Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

53. Anxiety Disorders I: Generalized Anxiety, Panic, and Social Anxiety Disorders

Sarah T. Melton and Cynthia K. Kirkwood


 Images The long-term goal in treatment of generalized anxiety disorder is remission with minimal or no anxiety symptoms and no functional impairment.

 Images Antidepressants are the agents of choice for the management of generalized anxiety disorder.

 Images Antidepressants have a lag time of 2 to 4 weeks or longer before antianxiety effects occur in generalized anxiety disorder.

 Images When monitoring the effectiveness of antidepressants in panic disorder, it is important to allow an adequate amount of time (8 to 12 weeks) to achieve full therapeutic response.

 Images Clonazepam and alprazolam extended-release are alternatives to alprazolam immediate-release for patients with panic disorder having breakthrough panic symptoms at the end of a dosing interval.

 Images The optimal duration of panic therapy is unknown; 12 to 24 months of pharmacotherapy is recommended before gradual drug discontinuation over 4 to 6 months is attempted.

 Images Social anxiety disorder is a chronic long-term illness requiring extended therapy. After improvement, at least a 1-year medication maintenance period is recommended.

 Images The selective serotonin reuptake inhibitors or venlafaxine are considered first-line pharmacotherapy for social anxiety disorder.

 Images An adequate trial of antidepressants in generalized social anxiety disorder lasts at least 8 weeks, and maximal benefit may not be seen until 12 weeks.

 Images The three principal domains in which improvement should be observed in generalized social anxiety disorder are symptoms, functionality, and well-being.

Anxiety is an emotional state commonly caused by the perception of real or perceived danger that threatens the security of an individual. It allows a person to prepare for or react to environmental changes. Everyone experiences a certain amount of nervousness and apprehension when faced with a stressful situation. This is an adaptive response and is transient in nature.

Anxiety can produce uncomfortable and potentially debilitating psychological (e.g., worry or feeling of threat) and physiologic arousal (e.g., tachycardia or shortness of breath) if it becomes excessive. Some individuals experience persistent, severe anxiety symptoms and possess irrational fears that significantly impair normal daily functioning. These persons often suffer from an anxiety disorder.1

Anxiety disorders are among the most frequent mental disorders encountered in clinical practice. Healthcare professionals often mistake anxiety disorders for physical illnesses, and only one quarter of patients receive appropriate treatment.2 Failure to diagnose and manage anxiety disorders results in negative outcomes including overuse of healthcare resources, increased morbidity, and mortality.3 Individuals with anxiety disorders develop cardiovascular, cerebrovascular, gastrointestinal, and respiratory disorders at a significantly higher rate than the general population.4

To treat anxiety appropriately, the clinician must make a reliable diagnosis. It is essential that the distinction between short-term symptoms of anxiety and anxiety disorders be understood. Common or situational anxiety is a normal response to a stressful circumstance. Although symptoms can be severe, they are temporary and usually last no more than 2 or 3 weeks. Although short-term, “as-needed” treatment with an anxiolytic agent such as a benzodiazepine is common and can provide some symptomatic relief, prolonged drug therapy is not recommended for situational anxiety.5


Anxiety disorders, as a group, are the most commonly occurring psychiatric disorders. According to the National Comorbidity Survey Replication of the prevalence, severity, and comorbidity estimates of mental disorders in the United States, the most recent 1-year prevalence rate for anxiety disorders was 19.1% in persons aged 18 years and older. Specific phobias were the most common anxiety disorder, with a 12-month prevalence of 9.1%. The 1-year prevalence of generalized anxiety disorder (GAD) was 2.7%, that of panic disorder was 2.7%, and that of social anxiety disorder (SAD) was 7.1%.6

In general, anxiety disorders are a group of heterogeneous illnesses that develop before age 30 years and are more common in women, individuals with social issues, and those with a family history of anxiety and depression. Patients often develop another anxiety disorder, major depression, or substance abuse.13 The clinical picture of mixed anxiety and depression is much more common than an isolated anxiety disorder.7


The differential diagnosis of anxiety disorders includes medical and psychiatric illnesses and certain drugs.7 Hypotheses on the etiology of anxiety disorders are based on interactions between a combination of factors including vulnerability (e.g., genetic predisposition and early childhood adversity) and stress (e.g., occupational and traumatic experience). The vulnerability may be associated with genetic factors and neurobiologic adaptations of the central nervous system (CNS).8

Medical Diseases Associated with Anxiety

Anxiety symptoms are an inherent part of the initial clinical presentation of several diseases, thus complicating the distinction between anxiety disorders and medical disorders.4,7 Anxiety disorders are strongly and independently associated with chronic medical illness, low levels of physical health-related quality of life (QOL), and physical disability.4 If anxiety symptoms are secondary to a medical illness, they usually will subside as the medical situation stabilizes. However, the knowledge that one has a physical illness can trigger anxious feelings and further complicate therapy. Persistent anxiety subsequent to a physical illness requires further assessment for an anxiety disorder. Common somatic symptoms of anxiety that frequently present in medical disorders include abdominal pain, palpitations, tachycardia, sweating, flushing, tremor, chest pain or tightness, and shortness of breath. Although less specific, symptoms of muscle tension, headache, and fatigue are also common manifestations of anxiety. Medical disorders most closely associated with anxiety are listed in Table 53-1.4,9,10

TABLE 53-1 Common Medical Illnesses Associated with Anxiety Symptoms


Psychiatric Diseases Associated with Anxiety

Anxiety can be a presenting feature of several major psychiatric illnesses. Anxiety symptoms are extremely common in patients with mood disorders, schizophrenia, dementia, and substance-use disorders. Most psychiatric patients will have two or more concurrent psychiatric disorders (comorbidity) within their lifetime.6 It is important to diagnose and treat all comorbid psychiatric conditions in patients with anxiety disorders.

Drug-Induced Anxiety

Drugs are a common cause of anxiety symptoms (Table 53-2). Anxiety occurs during the use of CNS-stimulating drugs in a dose-dependent manner, but ingestion of minimal amounts can result in marked anxiety, including panic attacks, in some individuals. The onset of drug-induced anxiety is usually rapid after the initiation of therapy. A thorough medication history evaluating for a recent drug or dosage change is important to rule out a drug-induced etiology for the anxiety.

TABLE 53-2 Drugs Associated with Anxiety Symptoms


Anxiety occurs occasionally during the use of CNS depressants, especially in children and the elderly; however, anxiety complaints are more common as complications of drug withdrawal after the abrupt discontinuation of these agents.7,10


Data from biochemical and neuroimaging studies indicate that the modulation of normal and pathologic anxiety states is associated with multiple regions of the brain and abnormal function in several neurotransmitter systems, including norepinephrine (NE), γ-aminobutyric acid (GABA), serotonin (5-HT), corticotropin-releasing factor (CRF), and cholecystokinin.11 Current neuroanatomic models of fear (i.e., the response to danger) and anxiety (i.e., the feeling of fear that is disproportionate to the actual threat) include some key brain areas. The amygdala, a temporal lobe structure, plays a critical role in the assessment of fear stimuli and learned response to fear.11,12 The locus ceruleus (LC), located in the brain stem, is the primary NE-containing site, with widespread projections to areas responsible for implementing fear responses (e.g., vagus, lateral and paraventricular hypothalamus). The hippocampus is integral in the consolidation of traumatic memory and contextual fear conditioning. The hypothalamus is the principal area for integrating neuroendocrine and autonomic responses to a threat.11,12

Neurochemical Theories

Noradrenergic Model

The basic premise of the noradrenergic theory is that the autonomic nervous system of anxious patients is hypersensitive and overreacts to various stimuli. Many anxious patients clearly display symptoms of peripheral autonomic hyperactivity. In response to threat or fearful situations, the LC serves as an alarm center, activating NE release and stimulating the sympathetic and parasympathetic nervous systems. Chronic central noradrenergic overactivity downregulates α2-adrenoreceptors in patients with GAD. This receptor is hypersensitive in some patients with panic disorder.11 By administering drugs that have a relatively specific effect on the LC, researchers have further explored the NE theory of anxiety and panic disorder. Drugs with anxiogenic effects (e.g., yohimbine [an α2-adrenergic receptor antagonist]) stimulate LC firing and increase noradrenergic activity. NE in turn increases glutamate release (an excitatory neurotransmitter).11 This produces subjective feelings of anxiety and can precipitate a panic attack in those with panic disorder, but not in normal volunteers.11 Drugs with anxiolytic or antipanic effects (e.g., benzodiazepines and antidepressants) inhibit LC firing, decrease noradrenergic activity, and block the effects of anxiogenic drugs.11

GABA Receptor Model

There are two superfamilies of GABA protein receptors: GABAA and GABAB. Drugs that reduce anxiety and produce sedation target the GABAA receptor. The GABAB receptor is a G-protein–coupled receptor postulated to be involved in the presynaptic inhibition of GABA release.1113 GABAA receptors are ligand-gated ion channels composed of five protein subunits. Several classes of subunits (i.e., α1–6β1–3γ1–3δ, ε, θ, π, ρ1–3) surround a central pore, and the receptor is connected to the cytoskeleton.14 Benzodiazepine ligands enhance the inhibitory effects of GABA.14 GABA, the major inhibitory neurotransmitter in the CNS, has a strong regulatory or inhibitory effect on the 5-HT, NE, and dopamine (DA) systems. When GABA binds to the GABAA receptor, neuronal excitability is reduced.

