14 - Approaches to the Treatment of Anxiety States

Editors: Shader, Richard I.

Title: Manual of Psychiatric Therapeutics, 3rd Edition

Copyright 2003 Lippincott Williams & Wilkins

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14

Approaches to the Treatment of Anxiety States1

Richard I. Shader

David J. Greenblatt

Anxiety is a ubiquitous experience. Many people function against a backdrop of anxiety generated by life's stresses, upheavals, stages, and phases every day. Anxiety is part of the internal signal system that alerts individuals to changes in their bodies and in the world around them. It can be adaptive or maladaptive, and it can generate concern or overconcern. Some degree of anxiety is experienced not only when things go wrong, but also when things are changed, unexpected, or just novel. Anxiety is an essential, but at times unpleasant, sense of tension, apprehension, or uneasiness that is experienced subjectively as apprehension or dread or that is observed in predictable, if idiosyncratic, physiologic changes, such as difficulty breathing, muscle tension, and shakiness. Most familiar is a pattern including clammy palms, butterflies in the stomach, racing pulse, and pounding in the chest that may occur when an imminent threat is sensed and the individual is alerted to cope with it. Another common presentation is the chronic worrier who looks tense and pale and whose brow is furrowed from the constant strain. Other typical complaints include intrusive thoughts (e.g., images, ruminations, frightening dreams), vigilance or trouble concentrating, or altered awareness of one's self or one's environment (e.g., depersonalization, derealization).

Coping with a serious threat or danger is usually accomplished through some form of fight or flight. The latter can take many forms, including escape and avoidance. Other responses, such as freezing and fragmentation, are less common, and thus they do not receive a comparable amount of attention. The still, crouched fawn hiding from danger is a familiar image. People seem to hide more to protect their sense of self (ego) than their bodies (see Chapter 1). Freezing and fragmentation are ego-protective responses, and these include distortion; displacement; and various forms of disconnection, including dissociation (see Chapter 4). Some anxious people may seem as if they pull the covers over their heads in much the same way that the ostrich buries its head in the sand. Dissociation is likely to occur when the threat feels overwhelming or when it comes from a trusted person.

Considerable overlap between anxiety and fear is observed when the threat or danger is external and real. In this context, anxiety has come to mean an exaggerated or excessive response that is disproportionate to the threat or the objective reality. The term anxiety is also used when the source of the threat is largely unrecognized, obscure, or unknown. This may occur when the anxiety reflects a conditioned response in which the connections to the original threatening stimulus are now suppressed, repressed, forgotten, or lost. Anxiety can also occur when one's sense of being able to take protective steps or effective action is blocked. Anxiety can be situational, intermittent or attack-like, or persistent; most often it is short-lived. When it reaches distressing levels and interferes with functioning, a clinical diagnosis of an anxiety disorder is made.

Clinical experience, controlled trials of pharmacologic treatment, and epidemiologic studies have led to a recognition of the need to separate anxiety as a symptom or momentary state from the more chronic or trait-like presentations. This has resulted in the development of a series of diagnostic criteria for various anxiety disorders and has increased recognition of their prevalence, natural history, and costs to society.

I. General Considerations

Widely accepted criteria for the diagnosis of anxiety disorders and their subtypes appear in currently used diagnostic manuals, such as the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, (DSM-IV) and the International

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Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10). Such diagnostic criteria generally include qualitative or descriptive features, with quantitative requirements for how many specific symptoms must be present, how often they must occur, and how long they should be present (note: by themselves, descriptive criteria convey no information about etiology).

Some of the following distinctions about anxiety states may seem arbitrary, but they are consistent with and are derived from clinical observation and patients' reports. The clinician should also note that anxiety rarely occurs in isolation; other accompanying symptoms, such as depression, anger, and somatic complaints, are common. Table 14.1 lists some of the many descriptors and complaints that are mentioned by anxious people or that are observed by their clinicians. Table 14.2 provides a simplified approach to differentiating, at a clinical level, among categories of anxiety delineated in the DSM-IV. Some of these are also discussed below and in section III in more detail.

The following subsections consider presentations of anxiety that are descriptively useful but that do not always constitute or conform to recognized diagnostic categories. Because many of the presentations of anxiety respond to the same medications, the idea that they represent phenotypic variations of the same underlying pathologic processes is quite possible. Some intervention strategies are also noted for each broad category.

A. Situational Anxiety

Situational anxiety, which is also known as context-specific anxiety, describes reactions to a variety of stressful stimuli, such as interviews, tests, public speaking, planned presentations, auditions, and surgery. Such anxiety

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is usually short-lived, and it ends once the experience is started or completed. Situational anxiety can reflect worry about, or fear of, the unknown; it can also be colored by a patient's low self-esteem. In these instances, irrational fears of rejection, failure, criticism, and social or interpersonal catastrophe may be prominent. Clinical and research experiences suggest that preparing and informing the patient may quiet situational anxiety. Examples include preparation for surgery by preoperative discussions with anesthesiologists, role playing or rehearsal in preparation for job interviews, and assertiveness training. However, this approach is less likely to be adequate when sensitive self-esteem issues or a high degree of irrationality are involved. For many patients, their own use of denial and minimization is sufficient. Some patients may benefit from pharmacotherapy (e.g., the short-term use of -adrenergic receptor antagonists for performance or public speaking anxiety). Some degree of situational anxiety is usually seen in all forms of formal anxiety disorders, including generalized anxiety disorder (GAD), panic disorder (PD), specific phobia, social phobia, posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (see Chapter 6).

TABLE 14.1. COMMON OBJECTIVE AND SUBJECTIVE DESCRIPTORS AND SYMPTOMS ASSOCIATED WITH ANXIETY STATES

Abdominal cramps
Anorexia
Anxious
Apprehensive
Breathless
Butterflies in the stomach
Chest pains
Choking sensations
Churning inside
Clutched up
Diarrhea
Dizzy
Dread
Dry mouth
Easily startled
Faint
Fearful
Flushing
Frightened
Giddy
Headache
Heart racing (tachycardia)
Impending doom feelings
Jittery
Jumpy
Keyed up
Lightheaded
Muscle tension
Nauseated
Overconcerned
Pallor
Palpitations
Panicky
Phobic
Preoccupied
Pupils dilated
Rapid respirations or respiratory distress (hyperpnea)
Restless
Scared for no reason
Shaky
Sweating
Syncope
Tense
Terrified
Threatened
Tightness in the chest
Tremulous
Troubled
Uneasy
Urge to urinate (and frequent urination)
Vertigo
Vomiting
Weakness
Worried
Wound up

TABLE 14.2. A SIMPLIFIED APPROACH TO DIFFERENTIATING AMONG FORMS OF ANXIETY

Description Diagnosis Usual Age at Onset
Innate or conditioned or learned fears Simple (specific) phobias Childhood or later
Social discomfort, shyness, a sense of not fitting in Social phobia (social anxiety disorder) Peaks in mid-adolescence or later
Excessive worry about the consequences of what you have done or not done or excessive worry about what lies ahead or about things that have not yet happened Generalized anxiety disorder Late adolescence or later
Worry and discomfort or distress when away from familiar places (e.g., home) or out of contact with people to whom one is especially attached, even for brief periodsof time; avoidance of anxiety-provoking contexts Separation anxiety; likely also seen in borderline personality disorder; likely present in agoraphobiaa Childhood or later
Traumatic anxiety from experiences that overwhelm coping capacities Posttraumatic stress disorder Childhood or later
Rituals, acts, or repetitive thoughts (sometimes intended to ward off danger) Obsessive-compulsive disorder Childhood or later
Panic attacks that sometimes occur spontaneously or without apparent triggers or contexts Panic disorder Late adolescence or later
Panic attacks that culminate after incremental anxiety Any of the above Uncommon in childhood
aThe authors consider agoraphobia to be a coping strategy rather than a diagnosis.

So-called illness or cancer phobias are sometimes considered situational because they can occur after hearing of an illness in someone else. They are not true phobias (see section I.B) because nothing that can be avoided to bring relief is present. Similarly, a reassuring physical examination rarely

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brings relief. Cancer and other illness phobias sometimes have an obsessional or delusional component (see Chapters 4 and 6); they usually occur along with other evidence of obsessional thinking or depression. Such illness phobias may also result from the somatic delusions that may occur in psychotic depressions (see Chapter 18).

B. Phobic Anxiety

This condition is a form of situational or context-dependent anxiety in which the primary method of coping is avoidance. In some instances, the etiology of the phobia is clearly discernible, and how to help is straightforward. For example, if a child is bitten by a dog and thereafter she fears being in the presence of dogs, one suitable approach would be systematic desensitization as follows: a planned progressive exposure to the fear-inducing stimulus using a friendly dog or its facsimile (e.g., photographs of a dog). Carefully planned increments of exposure are augmented by teaching the patient how to relax before confronting the threat and sometimes by coadministration of the appropriate pharmacotherapy. In patients who fear open spaces, heights, or elevators, the etiology and treatment may be more complex. Exposure and desensitization techniques combined with pharmacotherapy can be beneficial, particularly when these situations trigger panic attacks.

The intensity of and impairment from phobic feelings vary greatly from person to person. For example, among people who actually fly in airplanes, about 75% have no fears of flying. About 15% are anxious when they fly. The remaining 10% are quite afraid when they fly, yet they manage to fly. What differentiates this last group from those whose fear of flying keeps them grounded or that even stops them from boarding an airplane that remains on the ground is not at all clear.

Even more complex are those phobias in which the feared object has a private, symbolic, or unconscious meaning. These types of phobias are most likely to develop in the context of interpersonal conflict; they involve coping mechanisms such as projection, displacement, and regression. When these are present, supplementing pharmacotherapeutic approaches with other psychotherapeutic techniques designed to help the patient understand the evolution of the phobic anxiety in terms of his or her particular life experiences may be important.

