resist them (but resistance to very long-standing obsessions or compulsions may be minimal). At least one obsession or compulsion that is unsuccessfully resisted must be present.
    4. Experiencing the obsessive thought or carrying out the compulsive act is not in itself pleasurable. (This should be distinguished from the temporary relief of tension or anxiety.)
  3. The obsessions or compulsions cause distress or interfere with the patient's social or individual functioning, usually by wasting time.
  4. Most commonly used exclusion clause. The obsessions or compulsions are not the result of other mental disorders, such as schizophrenia and related disorders or mood [affective] disorders.
The diagnosis may be further specified by the following four-character codes:
   Predominantly obsessional thoughts and ruminations
   Predominantly compulsive acts [obsessional rituals]
   Mixed obsessional thoughts and acts
   Other obsessive-compulsive disorders
   Obsessive-compulsive disorder, unspecified
(From World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Copyright, World Health Organization, Geneva, 1993, with permission.)

Table 16.1-6 ICD-10 Diagnostic Criteria for Reactions to Severe Stress

Acute stress reaction
  1. The patient must have been exposed to an exceptional mental or physical stressor.
  2. Exposure to the stressor is followed by an immediate onset of symptoms (within 1 hour).
  3. Two groups of symptoms are given: the acute stress reaction is graded as:
    Mild
    Only Criterion (1) below is fulfilled.
    Moderate
    Criterion (1) is met, and there are any two symptoms from Criterion (2).
    Severe
    Either criterion (1) is met, and there are any four symptoms from criterion (2); or there is dissociative stupor.
    1. Criteria B, C, and D for generalized anxiety disorder are met.
      1. Withdrawal from expected social interaction.
      2. Narrowing of attention
      3. Apparent disorientation
      4. Anger or verbal aggression
      5. Despair or hopelessness
      6. Inappropriate or purposeless overactivity
      7. Uncontrollable and excessive grief (judged by local cultural standards).
  4. If the stressor is transient or can be relieved, the symptoms must begin to diminish after not more than 8 hours. If exposure to the stressor continues, the symptoms must begin to diminish after not more than 48 hours.
  5. Most commonly used exclusion clause. The reaction must occur in the absence of any other concurrent mental or behavioral disorder in ICD-10 (except generalized anxiety disorder and personality disorders) and not within 3 months of the end of an episode of any other mental or behavioral disorder.
Posttraumatic stress disorder
  1. The patient must have been exposed to a stressful event or situation (either short- or long-lasting) of an exceptionally threatening or catastrophic nature, which would be likely to cause pervasive distress in almost anyone.
  2. There must be persistent remembering or “reliving” of the stressor in intrusive “flashbacks,” vivid memories, or recurring dreams or in experiencing distress when exposed to circumstances resembling or associated with the stressor.
  3. The patient must exhibit an actual or preferred avoidance of circumstances resembling or associated with the stressor, which was not present before exposure to the stressor.
  4. Either of the following must be present:
    1. inability to recall, either partially or completely, some important aspects of the period of exposure to the stressor;
    2. persistent symptoms of increased psychological sensitivity and arousal (not present before exposure to the stressor), shown by any two of the following:
      1. difficulty in falling or staying asleep;
      2. irritability or outbursts of anger;
      3. difficulty in concentrating;
      4. hypervigilance;
      5. exaggerated startle response.
  5. Criteria B, C, and D must all be met within 6 months of the stressful event or of the end of a period of stress. (For some purposes, onset delayed more than 6 months may be included, but this should be clearly specified.)
(From World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Copyright, World Health Organization, Geneva, 1993, with permission.)

The main ICD-10 categories for “neurotic” anxiety disorders are phobic anxiety disorders (agoraphobia, social phobias, and specific phobias); other anxiety disorders (panic disorder, generalized anxiety disorder, and mixed anxiety and depressive disorder); and OCD (with predominantly obsessional thoughts, predominantly compulsive acts, or mixed obsessional thoughts and acts) (Tables 16.1-3,16.1-4,16.1-5).

In ICD-10, reaction to severe stress and adjustment disorders are grouped into one category, which is classed together with neurotic and somatoform disorders. The stress-related category differs from the other two categories, however, because it can be defined on the basis of both symptoms and one of two causative influences: a stressful life event causing an acute stress reaction or a significant life change producing an adjustment disorder. Stress-related disorders in all age groups, including children, fall into this category.

In this group, ICD-10 classifies reactions to severe stress (acute stress reaction, posttraumatic distress disorder) and adjustment disorders (see Chapter 26). ICD-10 also includes the dissociative (conversion) disorders in the category of stress-related disorders. (For a discussion of dissociative disorders, see Chapter 20.) The criteria for reactions to severe stress are given in Table 16.1-6.

References

Charney DS. Anxiety disorders: Introduction and overview. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. 8th ed. Vol. 1. Baltimore: Lippincott Williams & Wilkins; 2005:1718.

Doyle AC, Pollack MH. Establishment of remission criteria for anxiety disorders. J Clin Psychiatry. 2003;64[Suppl 15]:40–45.

Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry. 2005;62:182–189.

Pigott TA. Anxiety disorders in women. Psychiatr Clin North Am. 2003;26:621–672.

Schulz J, Gotto JG, Rapaport MH. The diagnosis and treatment of generalized anxiety disorder. Primary Psychiatry. 2005;12:58–67.

Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL. Inhibited and uninhibited infants “grown up”: Adult amygdala response to novelty. Science. 2003;300:1052–1053.

Stein MB. Attending to anxiety disorders in primary care. J Clin Psychiatr. 2003;64[Suppl 15]:35–39.

Sussman N. Anxiety disorders in the clinical setting. Primary Psychiatry. 2005;12:12.

Velting ON, Setzer NJ, Albano AM. Update on and advances in assessment and cognitive-behavioral treatment of anxiety disorders in children and adolescents. Professional Psychology—Research & Practice. 2004;35:42–54.

Wittchen HU, Beesdo K, Bittner A, Goodwin RD. Depressive episodes: Evidence for a causal role of primary anxiety disorders? Eur Psychiatry. 2003;18:384–393.