The specific role of the GABA receptors in anxiety disorders has not been established. The number of GABAA receptors can change with alterations in the environment (e.g., chronic stress), and the subunit expression can be altered by hormonal changes.14 In patients with GAD, benzodiazepine binding in the left temporal lobe is reduced.14 Abnormal sensitivity to antagonism of the benzodiazepine binding site and decreased binding was demonstrated in panic disorder.11,14 This is consistent with the suggestion that panic disorder is secondary to a lack of central inhibition that results in uncontrolled elevations in anxiety during panic attacks.13 Examination of whole brain and regional GABA in patients with SAD using proton magnetic resonance spectroscopy showed impairment of the GABA system.15

Serotonin Model

Although there are data suggesting that the 5-HT system is dys-regulated in patients with anxiety disorders, definitive evidence that shows a clear abnormality in 5-HT function is lacking. 5-HT is primarily an inhibitory neurotransmitter that is used by neurons originating in the raphe nuclei of the brain stem and projecting diffusely throughout the brain (e.g., cortex, amygdala, hippocampus, and limbic system). Abnormalities in serotonergic functioning through release and uptake at the presynaptic autoreceptors (5-HT1A/1D), the serotonin reuptake transporter (SERT) site, or effect of 5-HT at the postsynaptic receptors (e.g., 5-HT1A, 5-HT2A, and 5-HT2C) may play a role in anxiety disorders.11,13 Preclinical models suggest that greater 5-HT function facilitates avoidance behavior; however, primate studies show that reducing 5-HT increases aggression.11,13 It is postulated that greater 5-HT activity reduces NE activity in the LC, inhibits defense/escape response via the periaqueductal gray (PAG) region, and reduces hypothalamic release of CRF. The selective serotonin reuptake inhibitors (SSRIs) acutely increase 5-HT levels by blocking the SERT to increase the amount of 5-HT available postsynaptically, and are efficacious in blocking the manifestations of panic and anxiety.11

Low 5-HT activity may lead to a dysregulation of other neurotransmitters. NE and 5-HT systems are closely linked, and interactions between the two are reciprocal and vary. NE may act at presynaptic 5-HT terminals to decrease 5-HT release, and its activity at postsynaptic receptors can cause increased 5-HT release.

Buspirone is a selective 5-HT1A partial agonist that is effective for GAD but not for panic disorder. Because the selective 5-HT1A partial agonists reduce serotonergic activity, GAD symptoms may reflect excessive 5-HT transmission or overactivity of the stimulatory 5-HT pathways.16 There is circumstantial evidence for the involvement of serotonergic and dopaminergic systems in the pathophysiology of generalized SAD.17

Neuroimaging Studies

Functional neuroimaging studies support the crucial role of the amygdala, anterior cingulate cortex (ACC), and insula in the pathophysiology of anxiety.12 In GAD there is an abnormal increase in the brain’s fear circuitry, as well as increased activity in the prefrontal cortex, which appears to have a compensatory role in reducing GAD symptoms.18 Patients with panic have abnormalities of midbrain structures, including the PAG. Neuroimaging studies have shown activation of insula and upper brain stem (including the PAG), as well as deactivation of the ACC during experimental panic attacks.19 Patients with SAD have greater activity than matched comparison subjects in the amygdala and insula, structures linked to negative emotional responses.20,21 Both pharmacotherapy and psychotherapy decreased cerebral blood flow in the amygdala, hippocampus, and surrounding cortical areas in patients with SAD.21


The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision classifies anxiety disorders into several categories: GAD, panic disorder (with or without agoraphobia), agoraphobia, SAD, specific phobia, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and acute stress disorder.1 The characteristic features of these illnesses are anxiety and avoidance behavior. Anxiety symptoms must cause significant distress and impairment in social, occupational, or other areas of functioning, and should not be secondary to a drug or illicit substance or a general medical disorder, or occur solely as part of another psychiatric disorder.1 OCD and PTSD are discussed in Chapter 54.

Generalized Anxiety Disorder

The diagnostic criteria for GAD require persistent symptoms for most days for at least 6 months.1 The essential feature of GAD is unrealistic or excessive anxiety and worry about a number of events or activities.1 The anxiety or apprehensive expectation is accompanied by at least three psychological or physiologic symptoms. Anxiety and worry are not confined to features of another psychiatric illness (e.g., having a panic attack, being embarrassed in public).1

The onset, course of illness, and comorbid conditions of GAD are important considerations. GAD has a gradual onset with an average age of 21 years; however, there is a bimodal distribution. Onset occurs earlier when GAD is the primary presentation and later when GAD is secondary. GAD can be exacerbated or precipitated in later life by severe psychological stressors. Most patients present between the ages of 35 and 45 years, with women twice as likely to have GAD as men. The course of the illness is chronic (i.e., episodes can last for a decade or longer); there is a high percentage of relapse and low rates of recovery. The likelihood of remission at 2 years is 25%.1 Patients report substantial interference with their lives and have a high probability of seeking treatment.9 Lifetime comorbidity with another psychiatric disorder occurs in 90% of patients with GAD, with depression being found in over 60%.9

CLINICAL PRESENTATION Generalized Anxiety Disorder

Psychological and Cognitive Symptoms

    • Excessive anxiety

    • Worries that are difficult to control

    • Feeling keyed up or on edge

    • Poor concentration or mind going blank

Physical Symptoms

    • Restlessness

    • Fatigue

    • Muscle tension

    • Sleep disturbance

    • Irritability

Data from references 1 and 22.


Psychological Symptoms

    • Depersonalization

    • Derealization

    • Fear of losing control, going crazy, or dying

Physical Symptoms

    • Abdominal distress

    • Chest pain or discomfort

    • Chills

    • Dizziness or light-headedness

    • Feeling of choking

    • Hot flushes

    • Palpitations

    • Nausea

    • Paresthesias

    • Shortness of breath

    • Sweating

    • Tachycardia

    • Trembling or shaking

Data from references 1, 22, and 23.

Panic Disorder

Panic disorder begins as a series of unexpected (spontaneous) panic attacks involving an intense, terrifying fear similar to that caused by life-threatening danger. The unexpected panic attacks are followed by at least 1 month of persistent concern about having another panic attack, worry about the possible consequences of the panic attack, or a significant behavioral change related to the attacks.1 During an attack, patients describe at least four physiologic and physical symptoms. Panic attacks usually last no more than 20 to 30 minutes, with the peak intensity of symptoms within the first 10 minutes. Often patients seek help at a physician’s office or emergency department, only to have their symptoms resolve before or on arrival. Because panic symptoms mimic those present in several medical conditions, patients often are misdiagnosed, and multiple referrals are common.1


Fears of Being

    • Scrutinized by others

    • Embarrassed

    • Humiliated

Some Feared Situations

    • Eating or writing in front of others

    • Interacting with authority figures

    • Speaking in public

    • Talking with strangers

    • Use of public toilets

Physical Symptoms

    • Blushing

    • “Butterflies in the stomach”

    • Diarrhea

    • Sweating

    • Tachycardia

    • Trembling


    • Generalized: fear and avoidance extend to a wide range of social situations

    • Nongeneralized: fear limited to one or two situations

Data from references 1, 25, and 26.

Secondary to the panic attacks, up to 70% of patients develop agoraphobia.23,24 Agoraphobia is anxiety about being in places or situations in which escape might be difficult or where help might not be available in the event of a panic attack.1 As a result, patients often avoid specific situations (e.g., being in a crowd or flying) in which they fear a panic attack might occur.1

Complications of panic disorder include depression (10% to 65% have major depressive disorder), alcohol abuse, and high use of health services and emergency rooms.1 Patients with panic disorder have a high lifetime risk for suicide attempts compared with the general population.23,24 The usual course is chronic but waxing and waning.