C. Anticipatory Anxiety

Anticipatory anxiety (worry, anxious apprehension) is frequently associated with phobic anxiety, situational anxiety, or panic attacks. This, at times, is an arbitrary distinction, but many patients can describe anxiety that precedes the actual contact with dreaded objects or situations or can relate fears of having attacks of anxiety or panic. The intensity of anticipatory anxiety is highly variable, ranging from a mild sense of anticipation to extreme vigilance. When an acute intervention is needed, benzodiazepine anxiolytics are often beneficial.

D. Free-Floating Anxiety

This anxiety bears no close temporal relationship to the precipitating events or fear-inducing stimuli. It can sometimes be intense enough to feel like an unfocused sense of dread. It can present as a pattern of indiscriminate worry or anxious apprehension, and it is a major component of GAD. Careful inquiry sometimes reveals precipitants for the anxiety; for example, something triggered the emergence of forbidden feelings or painful memories, which were quickly suppressed, but the anxiety remained. Free-floating anxiety may vary in duration from hours to days; most patients describe it as chronic and as persisting over weeks to months. Pharmacotherapy is often effective for free-floating anxiety.

E. Traumatic Anxiety

Traumatic anxiety is a distinctive type of anxiety that occurs in survivors of tragic and usually unanticipated experiences, such as natural disasters (e.g., sudden floods, tornadoes, and fires) and shipwrecks. It can also appear in those who are involved in wars or other overwhelming events, such as

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rape (see Chapter 27) or kidnapping. It is usually associated with sleep disturbances or nightmares that involve the overwhelming event and with a daytime syndrome of anxiety, restlessness, irritability, headache, overactive startle reflex, feelings of isolation and distrust, a sense of inadequacy, and the restriction of social contacts and activities that may include reliving parts of the experience. When its appearance is delayed and sufficient impairment of functioning occurs, a diagnosis of PTSD is made.

Traumatic anxiety is less common in those who are able to participate in a helpful or effective manner during or after the traumatic event. Group discussion and grief work (see Chapter 16) can be valuable. Pharmacotherapy should be delayed until a careful workup can be carried out to identify the presence of a postconcussion syndrome or occult intracranial or extracranial bleeding. When such complications can be ruled out, relief from the stressor and rest sometimes assisted by the judicious use of antianxiety agents are the cornerstones of initial care. In DSM-IV, traumatic anxiety can be classified as acute stress disorder or as PTSD.

F. Psychotic Terror

This can be quite dramatic in the acutely disorganized, frightened, and easily startled patient. Paranoia and hallucinations may be prominent. Visual hallucinations in such patients may indicate a toxic psychosis due to amphetamines, cocaine, or anticholinergic substances. Some schizophrenic patients describe an earlier stage in their decompensations during which they feel anxious and fear they are going crazy. Treatment with antipsychotic agents is usually indicated (see Chapter 20), except in some toxic psychoses. When possible, the treatment of psychotic terror should include avoidance of overstimulation by providing a calm environment and familiar persons to stay with the patient. In rare instances, the use of seclusion may be beneficial (see Chapter 25).

G. Anxious Depression

In anxious depression, anxiety, tension, or agitation accompanies overt depressive affect. Over 60% of anxious patients eventually have symptoms of depression. Other patients are chronically depressed, with intermittent exacerbations of anxiety symptoms; they frequently complain of difficulty in falling asleep in addition to their early morning awakening (see Chapter 18). When the depressive picture is of minimal to mild intensity, psychotherapy aimed at altering negative styles of thinking and low self-esteem or at uncovering and articulating any underlying issues of disappointment, defeat, demoralization, or unresolved loss can be beneficial. Getting patients in touch with their anger and resentment may also be helpful because anxiety-bound hostility and guilt are sometimes prominent. Patients with concomitant anxiety and depression respond to a variety of pharmacotherapies, including benzodiazepines; selective serotonin reuptake inhibitors (SSRIs); more mixed inhibitors of monoamine reuptake (e.g., venlafaxine); tricyclic antidepressants (TCAs), such as doxepin and amitriptyline; and monamine oxidase inhibitors (MAOIs).

Caution is essential when treating elderly patients with anxiety and depression. Excessive sedation and resulting motor incoordination can have unwanted consequences, as can the anticholinergic, hypotensive, and arrhythmia-inducing properties of the TCAs. Combinations of low doses of antipsychotic agents and TCAs (e.g., perphenazine and amitriptyline) are still used in some countries and in some primary care settings, but few advantages appear to result from this approach unless psychotic elements are part of the presenting clinical picture.

H. Anxiety Secondary to Medical Conditions

These considerations must also include anxiety secondary to medical conditions. Table 14.3 lists medical conditions that may present with overt anxiety symptoms. Treatment should always be directed at the underlying medical condition. The anxiety associated with angina, for example, is best treated with nitroglycerin. Symptomatic treatment may be helpful in some

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conditions. Low doses of antipsychotic agents (e.g., risperidone, haloperidol) may be beneficial in some patients who show anxiety and agitation associated with delirium or dementia (see Chapter 5). Hypoxic states that produce anxiety or agitation are best treated with oxygen, rather than with sedative-hypnotics, anxiolytics, or antipsychotic agents, some of which could actually produce a further degree of respiratory depression. Stress also may be a factor in the medical conditions not listed in Table 14.3. For example, some patients with chronic dermatologic conditions, hypertension, or peptic ulcer may benefit from antianxiety agents even in the absence of overt anxiety.

TABLE 14.3. SOME CONDITIONS THAT MAY PRESENT WITH PROMINENT ANXIETY SYMPTOMS

Akathisia secondary to dopamine receptor antagonists or selective serotonin reuptake inhibitors
Angina pectoris
Aspirin intolerance
Bad trips and drug intoxications
Behavioral toxicity from drugs
Caffeinism
Carcinoid
Cerebral arteriosclerosis
Congestive heart failure
Epilepsy, particularly psychomotor or temporal lobe epilepsy
Hyperdynamic -adrenergic circulatory state (hyperventilation)
Hypoglycemia, hyperinsulinism
Hypoxic states (obstructive pulmonary disease, asthma)
M ni re disease
Mitral valve prolapse
Pain
Paroxysmal tachyarrhythmias and other cardiac arrhythmias
Pheochromocytoma
Premenstrual tension
Pulmonary embolism
Thyrotoxicosis (hyperthyroidism) or use of thyroid hormones
Use of monosodium glutamate
Use of stimulants or sympathomimetic agents (e.g., anorexigenics, decongestants)
Withdrawal from central nervous system depressant drugs

TABLE 14.4. THE FIVE Rs : CORE CONCEPTS USED IN THE REDUCTION OF ANXIETY OR STRESS

Recognition of the causes and sources of the threat or distress; education and consciousness raising
Relationships identified for support, help, reassurance
Removal from or of the threat or stressor; managing the stimulus
Relaxation through techniques, such as meditation, massage, breathing exercises, or imagery
Reengagement through managed reexposure and desensitization
From Shader RI. Stress, fear, and anxiety. In: Tupin JP, Shader RI, Harnett DS, eds. Handbook of clinical psychopharmacology. Northvale, NJ: Aronson, 1988:73 96, with permission.

II. Stress

Stress is not an anxiety disorder, nor is it a normative concept (i.e., everyone experiences stress); a person typically is stressed when positive or negative (e.g., threatening) experiences temporarily strain or overwhelm adaptive capacities. Stress is highly individualized, and it depends on variables such as the novelty, rate, intensity, duration, or personal interpretation of the input and genetic or experiential factors. From the stress perspective, even too much of a good thing can quite possibly be a source of stress one person's fun may be another person's stressor.

Both acute and chronic stress can intensify morbidity from anxiety disorders. Panic attacks, for example, are more frequent when the predisposed person is exposed to stressors. Stress-reduction strategies can be helpful to many anxious patients. Unfortunately, many anxious persons cannot concentrate enough to use such strategies for acute relief effectively. Most stress-reduction techniques have their greatest utility as elements of a prevention plan that attempts to raise one's threshold to anxiety-provoking experiences. Table 14.4 lists the 5Rs the core concepts that are the basic elements in a stress-reduction or anxiety-reduction program.

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Meditation techniques are currently popular, and these may be beneficial to some stress-prone or potentially anxious persons. Many variations exist (see Appendix IV). Most meditation techniques share common elements: (a) a focusing chant or mantra that distracts one from preoccupying thoughts and feelings, (b) deep rhythmic (usually abdominal) breathing that emphasizes a prolonged expiratory phase, and (c) muscle relaxation. For more information on stress reduction or meditation, the interested reader is encouraged to consult relevant references. Many factors influence people's choices of interventions and treatments. Table 14.5 lists some of the factors affecting both the choice and outcome of interventions for stress and of treatments for anxiety states and disorders.

For task-related or occupation-related stress, developing approaches that reduce stress is often possible. Table 14.6 lists one such effective strategy ( LESS STRESS ). Simple physical exercises that can be done in the workplace are also useful. These primarily involve relaxing tense muscles of the head, neck, or shoulders by stretching and relaxing the affected muscles in an alternating manner (e.g., squeezing a tennis ball to relieve writer's cramp).

III. Diagnostic Features of Anxiety Disorders

A. Generalized Anxiety Disorder

This syndrome is broadly recognized as being responsive in varying degrees to pharmacotherapy with benzodiazepines, azapirones (e.g., buspirone), SSRIs, or the mixed monoamine reuptake inhibitor venlafaxine. Unrealistic or excessive anxiety or worry about life circumstances characterizes the

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syndrome. Specific identifiable symptoms that reflect, for example, motor tension, autonomic hyperactivity, or excessive vigilance are also present (Table 14.7). The diagnosis of GAD requires that the specific or general symptoms are not attributable to a mood or psychotic disorder or that they are not secondary to a medical condition, such as hypoxia, thyrotoxicosis, pheochromocytoma, caffeinism, stimulant abuse, or alcohol or substance withdrawal (Table 14.3). Readers familiar with the DSM, 3rd edition, (-III) and the DSM, 3rd edition, revised, (-III-R) will likely note that the accompanying features of GAD emphasized in the DSM-IV have been reduced in number from 18 to 6 and that they are less dominated by manifestations of autonomic nervous system overactivity.