Social Anxiety Disorder

SAD is characterized by an intense, irrational, and persistent fear of being negatively evaluated or scrutinized in at least one social or performance situation. Exposure to the feared circumstance usually provokes an immediate situation-related panic attack. In generalized SAD, fear and avoidance extend to various social situations, whereas in the nongeneralized form of SAD, fear is confined to only one or two social situations. Blushing is the principal physical indicator and distinguishes SAD from other anxiety disorders. Adults with SAD usually recognize their fear is excessive and unreasonable; however, they are unable to overcome it without treatment. If necessary, the feared situation is avoided or endured with significant distress.1 In individuals younger than 18 years of age, the duration of symptoms must be at least 6 months to meet the diagnostic criteria.1

The mean age of onset of SAD is during the mid-teens. Rates of SAD are slightly higher among women than among men and more frequent in younger cohorts. It is a chronic disorder with a mean duration of 20 years.1 People with SAD can be reluctant to seek professional help despite the existence of beneficial treatments because consultation with a clinician is perceived as a feared social interaction.25

Differentiating SAD from other anxiety disorders can be difficult. Panic attacks occur in both SAD and panic disorder, but the distinction between the two is the rationale behind fear; fear of anxiety symptoms is characteristic of panic disorder, whereas fear of embarrassment from social interaction typifies SAD.1,26 A majority of SAD patients eventually develop a concurrent mood, anxiety, or substance abuse disorder.25,26

Specific Phobia

Specific phobia is marked and persistent fear of a circumscribed object or situation (e.g., insects or heights). Apart from contact with the feared object or situation, the patient is usually free of symptoms. Most persons simply avoid the feared object and adjust to certain restrictions on their activities.1


Generalized Anxiety Disorder

Desired Outcomes

The goals of therapy in the acute management of GAD are to reduce the severity and duration of the anxiety symptoms and to improve overall functioning. Images The long-term goal in GAD is remission with minimal or no anxiety symptoms, no functional impairment, and increased QOL.9 Prevention of recurrence is another long-term consideration.

General Approach to Treatment

Once GAD is diagnosed, a patient-specific treatment plan, which usually consists of both psychotherapy and drug therapy, is developed. The plan depends on the severity and chronicity of symptoms, age, medication history, and comorbid medical and psychiatric conditions.9 Factors such as anticipated adverse effects, history of prior response in the patient or family member, patient preference, and cost should be considered when treatment is initiated. Psychotherapy is the least invasive and safest treatment modality. Antianxiety medication is indicated for patients experiencing symptoms severe enough to produce functional disability. Table 53-3 lists drug choices for GAD, panic disorder, and SAD.

TABLE 53-3 Drug Choices for Anxiety Disorders


Nonpharmacologic Therapy

Nonpharmacologic treatment modalities in GAD include psychoeducation, short-term counseling, stress management, psychotherapy, meditation, or exercise. Psychoeducation includes information on the etiology and management of GAD. Anxious patients should be instructed to avoid caffeine, nonprescription stimulants, diet pills, and excessive use of alcohol. Most patients with GAD require psychological therapy, alone or in combination with antianxiety drugs, to overcome fears and to learn to manage their anxiety and worry.5 Cognitive behavioral therapy (CBT) is the most effective psychological therapy in GAD patients. CBT for GAD includes self-monitoring of worry, cognitive restructuring, relaxation training, and rehearsal of coping skills.5 Psychotherapy or medication alone has comparable efficacy in acute treatment.22 The relapse rate with CBT is less than with other types of psychological modalities.22Controlled trials comparing the efficacy of combining drug and psychotherapy over long-term treatment are lacking.22 Advantages of CBT over pharmacotherapy include patient preference and lack of troubling adverse effects. However, CBT is not widely available, requires specialized training, and entails weekly sessions for an extended time period (i.e., 12 to 20 weeks).5

Pharmacologic Therapy

The benzodiazepines are the most effective and commonly prescribed drugs for the rapid relief of acute anxiety symptoms (Table 53-4). All benzodiazepines are equally effective anxiolytics, and consideration of pharmacokinetic properties and the patient’s clinical situation will assist in the selection of the most appropriate agent.5,33

TABLE 53-4 Benzodiazepine Antianxiety Agents


Because of the lack of dependency and tolerable adverse effect profile, antidepressants have emerged as the treatment of choice for the management of chronic anxiety, especially in the presence of comorbid depressive symptoms. Buspirone is an additional anxiolytic option (Table 53-5) in patients without comorbid depression or other anxiety disorders (e.g., panic disorder and SAD). Because of the high risk of adverse effects and toxicity, barbiturates, antipsychotics, antipsychotic–antidepressant combinations, and antihistamines generally are not indicated in the treatment of GAD.3 The benzodiazepines are more effective in treating the somatic and autonomic symptoms of GAD as opposed to the psychic symptoms (e.g., apprehension and worry), which are reduced by antidepressants.3

TABLE 53-5 Nonbenzodiazepine Antianxiety Agents for Generalized Anxiety Disorder


The most recent treatment guidelines from the World Federation of Societies of Biological Psychiatry and the National Institute for Health and Clinical Evidence are evidence-based.3,28 A descriptive flowchart with recommendations based on levels of evidence from the International Psychopharmacology Algorithm Project for the psychosocial and pharmacologic management of GAD is shown in Figure 53-1.40


FIGURE 53-1 International Psychopharmacology Algorithm Project (IPAP) generalized anxiety disorder (GAD) algorithm flowchart. Yellow, first-line treatment (nodes 3–6); green, second-line treatment (nodes 8–12); blue, third-line treatment, no comorbidity (nodes 13–16); orange, third-line treatment, with comorbidity (nodes 14–16); light green, assessment and evaluation. Levels of evidence used in development of the flowchart were: 1, more than one placebo-controlled trial with sample sizes over 30; 2, one placebo-controlled trial (or active vs. active drug comparison) with sample size of 30 or greater; 3, one or small (n <30) placebo-controlled trial; 4, case reports or open-label trials; and 5, expert consensus without published evidence. (Flowchart is used by permission of the International Psychopharmacology Algorithm Project,

Alternative Drug Treatments

Hydroxyzine, pregabalin, and atypical antipsychotics are alternatives.9,22,34 The antihistamine hydroxyzine was effective in studies conducted for as long as 12 weeks in patients with GAD. Hydroxyzine is commonly used in the primary care setting, but it is considered be to be a second-line agent because of adverse effects and lack of efficacy for comorbid disorders.9 Pregabalin, which binds to the α2δ subunit of voltage-gated calcium channels to reduce nerve terminal calcium influx, acts on “hyperexcited” neurons. Pregabalin produced anxiolytic effects similar to lorazepam, alprazolam, and venlafaxine in acute efficacy trials.33 Quetiapine extended-release 150 mg/day monotherapy was superior to placebo in three studies, and as effective as paroxetine 20 mg/day and escitalopram 10 mg/day but with an earlier onset of action.34 In a 52-week treatment of GAD, quetiapine extended-release was superior to placebo in the prevention of anxiety relapse.34 Quetiapine is not FDA-approved for GAD, and the long-term risks and benefits of atypical antipsychotics in the treatment of GAD are unclear.34 Analysis of data from a pooled sample of trials found kava kava to be no more effective than placebo.41 Because of reports of hepatotoxicity, kava kava is not recommended as an anxiolytic.41 Although valerian, St. John’s wort, and passionflower have been used to manage GAD, there is insufficient evidence of their effectiveness and safety.42

Clinical Controversy

Pregabalin is classified as first-line treatment for GAD in evidence-based guidelines and is approved for treatment of anxiety in Europe. However, pregabalin is not approved for GAD in the United States, and experts with the IPAP pharmacologic algorithm do not support the first-line position of pregabalin because of lack of clinical experience and lack of data to establish efficacy for comorbid conditions.

Antidepressant Therapy

Images Antidepressants are considered first-line agents in the management of GAD. Venlafaxine extended-release, duloxetine, paroxetine, and escitalopram are FDA-approved antidepressants for GAD (see Table 53-5). Imipramine is considered a second-line agent, despite its efficacy, because of higher toxicity and adverse effect rates.3 Images The antianxiety response of antidepressants is delayed by 2 to 4 weeks or longer.3 The pharmacology, pharmacokinetics, and drug interactions of the antidepressants are reviewed in Chapter 51.

Efficacy Antidepressants are efficacious in the acute and long-term management of GAD. Data support the use of the SSRIs (e.g., escitalopram, paroxetine, sertraline), and the serotonin–norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine extended-release and duloxetine), for acute therapy (8- to 12-week trials) with response rates between 60% and 68%, and remission rates of 30%.3,22 A recent meta-analysis indicated that fluoxetine was most likely to achieve remission of GAD symptoms and sertraline was the most well tolerated. In a subanalysis comparing duloxetine, escitalopram, paroxetine, venlafaxine, and pregabalin, duloxetine was most likely to produce a beneficial response, escitalopram most likely to establish a remission, and pregabalin was best tolerated.43

Mechanism of Action The mechanism of action of antidepressants in anxiety disorders is not fully understood. Research indicates that antidepressants modulate receptor activation of neuronal signal transduction pathways connected to the neurotransmitters 5-HT, DA, and NE. In an animal model of anxiety, a number of candidate genes were identified that were normalized by fluoxetine treatment selectively in the hypothalamus.44 It is theorized that by activating stress-adapting pathways, SSRIs and SNRIs reduce the somatic anxiety symptoms and the general distress experienced by patients.