TABLE 14.5. SOME FACTORS AFFECTING THE CHOICE AND OUTCOME OF THERAPEUTIC INTERVENTIONS

Acuteness or chronicity of the disorder
Severity of impairment of functioning from the disorder
Availability, beliefs, and attitudes of supportive persons or systems
Cultural expectations or sanctions
Personal beliefs about, attitudes toward, and past experiences with issues, such as self-help and the use of medications
Awareness of the treatment outcomes of other patients (i.e., what helped)
Attitudes and beliefs of primary care physicians and other clinicians and other referral sources
Availability of alternative therapies and the skills and reputations of various practitioners
Logistics of getting to various treatment settings
Time requirements of various interventions (i.e., time per treatment, duration of treatment)
Costs of various interventions
Nature of the coverage provided by third-party payers

TABLE 14.6. LESS STRESS : A TASK-RELATED STRESS-REDUCTION APPROACH

List goals, both short and long range; eliminate those not attainable
Establish a hierarchy of tasks based on realistic time requirements and priorities
Subdivide remaining tasks into manageable units or projects
Start with achievable (doable) tasks; starting with the hardest task may promote procrastination
Simplify your work environment; avoid clutter, have good lighting
Tell yourself that saying no to additional work is okay when you are already doing more than you can handle
Remember to interrupt stressful periods with breaks for relaxation strategies (e.g., take 6 10 deep breaths, trying to fill the chest, while sitting in a relaxed way and having adequate support for your arms, shoulders, and neck)
Envision (in conjunction with the above relaxation strategy and with your eyes closed) your favorite place, trying to capture the sounds, smells, sights, and textures of the place
Share and discuss your situation with others
Structure nonwork hours to provide for adequate exercise, distraction, nutrition, and sleep
From Shader RI. Fear, stress, and anxiety. In: Tupin JP, Shader RI, Harnett DS, eds. Handbook of clinical psychopharmacology. Northvale, NJ: Aronson, 1988:73 96, with permission.

TABLE 14.7. DIAGNOSTIC FEATURES OF GENERALIZED ANXIETY DISORDER

Excessive worry (apprehensive expectation) or anxiety that is difficult to control voluntarily and that is focused on a variety of experiences or situations must have been present on a majority of days for a minimum of 6 months. The subjective cause for the worry or anxiety should not be limited to the features of an axis 1 disorder (e.g., having panic attacks in panic disorder, becoming contaminated in obsessive-compulsive disorder). At least three of the six symptoms that follow must also be present on a majority of days in this period and must not be secondary to the use of medications or abusable substances or to a medical condition. Similarly, these symptoms should not be present as a feature of a mood, psychotic, or pervasive developmental disorder. These symptoms and the worry or anxiety must be of sufficient magnitude to cause marked distress or a significant impairment of social or occupational functioning.
  1. Nervousness, restlessness, feeling keyed up or on edge
  2. Easy fatigability
  3. Concentration difficulties or having one's mind go blank
  4. Irritability
  5. Muscle tension
  6. Sleep difficulties, especially difficulty falling or staying asleep
From the American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text revision. Washington, D.C.: American Psychiatric Association, 2000, with permission.

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Patients presenting in primary care settings frequently do not meet the full syndromal criteria for GAD, and their clinicians often rely on the qualitative features of GAD in reaching a working diagnosis. In some rural areas and in certain cultures or subpopulations, patients use unique or limited descriptors for their anxiety (Table 14.1). Such patients may be no less ill or no less in need of treatment than those meeting the formal diagnostic criteria for GAD. (Note: Complaints of some degree of worry can be elicited from 70% to 90% of patients seeking any form of medical attention; most of these patients need attention given to the concerns underlying their worries, and they do not require specific forms of antianxiety interventions.)

When GAD was first codified in DSM-III, the time requirement for diagnosis was 1 month of continuous or persistent symptoms. In DSM-III-R, this was lengthened to 6 months, and more emphasis was placed on worry as a cardinal manifestation. The 6-month requirement has been maintained in DSM-IV. Again, patients with symptoms lasting weeks to less than 6 months are as much in need of relief as those who technically qualify for the GAD diagnosis. None of the current diagnostic systems distinguishes worry about the future (e.g., I am afraid this plane will crash ) from past-oriented worry (e.g., I am worried that what I said offended him ). This distinction may have treatment implications as worries about the future are more susceptible to reassurance, whereas past-focused worries may reflect greater contributions from factors such as low self-esteem, guilt, or depression.

B. Panic Disorder

PD is a diagnostic subtype that has been recognized for almost two decades. The central clinical feature of PD is the spontaneous panic attack, a discrete period usually lasting 5 to 30 minutes of intense fear or discomfort that does not occur in association with a specific anxiety-provoking situation (i.e., it appears to come out of the blue ). This is sometimes problematic because an incomplete or hurried history-taking may lead the clinician to miss the precipitants. Panic attacks are experienced as anxiety carried to its extreme; they frequently occur when patients find themselves restricted in either their freedom of movement or access to help. The sense of terror in panic attacks can be so severe that the patients appear disorganized, disoriented, and depersonalized. Patients fear that they will suffocate, go crazy, or die. These fears can be so extreme that they lead to a variety of avoidance and escape behaviors. Some patients abuse alcohol and sedative-hypnotics in their efforts to contain their fears.

Spontaneous attacks occur more frequently when a susceptible person is subjected to increased stress. Panic attacks arouse about one-third of patients from sleep when their carbon dioxide levels are increasing. PD patients have a greater likelihood of having experienced early separations and losses, including deaths, than do patients with major depressive disorder. Nevertheless, PD and major depressive disorder are highly comorbid. The modal age at onset for PD is in the mid-20s.

Current criteria for the diagnosis of PD are given in Table 14.8. Specific symptoms generally are associated with panic attacks, and the disorder is not secondary to a medical condition. PD may exist with or without agoraphobia, a state characterized by a fear of being in places or situations from which escape might be difficult or embarrassing or in which help might not be available in the event of a panic attack. The afflicted person usually stays at home and restricts travel, or he or she only ventures away from home or familiar places when accompanied by a known companion. The anxiety experienced by agoraphobic patients may be so severe that they will not leave home even to shop for food or other necessities. Many agoraphobic patients cannot even get to their clinicians' offices without accompaniment.

Although agoraphobia is considered a diagnosis in DSM-IV, viewing it as an adaptation or coping response to the panic attacks is also possible. By staying at home or leaving only with familiar persons, patients reduce their stress and thereby raise their thresholds for the emergence of panic attacks.

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The degree of avoidance behavior can range from mild, in which a relatively normal life-style can be pursued despite the need to endure some distress, to severe, in which the patient is completely housebound. Some patients experience agoraphobia without a history of PD. This subgroup has epidemiologic features similar to those observed among patients experiencing panic attacks. Agoraphobia occurring without prior panic attacks is sometimes classified as a form of social phobia. This latter group includes mostly women; the onset is typically gradual with symptoms beginning most often between very late adolescence and the mid-30s.

TABLE 14.8. DIAGNOSTIC FEATURES OF PANIC DISORDER

The essential feature of panic disorder (PD) is the panic attack, a period of intense fear, dysphoria, and physical discomfort lasting 5 30 minutes.a These panic attacks must be recurrent and at least some must occur spontaneously (i.e., unexpected, uncued), whereas others may be situational (i.e., cued). They must not be secondary solely to medications or substance abuse or to a medical condition. At least one of the panic attacks must have been followed by at least 1 month of anticipatory anxiety about further attacks; worry about dire outcomes, such as dying or going crazy; or clinically significant secondary behavior changes (e.g., various avoidance behaviorsb). The panic attacks in PD must include at least 4 of the 13 symptoms that follow:
  1. Palpitations, tachycardia
  2. Sweating
  3. Tremor, shaking
  4. Nausea, abdominal distress
  5. Numbness, paresthesias
  6. Chills, hot flushes
  7. Dizziness, faintness, unsteadiness
  8. Chest discomfort or pain
  9. Choking sensations
  10. Shortness of breath, fear of smothering
  11. Derealization, depersonalization
  12. Fear of dying (e.g., from a heart attack)
  13. Fear of losing control or going crazy
aIn DSM-IV, peak intensity must be reached in 10 minutes.
bIn DSM-IV, PD is classified as occurring Without Agoraphobia or With Agoraphobia.
From the American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text revision. Washington, D.C.: American Psychiatric Association, 2000, with permission.

In most PD patients, panic attacks can be reproduced after the administration of such diverse agents as intravenous sodium lactate, doxapram, or isoproterenol; oral caffeine, m-chlorophenylpiperazine, or yohimbine; or the inhalation of marijuana or of more than 4% to 5% carbon dioxide. Such exposures can sometimes be used for diagnostic clarification.

C. Specific and Social Phobias

  • Specific phobia. One formal definition of specific phobia is given in Table 14.9. This phobic presentation was called simple phobia in DSM-III and DSM-III-R. Many, but not all, specific phobias begin in childhood (e.g., bugs, thunder) and disappear spontaneously. Occasionally, childhood phobias have a symbolic or psychodynamic significance (e.g., the latency-age boy whose sudden fear of policemen reflects his ambivalence about his punitive father). Some patients develop their phobias in late adolescence or early adulthood (e.g., claustrophobia, fears of going into the water). Phobias that develop later in life are less likely to disappear spontaneously. Although most specific phobias are not treated, those severe enough to warrant a diagnosis could benefit from treatment. Treatment usually consists of any of a variety of cognitive-behavioral

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    strategies that combine education and understanding with some form of learned relaxation techniques and graded contact with the avoided situation or object (imagery usually precedes actual exposure). Brief pharmacotherapy with anxiolytics or -adrenergic receptor antagonists can sometimes be beneficial to ease the patient into the early stages of exposure. See Chapter 21 for a discussion of phobias in youth.

    TABLE 14.9. DIAGNOSTIC FEATURES OF SPECIFIC PHOBIA

    Specific phobia is a persistent and intense situational or context-dependent anxiety in which the threat (object, situation) is known and exposure to it immediately triggers anxiety. The patient understands that the anxiety is excessive, but he or she finds avoidance preferable to encountering the threat, even though the avoidance and anticipatory anxiety interfere with functioning or cause marked distress. The following five types are currently codified in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.:
          Animal type
          Blood, injection, injury type
          Other type (e.g., avoidance of situations that may lead to an illness, irrational avoidance of certain foods may fit here)
          Natural environment type (e.g., heights, water)
          Situational type (e.g., elevators, enclosed spaces)
    From the American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text revision. Washington, D.C.: American Psychiatric Association, 2000, with permission.

  • Social phobia. This phobia, which is also called social anxiety disorder, is considered in Table 14.10. Some degree of social phobia can be quite common in postpubertal females and in males beyond their mid-20s. In severe cases of social phobia, patients will go to great lengths to avoid the contexts in which they anticipate humiliation or embarrassment: for example, they will not eat or sign their names in front of others, and some men will not urinate at a public urinal. Although cognitive-behavior therapies (CBTs) can help some patients, many can benefit from pharmacotherapy (e.g., the use of an SSRI, such as paroxetine, currently approved for social anxiety disorder). Other agents, such as venlafaxine XR, have been used with some success as well. Rarely, the use of an MAOI, such as phenelzine or isocarboxazid, may be indicated. At least one trial supports the use of the anticonvulsant and -aminobutyric

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    acid analogue gabapentin. Several as yet unmarketed agents may also be effective in social anxiety disorder; one promising agent is pregabalin, another -aminobutyric acid analogue also under study for seizure control and reduction of neuropathic pain. Combining behavioral therapy and pharmacotherapies can be highly effective.

TABLE 14.10. DIAGNOSTIC FEATURES OF SOCIAL PHOBIA OR SOCIAL ANXIETY DISORDER

Social phobia is a persistent and intense situational (e.g., social situations, performance) anxiety in the presence of strangers or in the context of scrutiny by others. Such patients anticipate humiliation or that they will act in embarrassing ways, and they find avoidance preferable even though they know their concerns are excessive or unreasonable and that their avoidance and anticipatory anxiety interfere with functioning or cause marked distress. Entering or enduring these contexts is sometimes accomplished, but the individual experiences intense anxiety, discomfort, and distress. When a medical condition is present, the social or performance anxiety must not be secondary to it (e.g., worry about stuttering or trembling). The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. recognizes a generalized type, in which pervasive anxiety about most social situations is present.
From the American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text revision. Washington, D.C.: American Psychiatric Association, 2000, with permission.

D. Posttraumatic Stress Disorder

Current criteria for PTSD are given in Table 14.11. Why some people can experience extreme trauma and appear to emerge unscathed and others cannot or why some who are traumatized will develop immediate symptomatology and others may show a delayed onset or may only show a response when the trauma has been repeated remains unclear. War victims with this disorder have received the most attention; until recently, much less attention had been paid to those who suffered from early physical or sexual abuse, rape (see Chapter 27), kidnapping, or exposure to natural disasters.

TABLE 14.11. DIAGNOSTIC FEATURES OF POSTTRAUMATIC STRESS DISORDER

Posttraumatic stress disorder (PTSD)a follows exposure to a traumatic and stressful event in which the patient (a) experienced, witnessed, or was confronted by actual or threatened death or serious injury or a threat to his or her own or another's physical integrity (e.g., rape) and (b) felt intense fear, anxiety, helplessness, or horror. The resulting symptomatology is sufficiently severe to cause marked distress or impairment of functioning, and, even when the patient is removed from the event, it is persistently reexperienced for at least 1 month in at least one of the following five ways:
  1. Recurrent, intrusive, and distressing recollections (e.g., images, thoughts, perceptions).
  2. Recurrent and distressing dreams involving the event.
  3. Reliving the event or feeling as if it is recurring (e.g., illusions, flashbacks, hallucinations).
  4. Intense anxiety and distress triggered by reminders or internal cues that resemble or symbolize the event.
  5. Physiologic (autonomic nervous system-mediated) changes triggered by reminders or internal cues that resemble or symbolize the event.
The patient experiences a general numbing of responsiveness and avoids reminders and stimuli identified with the trauma; this is manifested for at least 1 month by at least three of the seven symptoms that follow:
  1. Avoidance of thought, feelings, or discussions linked to the trauma.
  2. Avoidance of people, places, or activities that prompt recollections of the trauma.
  3. Impaired or no recall of an important aspect of the trauma.
  4. Markedly diminished interest or involvement in significant experiences.
  5. Estrangement or detachment from others.
  6. Restricted range of affect (e.g., absence of loving feelings).
  7. Sense of a bleak, unfulfilled, or foreshortened future (e.g., expects an early death or failing relationships).
For at least 1 month, the patient experiences increased arousal that is manifested by at least two of the five symptoms that follow:
  1. Difficulty falling or staying asleep
  2. Irritability or outbursts of anger
  3. Exaggerated startle response
  4. Difficulty concentrating
  5. Hypervigilance
aThe Diagnostic and Statistical Manual of Mental Disorders, 4th ed, (DSM-IV) classifies PTSD as Acute (i.e., symptom duration of less than 3 months), Chronic, or With Delayed Onset (i.e., at least 6 months after the trauma). DSM-IV also contains an Acute Stress Disorder diagnosis for a more muted pattern of symptoms that follows the trauma by less than 4 weeks and lasts from 2 days to no more than 4 weeks.
From the American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Text revision. Washington, D.C.: American Psychiatric Association, 2000, with permission.

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A tendency may appear in some situations for the individual to claim causality that links (or blames) current distress or suffering to past experiences that may be unrelated or that may be the product of distorted memories of these experiences. Some caution may be appropriate, and not all connections should be taken at face value.

Although patients with PTSD share enough common features so that the disorder was recognized and defined, their treatment is most likely to be effective when it is individualized. Some need to be seen in groups and to hear from others before they can speak about their own experiences or begin to trust others. Others may need an individual therapist who can establish a trusting relationship and who can then help the patient acknowledge what happened, how they felt (e.g., they may have felt both shame and excitement; personal values may have been violated), and what their role, if any, may have been (personal accountability). Rebuilding self-esteem, personal pride, and self-control or mastery and working through any guilt are also essential. When and how to involve any available family members also requires thoughtful judgment. For these reasons, at the present time, the treatment of PTSD is best entrusted to clinicians with considerable experience in this area. Pharmacotherapy can sometimes be quite effective. Sertraline is approved for PTSD by the United States Food and Drug Administration (FDA). Other SSRIs may be helpful (see Chapter 27). When these agents are not effective, an MAOI (e.g., phenelzine) can be tried if the clinician is experienced with its use. Case reports and a few small sample studies have shown some improvement after the administration of valproic acid or carbamazepine, of clonidine as an adjunctive therapy to TCAs, or of -adrenergic receptor antagonists. Benzodiazepines, such as alprazolam and clonazepam, have also provided some symptom relief; sometimes they are coprescribed with an SSRI or an MAOI. (Note: Careful monitoring is advisable when using benzodiazepines in this population, because some degree of unpredictable disinhibition may occur.)

IV. Prevalence and Consequences

Population-based surveys of the American population identify a 1-year prevalence rate for all anxiety disorders as being in the range of 5% to 15% for the adult population. This rate reflects persons meeting full syndromal criteria; the prevalence rates for those with a few symptoms or subsyndromal presentations would obviously be much higher.

A. Generalized Anxiety Disorder

For GAD, which is three to four times more prevalent than PD, the 1-year prevalence estimates are in the 2.5% to 6.5% range. A frequently quoted figure is 64 per 1,000. In one major study, the lifetime prevalence for GAD in patients not meeting criteria for any other comorbid psychiatric disorder was 0.5%, which is quite low. A slight male predominance for GAD is seen. GAD is more concordant in monozygotic twins (40% to 50%) than in dizygotics (4% to 15%). About 80% of patients will have symptoms when examined 3 years later, and about 50% will relapse within a few months after an effective pharmacotherapy is discontinued. About one-fourth of the male relatives of GAD patients misuse alcohol. Most GAD patients are never treated; about one-fourth have subsequent panic attacks, and over half later meet criteria for major depressive disorder. The prognosis for GAD is worse when symptoms such as depersonalization, agitation, and syncope are prominent.

B. Panic Disorder

The lifetime prevalence of PD is in the range of 1% to 3.5%. It is two to four times higher in women than it is in men. Most studies suggest a genetic component. As was noted earlier, the modal onset is in the mid-20s, and about three-fourths meet PD criteria by the age of 30.

C. Other Disorders

Estimates here are highly variable. About 5% to 12.5% in the aggregate meet criteria for all other anxiety disorders. The 1-year prevalence rate for

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PTSD is often given as 1%, but this figure would change greatly in years in which many unnatural or natural disasters occurred.

V. Chronicity and Morbidity

Both GAD and PD are typically chronic illnesses. In some patients, these illnesses follow a periodic course characterized by remissions and exacerbations. In many instances, recurrence of symptomatology is triggered by situational stress. A frequent pattern for both disorders is a more or less continuous or unrelenting course. Although these disorders are frequently viewed as minor or trivial illnesses by many clinicians and third-party payers, the available data do not support this perspective. Some patients do maintain reasonable functioning despite continuing or intermittent distress. However, a substantial proportion is seriously impaired or is even disabled by the illness. About 15% of PD patients have chronic and disabling symptoms. Family and social dysfunction, financial dependency or economic loss due to impaired work function, and the perception of poor physical health are all identified correlates. GAD and PD patients use emergency departments and other health care facilities at increased rates, and they are more likely to use or abuse cigarettes, alcohol, or illegal drugs than is an age-matched general population sample. Anxiety is associated with significantly increased rates of mortality from all causes. PD by itself is associated with increased occurrence of suicidal ideation, as well as of actual suicide attempts.