Adverse Effects The adverse effects of medications used to treat generalized anxiety are given in Table 53-6. SSRIs and SNRIs are generally well tolerated, with GI adverse effects and sleep disturbances being the most commonly reported. Headaches and diaphoresis occur early in treatment and are often transient, whereas weight gain and sexual dysfunction may continue in long-term treatment. The use of tricyclic antidepressants (TCAs) is limited by troublesome adverse effects (e.g., sedation, anticholinergic effects, and weight gain) in some patients and the risk of toxicity in overdose.

TABLE 53-6 Monitoring of Adverse Effects Associated with Medications Used in the Treatment of Anxiety Disorders



Dosing and Administration The antidepressants can be dosed once a day (see Table 53-5). Some patients require small initial daily doses for the first week of therapy.

Benzodiazepine Therapy

Although all benzodiazepines possess anxiolytic properties, only 7 of the 14 currently marketed agents have FDA approval for the treatment of GAD (see Table 53-4). Estazolam, flurazepam, temazepam, quazepam, and triazolam are marketed as sedative–hypnotic agents. Clonazepam is marketed as an antipanic agent and anticonvulsant,45 and midazolam is labeled for preoperative sedation. Alprazolam is indicated for the treatment of panic disorder with or without agoraphobia, as well as GAD.46 Clobazam in indicated for adjunctive treatment of seizures in Lennox-Gastaut syndrome.32

Pharmacology and Mechanism of Action The GABA receptor model of anxiety theorizes that benzodiazepines ameliorate anxiety through potentiation of the inhibitory activity of GABA.14 Benzodiazepines bind on the GABAAreceptor at the α1α2α3, and α5 subunits in combination with a β subunit and the γ2 subunit.14 The anxiolytic effects of benzodiazepines are mediated at the α2 site, while sedative effects result from binding at the α1 subunit. The binding sites of benzodiazepines and GABA are at the receptor interfaces of α/β and α/γ2, respectively. The GABA receptor controls tonic inhibition to reduce neuronal excitability.14 Other neurotransmitters (e.g., 5-HT, NE, and DA) may also be involved in benzodiazepine activity.

Pharmacokinetics A wide difference in milligram potency exists between the benzodiazepine compounds; however, when appropriately dosed, all agents have similar anxiolytic and sedative–hypnotic activity. The variations in lipid solubility between compounds influence the pharmacokinetic properties of benzodiazepines. Knowledge of the different pharmacokinetic and pharmacodynamic properties can assist in choosing an appropriate anxiolytic (Table 53-7). After a single dose, the onset, intensity, and duration of pharmacologic effects are important factors to consider when using benzodiazepines for the short-term, intermittent, or as-needed treatment of anxiety.

TABLE 53-7 Pharmacokinetics of Benzodiazepine Antianxiety Agents


The primary determinant of a drug’s onset of effect after a single oral dose is the rate of drug absorption. Because of high lipophilicity, diazepam, and clorazepate are absorbed rapidly and distributed quickly into the CNS. Therefore, the onset of anxiolytic effect occurs within 30 to 60 minutes, which results in a rapid and intense relief of anxiety. High lipophilicity also increases the extent of drug redistribution into the periphery, particularly adipose tissue, resulting in a shorter duration of effect after a single dose than is suggested by single-dose elimination half-life studies.47 Clinically, patients perceive a rapid onset of action, but some experience an unpleasant feeling of drowsiness or loss of control. This “rush” can be euphoric and contribute to abuse.

Compared with diazepam, lorazepam and oxazepam are relatively less lipophilic and have a slower absorption and onset of effect. These benzodiazepines have smaller volumes of distribution and a resulting longer duration of action.47

Parenteral administration via the intramuscular route should be avoided with diazepam secondary to variability in the rate and extent of drug absorption. Intramuscular lorazepam provides rapid, reliable, and complete absorption.

After multiple dosing, the rate and extent of drug accumulation are functions of the drug’s elimination half-life in relation to dosing intervals, clearance, and formation of active metabolites. Differences in clinical effects that occur during and after repeated dosages with the benzodiazepines are related in part to variability in metabolism and metabolite accumulation.47

The benzodiazepines undergo two primary metabolic processes, hepatic oxidation (catalyzed by cytochrome P450 3A4) and glucuronide conjugation. With the exception of lorazepam and oxazepam (which are conjugated only) and clonazepam (which undergoes nitroreduction), all benzodiazepines are oxidized first and then conjugated and excreted renally.47 Diazepam’s metabolism is also catalyzed by cytochrome P450 2C19. Oxidation can be impaired in patients with liver disease, in the elderly, and in those who simultaneously use drugs that inhibit oxidation resulting in higher levels of the parent drug and/or an active metabolite.

Many benzodiazepines are converted to desmethyldiazepam (DMDZ), an active metabolite with a long elimination half-life (Table 53-7). DMDZ is further oxidized to oxazepam and then conjugated and excreted. After multiple dosing, accumulation of DMDZ is slow and extensive, providing a long-lasting antianxiety effect. If oxidation of DMDZ is impaired, the half-life is prolonged, and extensive drug accumulation can result with repeated dosing.

Clorazepate is a prodrug and possesses no anxiolytic effects until metabolized to DMDZ. Before absorption, clorazepate is metabolized rapidly in the stomach through a pH-dependent process under acidic conditions.

Benzodiazepines with shorter half-lives (e.g., alprazolam, lorazepam, and oxazepam) reach steady-state plasma concentrations rapidly, and drug accumulation after repeated dosing is minimal. Oxazepam and lorazepam have no active metabolites.

Benzodiazepine protein binding is extensive, especially for the drugs with a long elimination half-life. After a single dose of a benzodiazepine with a long elimination half-life, the expected duration of clinical activity may not parallel the drug’s pharmacokinetic half-life because of drug redistribution.47 After multiple dosing, drugs with long elimination half-lives and active metabolites require 1 to 2 weeks to reach steady state.

Efficacy Clinical trials of benzodiazepines show that 65% to 75% of patients with GAD have a marked to moderate response, with most of the improvement occurring in the first 2 weeks of therapy.28,29Benzodiazepines are more effective on the somatic symptoms of anxiety and fail to obviate the cognitive or psychic symptoms (e.g., worry).

Adverse Effects The most common adverse events associated with benzodiazepine therapy involve CNS depression (Table 53-6). This is manifested clinically as drowsiness, sedation, psychomotor impairment, and ataxia.48 A transient mild drowsiness is experienced commonly by patients during the first few days of treatment; however, tolerance often develops. Disorientation, depression, confusion, irritability, aggression, and excitement are reported.48

Impairment of memory and recall also can occur during benzodiazepine treatment. The memory loss induced by the benzodiazepines typically is limited to events occurring after drug ingestion (anterograde amnesia).48Anterograde amnesia is secondary to disordered consolidation processes that store information and is not impairment in the perception or retrieval of information.2 Benzodiazepines with high affinity for binding to the benzodiazepine receptor (e.g., alprazolam) appear to possess a higher potential for amnesia.48

Abuse, Dependence, Withdrawal, and Tolerance Two serious complications of benzodiazepine therapy are the potential for abuse and development of physical dependence. Benzodiazepine abuse is rare in the general population of users; however, individuals with a history of multiple drug abuse (e.g., alcohol or sedatives) are at the greatest risk for becoming benzodiazepine abusers.5,48

Because of the chronicity of illness, persons with GAD and panic disorder are at high risk of developing benzodiazepine dependence. Benzodiazepine dependence is a physiologic phenomenon demonstrated by the appearance of a predictable abstinence syndrome (withdrawal symptoms) on abrupt discontinuation of therapy.48 Withdrawal symptoms can result because of the sudden dissociation of a benzodiazepine from its receptor site. After abrupt discontinuation, an acute decrease in GABA neurotransmission results, producing a less inhibited CNS.

Benzodiazepine Discontinuation After benzodiazepine therapy is discontinued suddenly, several events can occur. Rebound anxiety represents an immediate but transient return of original symptoms having an increased intensity compared with baseline. Recurrence or relapse is the return of original symptoms with similar intensity as before treatment.

Withdrawal symptoms are the emergence of new symptoms and a worsening of preexisting symptoms after benzodiazepine discontinuation. Symptoms can persist for days to weeks and resolve gradually over months.