VI. General and Nonpharmacologic Treatment Considerations

Based on behavioral studies with animals, one may argue that some drug treatments for anxiety work by lessening learned (acquired) avoidance responses or by diminishing arousal and anticipatory responses to external or imagined danger or unpleasant situations. Decrements in anticipatory anxiety should be accompanied by a reduction in avoidance behaviors. Although avoidance and escape can be adaptive at times, for many people an appropriate reduction of anxiety could facilitate making better use of information, insights, or relationships in preparation for coping with stress or anxiety. Because some degree of arousal or anxiety is essential to promote effective coping strategies and learning, reducing the anxiety too much could be counterproductive. Once the anxiety is manageable, the patient can be helped to develop some perspective about the causes; manifestations (symptoms); and consequences, including the unwanted effects on relationships. The anxious patient can also learn whether any secondary gain comes from the anxiety (e.g., does it get others to act in a more thoughtful, caring, or giving manner?).

A. Therapeutic Listening

The clinician must learn not to become anxious when listening to patients' stories. The history-taking should permit the clinician to listen for any material suggesting that the patient becomes anxious about impulses that are forbidden or unacceptable or about painful memories or feelings that are threatening to emerge. Sometimes the sharing of memories, feelings, or impulses with a nonanxious, noncritical clinician will suffice to reduce anxiety. When the clinician does choose to offer a behavioral intervention or to prescribe medication, this should never be done as a substitute for empathic involvement.

B. Cognitive-Behavior Therapy

Most CBTs are based on the assumption that anxiety that does not arise solely as a manifestation of a medical condition reflects faulty or exaggerated appraisal of a threat or of one's appropriately aroused state; the degree of danger in the environment is misperceived, or one's own coping abilities are underestimated. Under these conditions, the apprehension and helplessness lead to a state of self-focused attention that amplifies and negatively interprets the inner physiologic sensations. Concomitant hypervigilance further narrows the attention, disrupts the concentration, or produces deteriorated performance and less successful coping and mastery.

CBTs try to restore mastery and coping by increasing lost self-confidence and overcoming demoralization, decreasing physical tension, decreasing avoidance, and breaking through negative feedback. Even something as

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simple as worry beads can be understood as a way of shifting focus from one's inner negative experiences into a calming ritual. Breathing exercises reestablish control and slow the heart rate. Education about the disorder is also an important component of many CBTs. Patients who recognize a panic attack for what it is and who know that it will end and that they will not go crazy or have a heart attack can reduce the likelihood of an uncontrollable escalation of symptomatology. Collecting more facts about fear-inducing situations, considering various options and alternatives for action when symptoms appear, and doing behavioral homework all can help. With few exceptions (see Chapter 27), no particular form of CBT is consistently more effective than another for any specific disorder. A flexible approach to the nonpharmacologic aspects of the care of anxious patients is essential.

VII. A Comment on the Prevalence of Pharmacotherapy

Data on psychotropic drug use in the United States fail to support the popular perception of Americans as excessive and inappropriate users of anxiolytic medications. Among adults identified as having enough symptomatology to warrant an intervention, only about one in four actually receives medication. Most antianxiety agent users take their medications as prescribed or use less. The typical use patterns are intermittent or occasional, or they last for relatively short periods of time. Only about 15% of all users of anxiolytic medications take medication continuously for over a year. During a typical 1-year interval, the overall prevalence of any use of an antianxiety agent, regardless of frequency or duration, for all diagnoses, including sleep and convulsive disorders, is estimated at 10% to 11% of the adult population. This puts Americans somewhere in the middle of the usage range among industrialized nations. Reliable data also indicate that anxiolytic users usually have significant levels of emotional distress and appropriate diagnoses. The prevalence of anxiolytic use has actually decreased somewhat over time. On balance, most data suggest that Americans use antianxiety agents conservatively and appropriately.

VIII. Pharmacotherapy

A. When to Treat

Approximately 50% of GAD patients will have prominent somatic distress that is referred to the cardiovascular, gastrointestinal, or another organ system. Therefore, the fact that most benzodiazepines and other sedative-hypnotics are prescribed by nonpsychiatric clinicians is not surprising. Most of these patients first undergo a medical evaluation for diseases other than anxiety; generally, no identifiable abnormality is revealed. Patients with symptoms consistent with a diagnosis of GAD or PD not secondary to some other cause should be considered for an initial trial of nonpharmacologic treatment, provided that their symptoms can be tolerated long enough for these alternatives to have time to work. Some approaches are short-term counseling or psychotherapy, various CBTs, reduction or elimination of caffeine intake or alcohol use, stress management techniques, physical exercise, or meditation. In many health care settings and rural areas, nonpharmacologic options for the treatment of anxiety may not be available at all. In such settings, pharmacotherapy may be the only appropriate option.

The decision to use a benzodiazepine or any other medication should be based on a risk-benefit assessment that weighs the degree of emotional distress and functional disability, the hazards of medication, the potential future hazards of nontreatment, and the probability of success of pharmacotherapy. Table 14.12 lists all the agents currently approved by the FDA for the range of anxiety disorders. Subsequent tables provide additional information.

B. Choosing a Specific Medication for GAD

  • Benzodiazepines as a class continue to be commonly prescribed anxiolytics in the United States. Table 14.13 lists the benzodiazepines currently marketed in the United States. Specific preferences, both of the patients and the prescribing clinicians, within this class have changed over the last decade. Until the early 1980s, diazepam was the most

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    widely prescribed benzodiazepine anxiolytic and was in fact one of the most frequently prescribed drugs in the world. Diazepam is the prototype of the longer half-life accumulating benzodiazepines. Multiple daily doses result in the accumulation of diazepam and its major metabolite desmethyldiazepam due to the long elimination half-life of both of these compounds. Potential benefits of this type of profile include the possibility of sustained drug effects throughout the day even with infrequent dosing, as well as a relatively low likelihood of rapid-onset discontinuation phenomena if treatment is abruptly stopped. Possible disadvantages include the potential for an increase in the sedative, performance-impairing, and amnestic effects that develop over time as a consequence of drug accumulation.

    TABLE 14.12. CURRENTLY USED UNITED STATES FOOD AND DRUG ADMINISTRATION APPROVED ANXIOLYTICS FOR GENERALIZED ANXIETY DISORDER, NONPSYCHOTIC ANXIETY, PSYCHONEUROTIC ANXIETY, OR UNSPECIFIED ANXIETYa

    Class (Most Common American Trade Name) Typical Starting Dosage in mg (and Range)b
    Benzodiazepinesc
       Alprazolam (Xanax) 0.25 (0.25 4)
       Chlordiazepoxide (Librium) 10 (5 100)
       Clorazepate (Tranxene) 7.5 (7.5 60)
       Diazepam (Valium) 2 (2 40)
       Lorazepam (Ativan) 1 (1 10)
       Oxazepam (Serax) 10 (10 90)
    Selective serotonin reuptake inhibitors (SSRIs)
       Paroxetined,e (Paxil) 10 (10 60)
       Sertralined (Zoloft) 25 (25 200)
    Conventional antipsychotic agents
       Prochlorperazine (Compazine)f 5 (5 20)
       Trifluoperazine (Stelazine)f 1 (1 6)
    Antihistamines
       Hydroxyzine (Atarax, Vistaril)g 25 (25 200)
    Other agents
       Buspironeh 5 (5 50)
       Doxepin 10 (10 75)
       Venlafaxine XR (Effexor XR)e 37.5 (37.5 225)
    a Obsessive-compulsive disorder is not considered in this table (see Chapter 6).
    bRanges may vary for specific indications; based on the authors' clinical experience.
    cOther benzodiazepines are available elsewhere.
    dOther SSRIs may be beneficial.
    eOnly agents with specific generalized anxiety disorder (GAD) indication.
    fUse should be for no longer than 12 weeks.
    gShort-term treatment of anxiety; available as tablets, capsules, syrup, or suspension.
    hFor anxiety; for children, capsules may be opened and mixed with applesauce.

    TABLE 14.13. BENZODIAZEPINE ANTIANXIETY (ANXIOLYTIC) AGENTS

    Parent Drug Typical Daily Rangea (mg) Effective Half-Life Active Metabolites
    Chlordiazepoxide (Librium and others) 15 100 Long Desmethylchlordiaz-epoxide
    Demoxepam
    Desmethyldiazepam
    Diazepam (Valium and othersb) 4 40 Long Desmethyldiazepam
    Oxazepam (Serax) 30 120 Short None
    Clorazepatec (Tranxene) 15 60 Long Desmethyldiazepam
    Lorazepam (Ativan and others) 2 6 Short to intermediate None
    Alprazolam (Xanax) 0.75 4 (for anxiety)
    1.5 10 (for panic disorder)
    Short to intermediate None
    Clonazepam (Klonopin) 0.5 4d Intermediate to long None
    aGiven as the usual adult dosage range. Lower doses recommended for elderly or debilitated patients.
    bAlso available in sustained-release as Valrelease (15 mg capsules).
    cPrecursor or prodrug for desmethyldiazepam.
    dClonazepam is United States Food and Drug Administration approved for the treatment of panic disorders.

    The introduction of alprazolam in the early 1980s shifted prescribing patterns; by 1988, alprazolam was the most commonly prescribed anxiolytic in the United States. (Note: In 1992, alprazolam was the third most frequently used medication among all types of medications.) Because of its short to intermediate half-life, it has a low potential for accumulation or for producing cumulative sedation with multiple doses. However, multiple daily doses are usually needed to achieve a sustained

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    effect, and discontinuation phenomena are more likely to occur after the abrupt discontinuation of treatment.

    This shift in prescribing patterns stems from a combination of accumulating scientific data, clinician preferences, and marketplace forces. Throughout the past 15 to 20 years, lorazepam has continued to be prescribed at relatively steady rates, although it is used less frequently than alprazolam and diazepam. Oxazepam; chlordiazepoxide; and clorazepate, a prodrug for desmethyldiazepam, are much less frequently prescribed. In recent years, clonazepam use for GAD has increased steadily, even though its FDA-approved indication is PD.