Common symptoms of benzodiazepine withdrawal include anxiety, insomnia, restlessness, muscle tension, and irritability. Less frequently occurring symptoms are nausea, malaise, coryza, blurred vision, diaphoresis, nightmares, depression, hyperreflexia, and ataxia. Tinnitus, confusion, paranoid delusions, hallucinations, and seizures occur rarely. Withdrawal seizures can occur with both therapeutic and high doses of benzodiazepines with a short elimination half-life, usually within 3 days of drug discontinuation. They can occur approximately 1 week after discontinuation of agents with a long elimination half-life. High benzodiazepine doses, a long duration of therapy, and concurrent ingestion of drugs that lower the seizure threshold are risk factors for withdrawal seizures.

The onset of withdrawal symptoms in patients ingesting benzodiazepines with short elimination half-lives occurs much earlier (within 24 to 48 hours) than in those taking benzodiazepines with long elimination half-lives (within 3 to 8 days). Other factors associated with an increased incidence and severity of benzodiazepine withdrawal include high doses and long-term benzodiazepine therapy.

A strategy to minimize the severity of benzodiazepine withdrawal is a 25% per week reduction in dosage until 50% of the dose is reached, and then dosage reduction by one eighth every 4 to 7 days.49 If therapy exceeds 8 weeks, a slow dosage taper over 2 to 3 weeks is recommended; however, if the duration of treatment is 6 months, a taper over 4 to 8 weeks should ensue.49 Long-term use of benzodiazepines (i.e., 1 year or longer) requires a 2- to 4-month slow taper.49 Tapering will not eliminate the emergence of withdrawal symptoms entirely but will prevent severe withdrawal. Slow drug taper is extremely important for the drugs with a short elimination half-life, because some individuals have greater difficulty with discontinuation. Withdrawal symptoms with short half-life benzodiazepines were no more severe than with longer half-life agents; therefore, switching from a short- to long-acting benzodiazepine before gradual taper is not supported.48,49 The addition of CBT facilitated benzodiazepine tapering in patients with GAD.50 Adjunctive use of carbamazepine or pregabalin can help reduce withdrawal severity during the benzodiazepine taper.49,51 Patients should avoid the intake of alcohol and stimulants during the withdrawal process. Although tolerance develops to the sedative, muscle relaxant, and anticonvulsant activities, the benzodiazepines do not appear to lose anxiolytic or antipanic efficacy. However, the anxiolytic efficacy of benzodiazepines in long-term clinical trials (greater than 6 to 8 months of chronic use) has not been documented.5

Drug Interactions Drug interactions with the benzodiazepines generally fall into two categories: pharmacodynamic and pharma-cokinetic. Simultaneous use of alcohol and a benzodiazepine results in additive CNS depressant effects. In addition, concurrent use of a benzodiazepine and other drugs with CNS depressant properties (e.g., opioids, antipsychotics, and antihistamines) can potentiate the adverse sedative effects. When ingested alone in an overdose attempt, benzodiazepines are rarely life-threatening; however, the combination of benzodiazepines with alcohol or other CNS depressant agents is potentially fatal.

Concurrent use of medications that inhibit cytochrome P450 3A4 (e.g., ketoconazole, nefazodone, and ritonavir) can increase the blood levels of alprazolam and diazepam. Drugs that induce cytochrome P450 3A4 (e.g., carbamazepine, St. John’s wort) can reduce benzodiazepine levels. Consult a drug interaction website ( for further information.

Dosing and Administration Benzodiazepine dosage requirements vary widely among patients and must be individualized. Therapy should be initiated using low doses (e.g., alprazolam 0.25 mg three times a day or equivalent doses of other benzodiazepines) and titrated upward to relieve anxiety symptoms and avoid adverse events. After an initial treatment response is achieved, agents with long elimination half-lives can be dosed at bedtime. Dosage adjustments should be made weekly. Three to 4 weeks of a daily dose at the maximum dose constitutes an adequate clinical trial (see Table 53-4).5

The duration of benzodiazepine therapy for the acute management of anxiety should be limited to 2 to 4 weeks. In general, benzodiazepines should be used with a regular dosing regimen and not on an as-needed basis.9 Only in the treatment of short-term distress (e.g., air travel, dental phobia) as-needed use may be justified.3,9 Individuals with persistent symptoms should be managed with antidepressants because of the risk of dependence with continued benzodiazepine therapy.

Patient education should include the anticipated length of drug therapy, potential side effects, and consequences of the ingestion of alcohol and other CNS depressants. Patients should understand that benzodiazepines provide symptomatic relief but do not solve underlying psychological problems. Patients should be instructed not to decrease or discontinue benzodiazepine usage without contacting their prescriber.

Buspirone Therapy

Buspirone is a nonbenzodiazepine anxiolytic that lacks anticonvulsant, muscle relaxant, hypnotic, motor impairment, and dependence properties. It is considered to be a second-line agent for GAD because of inconsistent reports of efficacy (particularly long term), delayed onset of effect (i.e., 2 weeks or longer), and lack of efficacy for other potential concurrent depressive and anxiety disorders.52 Unlike benzodiazepines, buspirone is effective for the psychic symptoms of anxiety.52

Pharmacology and Mechanism of Action Buspirone’s anxiolytic mechanism of action is unknown. It is thought to exert its anxiolytic effect through partial agonist activity at the 5-HT1A presynaptic receptors, thus reducing the firing of 5-HT neurons.47

Pharmacokinetics After an oral dose, buspirone is absorbed rapidly and completely and undergoes extensive first-pass metabolism. The mean elimination half-life is 2.5 hours, and it must be dosed two to three times daily, which adversely affects adherence to the drug regimen.47

Adverse Effects Adverse events include dizziness, nausea, and headaches47 (Table 53-6).

Drug Interactions Drugs that inhibit cytochrome P450 3A4 (e.g., verapamil, itraconazole, fluvoxamine) can increase buspirone levels. Rifampin caused a 10-fold reduction in buspirone levels. Buspirone reportedly elevates blood pressure in patients taking a monoamine oxidase inhibitor (MAOI).

Dosing and Administration The dose of buspirone can be titrated in increments of 5 mg/day every 2 to 3 days as needed.47 The onset of improvement in psychic symptoms precedes the relief of somatic symptoms; maximum therapeutic benefit might not be evident for 4 to 6 weeks.

Buspirone is a treatment option for patients with GAD, particularly for patients with uncomplicated GAD, in patients who fail other anxiolytic therapies, or in patients with substance abuse. It is not useful in clinical situations requiring immediate anxiolysis or for situations requiring as-needed anxiolytic therapy.47 Evidence suggests that buspirone may have less efficacy in patients who have previously used benzodiazepines.29

Special Populations

The management of anxiety in patients with substance abuse, pregnant women, children, elderly patients, and those patients with adherence problems requires special consideration in the choice of anxiolytic. Patients with GAD may misuse alcohol, cannabis, or other substances to manage anxiety. The symptoms of GAD are similar to those of withdrawal, and it is difficult to confirm the diagnosis of GAD until after abstinence is obtained. Benzodiazepine therapy should be avoided in this population.

There is evidence that maternal anxiety during pregnancy and the postpartum period potentially pose significant risk to the child. Clinical practice guidelines for anxiety disorders recommend use of fluoxetine, sertraline, or citalopram; however, jitteriness, myoclonus, and irritability in the neonate and premature infant have been reported.53 Paroxetine (Pregnancy Category D) should be avoided in pregnant women because of risk of cardiovascular malformations.35

Cleft lip, cleft palate, and other teratogenic effects are associated with benzodiazepine use, but a causal relationship is inconclusive. Clinicians should avoid benzodiazepine use during the first trimester, use the lowest dosage for the shortest period of time, divide the total daily dosage into two or three doses to prevent high peak plasma levels, and use the agent as monotherapy.9,53 Benzodiazepine risks during the third trimester include sedation, withdrawal symptoms, and “floppy baby syndrome” (e.g., hypotonia, low Apgar scores, hypothermia). Alprazolam should be avoided during pregnancy because of neonatal withdrawal. Should benzodiazepines be required during pregnancy, the preferred agents are diazepam and chlordiazepoxide.54 The antidepressants are favored for GAD during pregnancy based on safety considerations. Diazepam and clonazepam should not be used in nursing mothers because infants can experience sedation, lethargy, and weight loss.9

There are few controlled clinical trials of drugs in children and adolescents with GAD. CBT alone or in conjunction with antidepressants can have long-term benefits.9 Randomized controlled trials of fluvoxamine, fluoxetine, sertraline, and venlafaxine extended-release indicate short-term efficacy3,55; however, behavioral activation was reported with clonazepam.3 No antidepressant is FDA-indicated for GAD in children or adolescents. Increased monitoring for behavioral activation with benzodiazepines and suicide-related adverse effects with antidepressants is necessary if these agents are prescribed.

Patients with hepatic disease are at risk for drug accumulation and subsequent complications. Duloxetine use should be avoided in patients with hepatic insufficiency.36 Drug accumulation of benzodiazepines can result in the elderly secondary to a decreased capacity for oxidation and alterations in the volume of distribution. Therefore, intermediate- or short-acting benzodiazepines without active metabolites are preferred for chronic use. Elderly patients are also sensitive to the CNS adverse effects of benzodiazepines (regardless of half-life), and their use is associated with a high frequency of falls and hip fractures. Recent studies of buspirone, duloxetine, escitalopram, sertraline, venlafaxine, and pregabalin showed efficacy in elderly patients with GAD.3,5658

Personalized Pharmacotherapy

The need for treatment is determined by patient-specific factors including severity and duration of symptoms, degree of disability, and the presence of coexisting disorders (i.e., mood or other anxiety disorders). The patient should be assessed for response to or intolerance of previous treatment approaches. The selection of a specific treatment modality should be based on concurrent medical conditions, contraindications, patient’s preference of treatment, and the availability of potential treatment options. The clinician should consider FDA warnings (e.g., QTc prolongation for citalopram) and potential for adverse events with medical disease (e.g., anticholinergic effects and weight gain with paroxetine in patients with diabetes, obesity, or benign prostatic hyperplasia) when selecting an agent. Increased risk of suicidality should be considered in patients taking antidepressants who are less than 25 years of age. All patients should receive education that includes information about GAD, treatment choices, and resources for support in the community. The patient should be an integral part of decision making and should be informed about effectiveness, common adverse effects, duration of treatment, cost associated with treatment, and what to expect when treatment is discontinued.29

Evaluation of Therapeutic Outcomes

Initially, anxious patients should be monitored once every 2 weeks for a reduction in the frequency, duration, and severity of anxiety symptoms and improvement in functioning.29 The clinician should assess the patient for response to treatment by asking about specific target symptoms of anxiety and emergence of adverse events. Ideally, the patient should have no or minimal anxiety or depressive symptoms and no functional impairment. Use of an objective measurement of remission of GAD (e.g., Hamilton Rating Scale for Anxiety score less than or equal to 7 and a Sheehan Disability Scale score less than or equal to 1 on each item) can assist in the evaluation of drug response.9,29 The definition of treatment resistance is defined as a poor, partial, or lack of response with at least two antidepressants from different classes. Treatment strategies for patients who do not achieve an appropriate response with a first-line agent include increasing the dose of the SSRI/SNRI, changing to a different agent in the same class, changing to a different agent of a different class, or augmentation of therapy. At any point of nonresponse or loss of previous response, the clinician should assess for (a) symptoms (e.g., psychotic symptoms) that may suggest a need for additional medications or (b) reasons for treatment nonadherence (e.g., adverse effects, cost of medications, limited understanding of the illness or treatments).9 Patients should also be assessed for concurrent substance abuse, concurrent illnesses, and suicidal thoughts. Once a patient has responded to pharmacotherapy, the regimen should be continued for at least 1 year.9 Early discontinuation is associated with a greater risk of relapse.9


Panic Disorder

Desired Outcomes

The goal of therapy in panic disorder is remission. Patients should be free of panic attacks, have no or minimal anticipatory anxiety and agoraphobic avoidance, and have no functional impairment.27

General Approach to Treatment

Therapeutic options include single or combined pharmacologic agents, concurrent psychotherapy, or psychotherapy followed by pharmacotherapy. Most patients without agoraphobic avoidance will improve with pharmacotherapy alone; however, if avoidance is present, CBT typically is initiated concurrently. With all effective drug therapies, resolution of agoraphobic avoidance tends to occur slowly. A meta-analysis comparing the use of SSRIs and venlafaxine in panic disorder showed response to be similar among treatments.59 Adding psychosocial treatment to pharmacotherapy may improve long-term outcomes by reducing the likelihood of relapse when pharmacotherapy is stopped.27

Nonpharmacologic Therapy

Patients should be educated to avoid substances that can precipitate panic attacks, including caffeine, nicotine, alcohol, drugs of abuse, and nonprescription stimulants.1,27 Epidemiologic data suggest that daily smoking increases risk for panic attacks and may be a causal or exacerbating factor in some individuals with panic disorder.27 Preliminary evidence suggests that aerobic exercise (e.g., walking for 60 minutes or running for 20 to 30 minutes 4 days/wk) may benefit patients with panic disorder.28 CBT is associated with short-term improvement in 80% to 90% of patients and 6-month improvement in 75% of patients. A course of CBT for panic disorder is 16 to 20 hours in length conducted over a period of 4 months.28 Bibliotherapy (the use of self-help books), exercise, and Internet-based CBT are other options.27

Pharmacologic Therapy

Panic disorder is treated effectively with several drugs including the SSRIs, the SNRI venlafaxine, the TCA imipramine, and the benzodiazepines alprazolam and clonazepam27,28 (Table 53-8). Alprazolam, clonazepam, fluoxetine, paroxetine, sertraline, and venlafaxine are approved for this indication. SSRIs are the first-line agents because of their tolerability and efficacy in acute and long-term studies3,27; however, the benzodiazepines are the most commonly used drugs for panic disorder.27 In a meta-analysis of the pharmacotherapy of panic disorder, the following antidepressants were significantly superior to placebo with the following increasing order of effectiveness: citalopram, sertraline, paroxetine, fluoxetine, and venlafaxine for panic symptoms and paroxetine, fluoxetine, fluvoxamine, citalopram, venlafaxine, and mirtazapine for overall anxiety symptoms.59 Imipramine is effective for panic disorder; however, it is considered to be a second-line agent because of the significant cardiovascular and anticholinergic effects associated with it. Five practice guidelines are published.3,22,2729 An algorithm for the pharmacologic therapy of panic disorder appears in Figure 53-2.

TABLE 53-8 Drugs Used in the Treatment of Panic Disorder



FIGURE 53-2 Algorithm for the pharmacotherapy of panic disorder. Strength of recommendations: A, directly based on category I evidence (i.e., meta-analysis of randomized controlled trials [RCT] or at least one RCT); B, directly based on category II evidence (i.e., at least one controlled study without randomization or one other type of quasi-experimental study); C, directly based on category III evidence (i.e., nonexperimental descriptive studies); D, directly based on category IV evidence (i.e., expert committee reports or opinions and/or clinical experience of respected authorities). (BZ, benzodiazepine; SSRI, selective serotonin reuptake inhibitor.) (Data from references 27 and 28.)

Benzodiazepines are considered second-line agents. Because of the risk of dependency, benzodiazepines should be used only after several trials of antidepressants have failed.3,27 Because of potential emergence of depressive symptoms during treatment, benzodiazepines should not be used as monotherapy in a patient who is clinically depressed or has a history of depression. In patients whose illness is complicated by a history of alcohol or drug abuse, benzodiazepine use should be avoided.27 Controlled trials have established that the short-term (4- to 6-week) addition of alprazolam or clonazepam to antidepressants produces a more rapid therapeutic response, with discontinuation of the benzodiazepine by week 7 of therapy.29

Alternative Drug Treatments

Buspirone, trazodone, bupropion, antipsychotics, antihistamines, and β-blockers are ineffective in panic disorder.3,22,27 The majority of studies assessing the efficacy of MAOIs in treating panic disorder were open-labeled, and lacked adequate sample sizes. MAOIs are reserved for the most refractory or difficult patients.27

Antidepressant Therapy

Tricyclic Antidepressants

Efficacy Imipramine is the most studied TCA, alleviating panic attacks in 75% of patients with panic disorder. Imipramine effectively blocks panic attacks within at least 4 weeks; however, maximal improvement (including antiphobic response) does not occur until 8 to 12 weeks.27

Adverse Effects The adverse effects of medications used to treat panic disorder are found in Table 53-6. Up to 40% of patients experience stimulant-like effects, including anxiety, insomnia, and jitteriness.27These adverse effects often affect patient adherence, prevent medication dosage increases, and interfere with the overall treatment outcome.

Other problems with TCA use in panic disorder are well documented and include anticholinergic effects, orthostatic hypotension, delayed onset of antipanic effects, and toxicity in overdose.27 Approximately 25% of patients reportedly discontinue treatment because of side effects, especially weight gain.27

Dosing and Administration When using imipramine, treatment should be slowly increased by 10 mg every 2 to 4 days as tolerated (Table 53-8).

Selective Serotonin Reuptake Inhibitors

Efficacy Clinical studies indicate that all SSRIs are effective in panic disorder.27 The percentage of patients who become panic-free ranges between 60% and 80%.27 Images The antipanic effect of SSRIs is delayed for at least 4 weeks, and some patients do not respond for 8 to 12 weeks.27

Adverse Effects Typical antidepressant doses of SSRIs can cause side effects of insomnia, jitteriness, restlessness, and agitation, and lead to drug discontinuation in patients with panic disorder. Other adverse effects associated with SSRI use in panic disorder are listed in Table 53-6.