    For the treatment of GAD, the benzodiazepines listed in Tables 14.12 and 14.13 are consistently more effective than a placebo during short-term outpatient treatment. Long-term efficacy has never been unequivocally established. Some research (e.g., discontinuation or naturalistic studies) and patient reports are consistent with long-term benefit. The increment in therapeutic response that is attributable to a benzodiazepine compared with that of a placebo is variable from study to study because high placebo response rates are often observed in controlled trials. As one might expect, controlled trials comparing specific benzodiazepines with each other fail to demonstrate any consistent differences in efficacy within the class. The available scientific data indicate that the proper and thoughtful use of any of these benzodiazepines has an approximately equal likelihood of producing a reasonable therapeutic benefit in the treatment of patients with GAD. No evidence indicates that either the response to treatment or the potential hazards of these medications will be different for patients fulfilling formal diagnostic criteria for anxiety disorder than for those with anxiety as identified by primary care physicians and other clinicians using less formal and more qualitative diagnostic features.

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    That many clinicians avoid the use of benzodiazepines for a variety of both rational and nonevidence-based reasons should be noted. Their drugs of choice for initiating treatment are the SSRIs and other antidepressants.

  • Only one SSRI, paroxetine, has received FDA approval for use in GAD on the basis of controlled trials. In the authors' experience, all SSRIs can be effective in specific patients. The SSRIs are preferred by some clinicians and many patients because of concerns about the abuse potential, anterograde memory loss, and possible addiction liability of benzodiazepines in some patients. Although this could be a concern for particular patients, this issue needs to be balanced against the weight gain, sedation, and sexual side effects experienced by some patients on SSRIs. Because SSRI use may be accompanied by a slow onset of action and an initial incremental increase in anxiety, some clinicians may start a benzodiazepine, such as lorazepam or clonazepam, concurrently with the SSRI for the first 4 to 6 weeks and may then discontinue the benzodiazepine using a gradual tapering procedure (see Chapter 9). Because discontinuation reactions can occur with some SSRIs, (especially paroxetine), the SSRI should be gradually tapered when stopping the drug is indicated. Paroxetine is an inhibitor of cytochrome P-450 (CYP) 2D6, and it may inhibit its own metabolism (see Chapter 29).

  • Venlafaxine XR, a sustained-release preparation that is an inhibitor of both serotonin and norepinephrine presynaptic transporters, is also FDA approved for use in GAD. Reminding patients not to divide, chew, or crush these capsules is important. When discontinuing the use of this medication, the recommendation is that a tapering process should be followed, rather than abruptly discontinuing its use. Hypertension can be a problem for some patients on Venlafaxine XR, and blood pressure should be monitored, at least during the initial weeks of treatment and with subsequent dosage increases. Tremor can also occur. Venlafaxine XR is unique in that its beneficial effects are supported by a controlled trial that lasted for 26 weeks.

  • Buspirone, an azapirone anxiolytic, is also effective in GAD, but the response rates are more variable and the onset of action is slower for some patients (i.e., up to 2 to 3 weeks) compared with that of the benzodiazepines. When buspirone is effective for a particular patient, it offers some advantages, such as less potential for dependence and little, if any, memory or motor impairment. Some data suggest that buspirone may be most helpful in patients whose worries focus on the past, in those with minimal to mild concomitant depressive symptoms, or in those who do not welcome the mild sedation that is produced by benzodiazepines.

  • Doxepin2 has demonstrated effectiveness in some GAD patients, even those who have not yet shown any concurrent depressive symptoms. It is FDA approved for symptoms of anxiety.

  • Barbiturates, such as amobarbital, butabarbital, and phenobarbital, are not particularly efficacious for GAD or any other anxiety disorder. However, they are the least expensive antianxiety agents; some increase in their use has occurred in states controlling and regulating benzodiazepine use. Because barbiturates produce generalized central nervous system (CNS) depression and, in many patients, an unacceptable amount of sedation, their use involves considerable risk, particularly in patients who may overdose. Intentional overdosage is frequently lethal. Barbiturates induce hepatic microsomal enzymes, and dependence and tolerance can occur (see Chapter 9).

  • Propanediols, such as meprobamate, were popular for the treatment of anxiety in the late 1950s and early 1960s. Controlled trials did not

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    support their use in any specific anxiety disorder. Meprobamate has significant addiction potential, and completed suicides have occurred with some frequency. Drowsiness and ataxia are common unwanted effects. Unfortunately, meprobamate use has slightly increased in states regulating the use of benzodiazepines.

  • Antipsychotic agents are also occasionally prescribed for the treatment of GAD-like states in nonpsychotic patients. Their major use is in states of acute psychotic terror, but they may be helpful in certain anxious and agitated elderly patients showing signs of delirium or dementia, particularly when irascibility and aggression are part of the clinical picture. Some nonpsychotic anxious patients occasionaly find antipsychotic agents beneficial, although trying other agents first is usually preferable. Examples include (a) patients whose anxiety is associated with a high degree of distractibility; (b) those with racing thoughts, periods of thought blocking, or both; (c) those with strong imaginations, considerable magical thinking, and occasionally poor reality testing; and (d) those for whom other antianxiety regimens have been successful. Although some of these patients may seem psychotic, many show no further evidence of disorganization or decompensation.

    When antipsychotic regimens are selected for nonpsychotic patients, the dosages should be kept as low as possible; for example, prochlorperazine (5 to 10 mg per day) or trifluoperazine (1 to 2 mg per day) should be given for no more than 12 consecutive weeks, usually in a single bedtime dose. Unwanted effects even at low dosages, however, typically make the use of antipsychotic agents undesirable (e.g., drowsiness, ataxia, dry mouth, blurred vision, postural hypotension, weakness, and feelings of unreality). Extrapyramidal side effects and tardive dyskinesia are less common at low dosages and with short durations of use, but they may still occur.

    No published experience with the use of atypical antipsychotic agents in GAD exists at this time, and no agent has FDA approval for this indication.

  • Antihistamines are still prescribed by some clinicians. Some antihistamines have weak nonspecific CNS effects; most are also anticholinergic. Hydroxyzine is the most commonly used drug within this group. It may have a special usefulness in patients with anxiety-related pruritic dermatoses. Hydroxyzine is usually prescribed at oral dosage levels of 25 to 200 mg per day.

  • -Adrenergic receptor antagonists may reduce symptoms, such as tachycardia, palpitations, tremor, and hyperventilation, but they are not effective in GAD. -Adrenergic receptor antagonists may, however, be of some use in social phobia. The most commonly studied drug of this class is propranolol. Its use is contraindicated in patients whose cardiac compensation depends on sympathetic stimulation. It is also contraindicated in patients with obstructive lung diseases and asthma, and it should be used with caution in patients with diabetes mellitus. The key to using -adrenergic receptor antagonists is to prescribe them at an appropriate dose and for a sufficient duration so that -receptor antagonism will be achieved. Oral dosages of 30 to 120 mg per day in three to four divided doses are typically used.

    Atenolol at 25 to 50 mg per day is another alternative. It is preferred by some clinicians because it has fewer CNS side effects (e.g., depressed mood) than does propranolol. Clinicians prescribing these agents should be alert to their potential to cause or exacerbate symptoms of depression.

C. Choosing a Specific Medication for Panic Disorder (Table 14.14)

  • Antidepressants. Moderate to longer term pharmacotherapy of PD patients may be quite satisfactory with SSRIs; paroxetine and sertraline have FDA approval for PD. Other agents, such as imipramine and MAOIs like phenelzine, have been successfully used in PD. These agents may be most beneficial for blocking further panic attacks; they are

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    not effective acutely (i.e., they are not effective during a panic attack). The dosage requirements for all of these are variable. Occasional patients respond to doses as low as 10 mg per day of paroxetine or even as little as 10 mg per day of imipramine when enough time (sometimes up to 6 weeks) is allowed for determining whether that dosage level will be effective. Troublesome side effects generally are more common with all these antidepressants than they are with the benzodiazepines.

    TABLE 14.14. UNITED STATES FOOD AND DRUG ADMINISTRATION APPROVED AGENTS FOR THE TREATMENT OF PANIC DISORDER

    Class Typical Mean Daily Dosage in mg (Range)a
    Benzodiazepines
       Alprazolam 4 (2 10)
       Clonazepam 2 (0.5 4)
    Selective serotonin reuptake inhibitors
       Paroxetine 40 (10 60)
       Sertraline 75 (25 200)
    aBased on the authors' clinical experience.

  • Benzodiazepines. These are effective agents for both the reduction of any anticipatory anxiety and for acute care in PD. Approaches to initiating benzodiazepine therapy in PD are derived from clinical experience and common sense rather than from well-established scientific guidelines. Based on factors such as age, gender, body size, and prior medication experience, a dosage at the low end of the usual effective range is chosen and is titrated upward every few days until therapeutic benefit is achieved or side effects supervene. When side effects are encountered at a given dose, further dosage increments can be delayed, or the dose can be somewhat reduced. Many patients who experience drowsiness or other sedative side effects early in the course of therapy will report that these symptoms diminish with continued therapy. This is attributable to adaptation or tolerance. In most patients, a daily dosage can be found that produces significant clinical improvement with either no sedative side effects or with side effects mild enough to be tolerated.

    Most of the published experience and research in the treatment of PD has focused on alprazolam; its efficacy has been shown to be significantly greater than a placebo in reducing the frequency and severity of panic attacks and associated anticipatory anxiety and avoidance behavior. The published documentation with clonazepam is more limited; however, both are FDA approved for PD. Limited data suggest that other benzodiazepine derivatives, such as diazepam and lorazepam, may have comparable efficacy in specific patients.