Dosing and Administration Low initial doses of SSRIs are recommended (see Table 53-8) to avoid stimulatory side effects (e.g., insomnia or nervousness), and should be maintained for the first week of therapy. Doses at the upper end of the dosing range can be necessary to achieve response.28

Serotonin–Norepinephrine Reuptake Inhibitors

Efficacy Approximately 54% to 60% of patients were panic-free on venlafaxine extended-release 75 or 150 mg daily. The remission rates were 44% for both dosages in acute efficacy studies.60

Adverse Effects The most common adverse effects of venlafaxine extended-release in panic trials were nausea, dry mouth, constipation, anorexia, insomnia, somnolence, tremors, sweating, and sexual dysfunction.27

Dosing and Administration The dosage of venlafaxine extended-release is 37.5 mg/day for the first 3 to 7 days, and then increased to a minimum of 75 mg/day (Table 53-8). Increasing the dose to 150 mg/day after initial nonresponse or partial response is recommended. A dose–response relationship was not evident in clinical trials.38


Efficacy The high-potency benzodiazepines clonazepam and alprazolam are the preferred agents.27,28 Diazepam and lorazepam are possibly effective in treating panic disorder when taken in sufficiently high doses.27 Alprazolam provides rapid relief for patients in distress, but because of its short half-life, multiple daily dosing is required and often results in profound withdrawal symptoms with missed doses.27Therapeutic response to benzodiazepines occurs in 1 to 2 weeks. Relapse rates of 50% or higher are common despite slow drug tapering.49

Adverse Effects Patient acceptance of benzodiazepines usually is not a problem, and except for sedation, side effects are reported rarely (Table 53-6).

Dosing and Administration Doses of clonazepam can be increased by 0.25 or 0.5 mg every 3 days to 4 mg/day if needed.45 Alprazolam can be slowly increased over several weeks to reach an ideal dose. Images The duration of action of immediate-release alprazolam can be as little as 4 to 6 hours with resulting breakthrough symptoms; use of the extended-release alprazolam or clonazepam will avoid this problem. Most patients require 3 to 6 mg/day of alprazolam, and some need higher doses to obtain a full therapeutic (antipanic and antiphobic) response.

Clinical Controversy

The role of long-term benzodiazepine use in the treatment of anxiety disorders is controversial. Most experts and regulatory guidelines recommend that use of benzodiazepines be limited to short-term in treatment of anxiety disorders because of the risk for tolerance, dose escalation, and dependence. Other experts argue that the benefits of long-term benzodiazepine use outweigh the potential adverse effects for most patients.

Treatment Resistance Common reasons for treatment failures are comorbid psychiatric disorders, rapid dosage increases with resulting intolerable side effects, and underdosage.27 All standard treatments should be tried before using augmentation strategies. In patients with a partial response to one agent, a low dose of another antipanic agent (e.g., a TCA, benzodiazepine, or an SSRI) can be added.27

Phases of Therapy

Acute Phase The main goal of therapy in the acute phase is reduction of symptoms (e.g., resolution of panic attacks, reduction in anxiety and phobic fears, resumption of the patient’s usual activities).22,27 The duration of this phase is generally 1 to 3 months depending on the choice of drug. Therapy should be altered if there is no response after 6 to 8 weeks of an adequate dose.

The guiding principle for SSRIs and SNRIs in panic disorder is to start with low doses (approximately one fourth to one half of the starting doses for depression), use an adequate dose, and treat for about 12 weeks.22,27 Adverse effects, often from too high an initial dose, can prevent achievement of an optimal dosage, compromise treatment response, and contribute to patient nonadherence.

The duration of the acute phase with benzodiazepines is approximately 1 month because response is rapid. A regular dosing schedule rather than an “as-needed” schedule is preferred for patients with panic disorder who are taking benzodiazepines, where the goal is to prevent panic attacks rather than reduce symptoms once an attack has already occurred.27

Maintenance Phase and Discontinuation Images The optimal length of therapy is unknown; however, the total duration of therapy appears to be 12 to 24 months before drug discontinuation over 4 to 6 months is attempted.27 The dose used in the acute phase is continued into the maintenance phase.27 When drugs are discontinued too early, a high rate of relapse occurs; thus, longer periods of treatment are associated with a more sustained response. Reinstitution of drug usually results in renewed clinical response.27 Pharmacotherapy, even at long duration, might not prevent relapse, and many patients require long-term therapy.

The most important determinant of adherence with maintenance therapy is the tolerability of adverse events.27 Some adverse events that are experienced short term become unbearable during long-term management (e.g., sexual dysfunction and weight gain). TCAs, SSRIs (except fluoxetine), and venlafaxine can be associated with discontinuation symptoms.

The primary risk of long-term benzodiazepine use is the development of dependence and withdrawal reactions on discontinuation. Abuse of benzodiazepines usually is confined to patients with a personal or family history of substance or alcohol abuse.5,48 The approach to benzodiazepine discontinuation involves a slow and gradual tapering of the dose because withdrawal symptoms and rebound anxiety may occur during discontinuation. Benzodiazepines should be tapered over 2 to 4 months at rates no higher than 10% of the dose per week.27,49 Patients receiving benzodiazepines and antidepressants should be told not to decrease or discontinue therapy unless authorized by their clinician.28

Special Populations

Elderly patients with panic disorder have fewer, less intense symptoms and avoidant behavior than younger patients.61 Youth often present with fear that they are dying or being smothered, and agoraphobia can be manifested as a fear of leaving home.55 CBT is effective in both populations. If pharmacotherapy is used, antidepressants, especially the SSRIs, are preferred for management of panic disorder, and benzodiazepines are second-line agents because of potential problems with disinhibition in these two populations.

Personalized Pharmacotherapy

Research is evolving regarding pharmacogenetic properties related to benzodiazepine agents. While all benzodiazepines bind to the GABAA receptor, they have different physiochemical properties, most notably lipid solubility, which influence their pharmacokinetics, including rate of absorption and diffusion. Pharmacogenomic studies of benzodiazepines have focused on metabolizing enzymes. In particular, benzodiazepines are biotransformed by different cytochrome P450 isoforms and also by different UDP-glucuronosyltransferase subtypes. Evaluation of these factors in patients with genetic alterations in metabolism is an important part of personalized therapy. The most recent data available regarding research on the effects of pharmacogenetic properties of the benzodiazepines can be located online at The Pharmacogenomics Knowledgebase.62

Considerations that guide selection of the treatment modality for panic disorder include patient preference, past treatment history, the presence of co-occurring medical or other psychiatric conditions, cost, and treatment availability. Psychosocial treatment in the form of CBT is recommended for patients who prefer nonpharmacologic therapy and who are able to invest the effort and time to attend weekly sessions and between-session homework exercises. Pharmacotherapy with a first-line agent is recommended for patients who prefer medications or who do not have access to or resources to engage in CBT. Combination with psychotherapy and pharmacotherapy is appropriate for patients who have failed monotherapy with medication or CBT.

Providing education about the disorder may relieve some of the symptoms of panic by helping the patient to realize that the symptoms are neither life-threatening nor uncommon. Patients should be informed regarding the lag time before a therapeutic response will occur and any problematic side effects that might affect early adherence (i.e., jitteriness syndrome). Many patients are reluctant to take drugs for fear that their illness will worsen or that they will become addicted. Adverse events are often perceived as a worsening of the illness and can contribute to nonadherence or prevent necessary dosage increases. A strong therapeutic alliance between the clinician and the patient is important in supporting the patient through the aspects of the treatment that may provoke anxiety.

Evaluation of Therapeutic Outcomes

During the first few weeks of the acute phase of therapy, patients with panic disorder should be seen every 1 to 2 weeks when starting a new medication, and then every 2 to 4 weeks to adjust drug dosages based on improvement in panic symptoms and to monitor for adverse events.27,28 After the dose is stabilized and symptoms have decreased, visits every 2 months should suffice.28 The patient should be counseled to maintain a diary to record the date, time, frequency, duration, and intensity of panic episodes, level of anticipatory anxiety or agoraphobic avoidance, and the severity of distress and impairment related to the panic disorder. Treatment outcomes can be assessed objectively by use of the Panic Disorder Severity Scale. Remission is defined as equal to or less than 3 with no or mild agoraphobic avoidance, anxiety, disability, or depressive symptoms. Treatment response is indicated by a 40% or greater reduction in overall score.29

At scheduled visits, the clinician can inquire about the level of disability experienced by the patient and have the patient complete the Sheehan Disability Scale (with a goal of less than or equal to 1 point on each item). During drug discontinuation, the frequency of appointments should be increased to evaluate for emergence of potential withdrawal symptoms and monitor for relapse.