    For alprazolam, enough data exist to recommend using plasma alprazolam levels for titrating therapy. Steady-state levels of less than 20 ng per mL are associated with little or no improvement in PD patients; levels in the range of 20 to 40 ng per mL are generally associated with clear benefit in terms of global clinical improvement and reduction of specific symptoms of anxiety. Some data suggest that levels in excess of 40 ng per mL may be required for the suppression of both spontaneous and precipitated panic attacks, but this is not clearly established. Increments of 1 mg per day of alprazolam appear to raise plasma levels by about 10 ng per mL; 1 mg three times a day could be expected to result in steady-state levels of 30 ng per mL, a concentration that is likely to be beneficial in PD. The maximum recommended dose is 10 mg per

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    day, although some patients occasionally benefit from and tolerate higher doses (Table 14.14). An extended release form of alprazolam was recently approved for use in the United States. Many clinicians find it to be clinically comparable with the immediate release agent clonazepam.

    For other benzodiazepines, no clear dose-response or concentration-response relationships have been established. However, a few plasma level ranges associated with usual therapeutic doses can be identified as follows: for diazepam, 300 to 1,000 ng per mL each of diazepam and its metabolite desmethyldiazepam; for clorazepate, 600 to 1,500 ng per mL of desmethyldiazepam; and for lorazepam, 20 to 80 ng per mL of lorazepam. Even when clear therapeutic ranges are not available, benzodiazepine plasma level monitoring may still be useful in some clinical situations in patients with PD. For example, a patient with poor therapeutic response might be either an intrinsic nonresponder to typical drug concentrations (i.e., steady-state plasma levels are in the usual range) or a person with rapid metabolism or questionable adherence (i.e., low or zero plasma levels are found). Similarly, treatment of a patient with a symptom such as fatigue, which could be attributable either to the underlying disease or to the medication, could be assisted by plasma level monitoring. An extremely high steady-state plasma level would suggest a drug-related side effect, whereas a low level would suggest the persistence of original symptoms due to undertreatment.

  • Anticonvulsants. Valproate and gabapentin have shown evidence of efficacy in PD. However, data are not sufficient at the present time to recommend their use.

D. Duration of Medication Use

  • GAD. GAD is a chronic illness. Nevertheless, a patient's need for the medication should be periodically reassessed. Some patients with GAD have persistent symptoms, and, in order to live productive and more comfortable lives, these individuals need more or less indefinite treatment. Continuing an antidepressant-based regimen (e.g., an SSRI or venlafaxine XR) for at least several years to promote a symptom-free period of stability seems reasonable. Then, a well-planned taper should be considered to determine the value of more extended treatment. In most instances, benzodiazepine use should not be continued without interruption. Periodic reassessment of the need for medication makes both clinical and medicolegal sense. At about 4-month to 6-month intervals, gradual tapering of the medication dosage can be initiated. Some patients will reach zero dosage without the recurrence of symptoms; others will experience a recurrence during or after the taper period. Medication can then be reinstituted when enough emotional distress is seen to warrant restarting treatment. A strategy of periodic discontinuation may reveal the subgroup of benzodiazepine-responsive patients whose anxiety is persistent and for whom chronic therapy may be uniquely beneficial. At the present time, the size of this group is unknown, and no criteria exist to identify these patients.

  • Panic disorder. Similar issues pertain to PD. In this condition, however, treatment is often initiated with a combination of a benzodiazepine and an antidepressant. The benzodiazepine can usually be tapered after 4 to 6 weeks, and treatment with the antidepressant alone is usually sufficient. After several years of stability, a planned tapered discontinuation should be considered.

E. Side Effects

Side effects caused by a medication must be clearly distinguished from unrelated effects occurring while a medication is being taken and from symptoms of the underlying disorder.

  • Benzodiazepines. An expected consequence of benzodiazepine use is nonspecific CNS depression or sedation. The intensity and time course of sedation produced by single doses of any benzodiazepine depend on

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    the magnitude of the dose, the resulting plasma and brain concentrations, and the degree of receptor occupancy. Sedation should be the most common and predictable side effect for all benzodiazepines.

    • Sedation may be revealed through the patient's reports of fatigue, tiredness, drowsiness, or sleepiness. Patients may also report difficulties with concentration or in staying awake, problems with visual accommodation, the feeling of having their thought processes slowed down, or ataxia and difficulties with balance. Controlled psychomotor testing procedures can be used to document a slowing of psychomotor performance speed, reaction time, or impairment of coordination.

    • Anterograde amnesia appears to be another consequence of nonspecific CNS depression. Patients may have impairment of information acquisition, impairment of storage of recently acquired information, or both. Patients typically report a partial or complete failure to recall information that has been acquired or acts that have been performed after their last dose.

      Both of these effects are temporary and reversible, and they will diminish and disappear as the drug is eliminated from the body and cleared from the brain. No consistent evidence indicates that one benzodiazepine differs from another in its capacity to produce such dose-dependent and concentration-dependent sedative effects. Some studies suggest that the emergence of daytime drowsiness is more likely to occur during treatment with long half-life accumulating benzodiazepines than it is with short half-life nonaccumulating compounds. However, this is not a constant finding. The clinical consequences of sedative side effects during repeated administration of benzodiazepines are partly counterbalanced by the development of tolerance to these effects. Tolerance reflects an intrinsic change in receptor sensitivity that occurs as a consequence of continued drug exposure. In clinical terms, patients frequently report a diminution or disappearance of sedative effects despite the continued use of the medication. (Note: Tolerance to nonspecific sedative effects of benzodiazepines is not accompanied by tolerance to their antianxiety effects.)

    • Seemingly paradoxical effects of benzodiazepines have received attention in the lay media that is vastly out of proportion to their incidence and clinical importance. Very rarely, benzodiazepine users report experiencing increased feelings of anger or hostility, feelings that are the opposite of the usual and expected calming effects of these drugs. From one perspective, such effects would not always be paradoxical they could represent the consequences of anxiolytic effects in persons having feelings of anger that were previously held in check by their anxiety. A drug-induced reduction of anxiety could facilitate the release or expression of any suppressed anger. To date, this effect has been demonstrated only rarely, and it has been seen principally in controlled laboratory studies in which feelings of anger or hostility are measured by rating scales or psychologic tests. Any assumption that these laboratory findings extend to the occurrence of antisocial expressions of anger or hostility, such as aggressive or assaultive behavior, has not been proved. No documented medical or scientific evidence indicates that benzodiazepine use directly or reproducibly impairs impulse control or conscience or leads to aggressive or self-destructive acts. Similarly, no evidence appears to indicate that benzodiazepine use is causally related to the occurrence of psychotic behavior, delusions, hallucinations, or depersonalization.

    • Discontinuation syndrome is the term applied to the clinical worsening that results from stopping benzodiazepines. At least three distinct syndromes can be identified, and distinguishing among these is clinically important.

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      • Recurrence. Because benzodiazepines do not cure GAD, PD, or insomnia, the symptoms of these chronic conditions can be expected to recur in most patients after treatment discontinuation. The symptoms should resemble those for which the drug was originally given. Recurrence of symptoms may be rapid once treatment is stopped, but, in most patients, they reappear relatively slowly.

      • Rebound. The rebound syndrome is similar or identical in character to the original disorder for which the benzodiazepine was prescribed; however, it is transiently more intense than the premorbid condition. Rebound anxiety and insomnia have been clearly established as possible consequences of benzodiazepine discontinuation, particularly after stopping benzodiazepines with short half-lives. Rebound phenomena usually last only a few days after discontinuation; they may be followed by the recurrence of the underlying disorder. (Note: Rebound does not imply physical dependence.)

      • Withdrawal. The occurrence of an objective autonomic withdrawal syndrome implies some degree of physical dependence. Withdrawal is likely to include psychologic and physiologic symptoms, such as increased anxiety, fearfulness, easy startling, hyperacusis, increased heart rate and blood pressure, and insomnia. As Chapter 9 discusses, the benzodiazepine withdrawal syndrome is self-limited, and complete recovery from all manifestations should occur. (Note: Recurrence of the underlying disorder may follow a withdrawal syndrome.)

        Although these three syndromes can be distinguished in concept, they may be difficult to distinguish in clinical practice, particularly when they occur simultaneously or sequentially in the same patient.

    • Short half-life benzodiazepines should be tapered when discontinuing their use as abrupt discontinuation of short half-life benzodiazepines is associated with an increased likelihood of discontinuation syndromes of relatively rapid onset. That short half-life benzodiazepines should be tapered rather than abruptly stopped is now well recognized.

      Many tapering schemes have been used with success. One example is the quarter per week approach in which the daily dose is reduced by 25% once a week. For example, a patient taking 4 mg per day of alprazolam would reduce the daily dose to 3 mg in week 1, 2 mg in week 2, and 1 mg in week 3 and would then discontinue it completely in week 4. Flexibility and close monitoring are essential during the taper period. In some patients, the final phase of the taper (i.e., 1 mg down to zero) may be difficult; in these patients, it must be extended in duration and may then be undertaken in even smaller decrements.

  • SSRIs. The side effects of SSRIs are generally tolerable. Among the most common initial side effects are nausea, diarrhea, insomnia or nervousness, and sometimes sedation. Sexual dysfunction can be quite troublesome. Weight gain with extended use can also be problematic. Discontinuation syndromes are also noted with agents without active metabolites. Paroxetine is associated with the highest incidence of discontinuation reactions. Tapering of SSRIs is advisable. Chapter 18 contains more information on the side effects of SSRIs and other antidepressants

IX. Anxiety Disorders Association of America (ADAA)

The Anxiety Disorders Association of America (ADAA) provides advocacy and support for improved care, education, and research in the area of anxiety disorders. The ADAA can be reached by mail at Anxiety Disorders Association of America, 11900 Parklawn Drive, Suite 100, Rockville, MD 20852 (United States); by telephone at 301-231-9350; or on their website at http://www.adaa.org/.

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X. A Categorization of Phobias

The following website can be consulted for the accepted names of various phobias: http://www.health.discovery.com/stories/phobias/phobias.html.

ADDITIONAL READING

American Psychiatric Association. Practice guidelines for the treatment of patients with panic disorder. Am J Psychiatry 1998;155:1 34.

Angst J, Vollrath M. The natural history of anxiety disorders. Acta Psychiatr Scand 1991;84:446 452.

Ballenger JC, Wheadon DE, Steiner M, et al. Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry 1998;155:36 42.

Barlow DH. Anxiety and its disorders. New York: Guilford, 1988.

Barlow DH, Gorman JM, Shear MK, et al. Cognitive-behavioral therapy, imipramine, or their combination in panic disorder. JAMA 2000;283:2529 2536.

Beck AT, Emery G, Greenberg R. Anxiety disorders and phobias. New York: Basic Books, 1985.

Beck AT, Sokol L, Clark DA, et al. A crossover study of focused cognitive therapy for panic disorder. Am J Psychiatry 1992;149:778 783.

Black DW, Wesner R, Bowers W, et al. A comparison of fluvoxamine, cognitive-therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993;52:44 50.

Borkovec TD, Inz J. The nature of worry in generalized anxiety disorder: predominance of thought activity. Behav Res Ther 1990;28:153 158.

Brown TA, Barlow DH. Long-term outcome of cognitive behavioral treatment of panic disorder. J Consult Clin Psychol 1995;63:754 765.

Butler G, Fennell M, Robson P, et al. A comparison of behavior therapy and cognitive behavior therapy in the treatment of generalized anxiety disorder. J Consult Clin Psychol 1991;59:167 175.

Charney D, Drevets W. The neurobiological basis of anxiety disorders. In: Davis KL, Charney D, Coyle JT, et al., eds. Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002:901 930.

Ciraulo DA, Antal EJ, Smith RB, et al. The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol 1990;10:27 32.

Cowley DS. Alcohol abuse, substance abuse, and panic disorder. Am J Med 1992;92:41S 48S.

Croft-Jeffreys C, Wilkinson G. Estimated costs of neurotic disorder in UK general practice 1985. Psychol Med 1989;19:549 558.

Cross-National Collaborative Panic Study, Second Phase Investigators. Drug treatment of panic disorder: comparative efficacy of alprazolam, imipramine, and placebo. Br J Psychiatry 1992;160:191 202.

Curran HV. Benzodiazepines, memory and mood: a review. Psychopharmacology 1991;105:1 8.

DeMartinis N, Rynn M, Rickels K, et al. Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder. J Clin Psychiatry 2000;61:91 94.

Dietch JT, Jennings RK. Aggressive dyscontrol in patients treated with benzodiazepines. J Clin Psychiatry 1988;49:184 188.

Eaton WW, Kessler RC, Wittchen HU, et al. Panic and panic disorder in the United States. Am J Psychiatry 1994;151:413 420.

Fried R. The hyperventilation syndrome. Baltimore: Johns Hopkins, 1987.

Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder. JAMA 2000;283:3082 3088.

Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: a review. Anesthesiology 1990;72:926 938.

Greenblatt DJ, Miller LG, Shader RI. Benzodiazepine discontinuation syndromes. J Psych Res 1990;24:73 79.

P.208


Greenblatt DJ, Shader RI. Benzodiazepines in clinical practice. New York: Raven, 1974.

Greenblatt DJ, Shader RI, Abernethy DR. Current status of benzodiazepines. N Engl J Med 1983;309:354 358,410 416.

Hindmarch I, Kerr JS, Sherwood N. The effects of alcohol and other drugs on psychomotor performance and cognitive function. Alcohol Alcoholism 1991;26:71 79.

Katon WJ, von Korff M, Lin E. Panic disorder: relationship to high medical utilization. Am J Med 1992;92:78 118.

King DJ. Benzodiazepines, amnesia, and sedation: theoretical and clinical issues and controversies. Hum Psychopharmacol 1992;7:79 87.

LeCrubier Y, Bakker A, Dunbar G, et al. A comparison of paroxetine, clomipramine and placebo in the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand 1997;95:145 152.

Lepola UM, Wade AG, Leinonen EV, et al. A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder. J Clin Psychiatry 1998;59:528 534.

Lucki I, Rickels K, Geller AM. Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology 1986;88:426 433.

Lydiard RB, Lesser IM, Ballenger JC, et al. A fixed-dose study of alprazolam 2 mg, alprazolam 6 mg, and placebo in panic disorder. J Clin Psychopharmacol 1992;12:96 103.

Mavissakalian M, Perel JM. Clinical experiments in the maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. Arch Gen Psychiatry 1992;49:318 323.

Mellinger GD, Balter MB, Uhlenhuth EH. Prevalence and correlates of the long-term regular use of anxiolytics. JAMA 1984;251:375 379.

Mental, behavioral, and developmental disorders. In: International classification of statistical diseases and related health disorders, tenth revision. Vol 1. Geneva: World Health Organization, 1992:311 387.

Modigh K, Westberg P, Ericksson E. Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial. J Clin Psychopharmacol 1992;12:251 261.

Murphy SM, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone. Br J Psychiatry 1989;154:529 534.

Nair NP, Bakish D, Saxena B, et al. Comparison of fluvoxamine, imipramine, and placebo in the treatment of outpatients with panic disorder. Anxiety 1996;2:21 32.

Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 1999;19:341 348.

Pohl RB, Wolkow RM, Clary CM. Sertraline in the treatment of panic disorder: a double-blind multicenter trial. Am J Psychiatry 1998;155:1189 1195.

Pollack MH, Matthews J, Scott EL. Gabapentin as a potential treatment for anxiety disorders. Am J Psychiatry 1998;155:992 993.

Rapee RM, Barlow DH, eds. Chronic anxiety. New York: Guilford, 1991.

Reich J. The epidemiology of anxiety. J Nerv Ment Dis 1986;174:129 136.

Rickels K, DeMartinis N, Aufdembrinke B. A double-blind, placebo-controlled trial of abercanil and diazepam in the treatment of patients with generalized anxiety disorder. J Clin Psychopharmacol 2000;20:12 18.

Rickels K, Schweizer E. Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol 1998;18:12S 18S.

Rickels K, Schweizer E, Case WG, et al. Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry 1990;47:899 907.

Romach MK, Somer GR, Sobell GR, et al. Characteristics of long-term alprazolam users in the community. J Clin Psychopharmacol 1992;12:316 332.

Rosenbaum JF, Moroz G, Bowden CL. Clonazepam in the treatment of panic disorder with and without agoraphobia. J Clin Psychopharmacol 1997;17:390 400.

Roy-Byrne PP, Cowley DS, eds. Benzodiazepines in clinical practice: risks and benefits. Washington, D.C.: American Psychiatric Press, 1991.

Roy-Byrne PP, Stang P, Witchen HU, et al. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Br J Psychiatry 2000;176:229 235.

Rudolph RL, Entsuah R, Chitra R. A meta-analysis of the effects of venlafaxine on anxiety associated with depression. J Clin Psychopharmacol 1998;18:136 144.

P.209


Schneier FR, Leibowitz MR, Davies SO, et al. Fluoxetine in panic disorder. J Clin Psychopharmacol 1990;10:119 121.

Shader RI. Stress, fear, and anxiety. In: Tupin JP, Shader RI, Harnett DS, eds. Handbook of clinical psychopharmacology. Northvale, NJ: Aronson, 1988:73 96.

Shader RI, Dreyfuss D, Gerrein JR, et al. Sedative effects and impaired learning and recall following single oral doses of lorazepam. Clin Pharmacol Ther 1986;39:526 529.

Shader RI, Goodman M, Gever J. Panic disorders: current perspectives. J Clin Psychopharmacol 1982;2:2S 10S.

Shader RI, Greenblatt DJ. Some practical approaches to the understanding and treatment of symptoms of anxiety and stress. In: Berger PA, Keith H, Brodie H, eds. American handbook of psychiatry. Vol. 8. New York: Basic Books, 1986:597 619.

Shader RI, Greenblatt DJ. Use of benzodiazepines in anxiety disorders. N Engl J Med 1993;328:1398 1405.

Snaith P, Owens D, Kennedy E. An outcome study of a brief anxiety management programme: anxiety control training. Irish J Psychol Med 1992;9:111 114.

Spiegel DA, Bruce TJ. Benzodiazepines and exposure-based cognitive behavior therapies for panic disorder. Am J Psychiatry 1997;154:773 781.

Stein MB, Liebowitz MR, Lydiard RB, et al. Paroxetine treatment of generalized social phobia (social anxiety disorder): a randomized controlled trial. JAMA 1998;280:708 713.

Uhlenhuth EH, Balter MB, Ban TA, et al. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications. IV. Therapeutic dose dependence and abuse liability of benzodiazepines in long-term treatment of anxiety disorders. J Clin Psychopharmacol 1999;19:23S 29S.

Van Ameringen M, Mancini C, Streiner DL. Fluoxetine efficacy in social phobia. J Clin Psychiatry 1993;54:27 32.

van Vliet IM, den Boer JA, Westenberg HG, et al. A double-blind comparative study of brofaromine and fluvoxamine in outpatients with panic disorder. J Clin Psychopharmacol 1996;16:299 306.

Wincor MZ, Munjack DJ, Palmer R. Alprazolam levels and response in panic disorder: preliminary results. J Clin Psychopharmacol 1991;11:48 51.

Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacol Rev 1992;44:151 347.

Woods JH, Katz JL, Winger G. Use and abuse of benzodiazepines: issues relevant to prescribing. JAMA 1988;260:3476 3480.

Worsening C, Lavori PW. Excess mortality among 3302 patients with pure anxiety neurosis. Arch Gen Psychiatry 1991;48:599 602.

Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. J Clin Psychiatry 1997;58:291 297.

1This chapter is partly based on other publications by both authors that appear among the works listed under Additional Reading.

2Doxepin is sometimes particularly helpful for patients with pruritus as one of their anxiety complaints. Doxepin has strong antihistaminic actions; consistent with this property, it is quite sedating. Doxepin is marketed in a topical form for pruritus. Doxepin is a CYP 2D6 inhibitor.



Manual of Psychiatric Therapeutics Paperback
Manual of Psychiatric Therapeutics: Practical Psychopharmacology and Psychiatry (Little, Browns Paperback Book Series)
ISBN: 0316782203
EAN: 2147483647
Year: 2002
Pages: 37

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