Social Anxiety Disorder

Desired Outcomes

The goals of therapy in the acute phase of treatment are to reduce physiologic symptoms of anxiety (e.g., tachycardia, flushing, and sweating), social anxiety, and phobic avoidance. The duration of this phase is 4 to 12 weeks, depending on the drug therapy.

The goals of therapy in the continuation phase (3 to 6 months) are to extend the therapeutic benefits, especially the patient’s ability to participate in social activities, and improve QOL. Although the primary goal of treatment is to reduce anxiety symptoms to manageable levels, even modest reductions in avoidance and discomfort can be highly valued by patients.25

Images At least a 1-year medication maintenance period is recommended to maintain improvement and decrease the rate of relapse.2,26,29 Situations suggesting a possible need for long-term treatment include the presence of unresolved symptoms or comorbidity, an early onset of disease, and a prior history of relapse.25 The long-term goal in the treatment of SAD is remission with the disappearance of the core symptoms of social anxiety, little or no anxiety, and no functional impairment or concurrent depressive symptoms.25

General Approach to Treatment

Patients with generalized SAD should be treated aggressively. Obstacles to effective treatment include patient avoidance of therapy secondary to fear and shame, treatment directed toward somatic symptoms or concurrent conditions, and financial barriers.25,63 Patients with SAD often respond more slowly and less completely than patients with other anxiety disorders. Therefore, it is important to set reasonable expectations for response to therapy. Consideration of current symptoms, prior treatments, concurrent conditions, and history of substance abuse guide treatment selection.

CBT and pharmacotherapy are effective in the treatment of SAD.3,25,63 Pharmacotherapy is often the most practical choice because CBT might not be available outside of large urban areas. Acute treatment outcomes for CBT and pharmacotherapy are equal.3,29 Drug therapy is superior in reducing subjective general anxiety acutely, although CBT has a greater likelihood of maintaining response after termination.29,63

There are no data to predict which patients will respond best to pharmacotherapy, CBT, or a combination, or maintain gains after discontinuing pharmacotherapy. The only significant indication of treatment response in pharmacotherapy is duration of treatment.25,26 Some patients elect lifelong therapy, and many are reluctant to attempt drug discontinuation because of fear of relapse.

Nonpharmacologic Therapy

Patients should be educated about SAD and support groups. Self-help group programs that focus on effective communication can benefit people with public speaking phobia.

CBT consists of exposure therapy, cognitive restructuring, relaxation training techniques, and social skills training.3,25,26 Through CBT, patients learn to overcome anxiety in social situations and alter the beliefs and responses that maintain this anxiety. Therapy usually lasts several months and often is conducted in groups. In clinical trials, one-half to two-thirds of patients responded at 12 weeks.25

Clinical Controversy

The question of which component of CBT is the most effective in the treatment of SAD is controversial. Recent evidence suggests that including a cognitive component is crucial. Individual therapy may be more effective than group therapy. Additional research is needed to determine the efficacy of CBT in the context of real-world experiences.

Pharmacologic Therapy

Antidepressant Therapy

Images The SSRIs and venlafaxine are beneficial for concurrent depression, and are safe when used in patients with substance abuse. Paroxetine, sertraline, venlafaxine extended-release, and fluvoxamine extended-release are approved for the treatment of generalized SAD, and are considered first-line agents because of efficacy and tolerability (Table 53-9). Controlled trials comparing different SSRIs, or SSRIs and an SNRI, demonstrated equivalent efficacy between agents.25,63 TCAs are not effective in SAD.25 Evidence-based guidelines for the treatment of SAD were published by the World Federation of Societies of Biological Psychiatry, the British Association for Psychopharmacology, the National Institute for Health and Clinical Excellent, and the Canadian Psychiatric Association.3,22,29,64 An algorithm for the pharmacotherapy of generalized SAD appears in Figure 53-3.

TABLE 53-9 Drugs Used in the Treatment of Generalized Social Anxiety Disorder



FIGURE 53-3 Algorithm for the pharmacotherapy of generalized social anxiety disorder. Strength of recommendations: A, directly based on category I evidence (i.e., meta-analysis of randomized controlled trials [RCT] or at least one RCT); B, directly based on category II evidence (i.e., at least one controlled study without randomization or one other type of quasi-experimental study); C, directly based on category III evidence (i.e., nonexperimental descriptive studies); D, directly based on category IV evidence (i.e., expert committee reports or opinions and/or clinical experience of respected authorities). (SSRI, selective serotonin reuptake inhibitor. (Data from references 3 and 26.)

Selective Serotonin Reuptake Inhibitors

Efficacy Large trials of escitalopram, fluvoxamine (immediate-and controlled-release), paroxetine, sertraline, and venlafaxine extended-release have shown efficacy and tolerability. Results of studies with fluoxetine have been inconsistent. The onset of effect was delayed 4 to 8 weeks, and maximum benefit was often not observed until 12 weeks or longer. Large relapse prevention trials with escitalopram, paroxetine, and sertraline demonstrated relapse rates of 4% to 14% with continued drug treatment, compared with 36% to 39% with placebo.26

Dosing and Administration SSRIs should be initiated at doses similar to those used for the treatment of depression and administered as a single daily dose (see Table 53-9). If the patient suffers from comorbid panic disorder, the SSRI dose should be started at one-fourth or one-half of the dose. The dose–response curve for SSRIs tends to be relatively flat, but individual patients can require higher doses. Increase the dose as tolerated in patients who have not responded after 4 weeks of therapy.26,63 When discontinuing an SSRI, the dosage should be tapered monthly (i.e., decreasing sertraline by 50 mg or paroxetine by 10 mg) to reduce the risk of relapse and discontinuation symptoms.


Efficacy The efficacy of venlafaxine extended-release was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study.38 Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these five trials, venlafaxine extended-release was significantly more effective than placebo on change from baseline to end point on the LSAS total score.38

Adverse Effects Adverse effects included anorexia, dry mouth, nausea, insomnia, and sexual dysfunction (Table 53-6).

Dosing and Administration Additional therapeutic benefits of venlafaxine extended-release above 75 mg/day were not shown.38 Venlafaxine should be tapered slowly (i.e., decreasing by 37.5 mg/mo) to decrease the risk of relapse during discontinuation.

Alternative Agents

Benzodiazepines Benzodiazepines are commonly used in the treatment of patients who cannot tolerate or fail to respond to antidepressants. They are not considered first-line therapy for SAD because of concerns over the adverse effects, potential for dependence, the possibility of rebound anxiety, and ineffectiveness in the treatment of depression. Clonazepam is the most extensively studied benzodiazepine for the treatment of generalized SAD.29

If clonazepam is prescribed, the acute phase of therapy is about 1 month. Patients should be instructed not to decrease or discontinue clonazepam without consulting their clinician because of the risks of rebound anxiety and withdrawal symptoms. Patients on clonazepam for 6 months who were slowly tapered over 5 months maintained their treatment response.26 Clonazepam should be gradually tapered at a rate not to exceed 0.25 mg every 2 weeks.

Anticonvulsants Gabapentin and pregabalin were effective in controlled trials, whereas levetiracetam was ineffective.26

β-Blockers β-Blockers decrease the perception of anxiety by blunting the peripheral autonomic symptoms of arousal (e.g., rapid heart rate, sweating, blushing, and tremor), and they are often used to decrease anxiety in performance-related situations. For patients with specific SAD, 10 to 80 mg of propranolol or 25 to 100 mg of atenolol can be taken 1 hour before a performance as needed.25 A test dose should be taken at home before the presentation to assure that β-blockade is sufficient and there are no adverse events. Controlled trials with β-blockers do not support daily use in generalized SAD.3,29

Treatment Resistance Images An adequate antidepressant trial usually consists of 8 to 12 weeks (at maximum dosages).3,25,29 Subsequent options include a trial of a second SSRI or venlafaxine extended-release. Some patients experience clinical benefit during the first 4 weeks of therapy.3,25,29 If nonresponsiveness continues, a trial of an alternative agent is warranted.

There are little data on the choice of treatments if antidepressants fail. Published studies offer preliminary support for the combination of an SSRI with a benzodiazepine, but not with pindolol.26

Atypical antipsychotics and MAOIs are options in treatment-resistant SAD. Quetiapine monotherapy showed a large effect size on the Social Phobia Inventory when compared with placebo.63 Although phenelzine is effective in 77% of patients with SAD,3,29 dietary restrictions, potential drug interactions, and adverse effects (e.g., weight gain and hypertensive crisis) have limited its use. If a patient is switched from another antidepressant to phenelzine, an appropriate washout period should be followed.

Special Populations

SAD can present in children of preschool to elementary school age. If the disorder is not treated, it can persist into adulthood and increase the risk of depression and substance abuse. CBT and social skills training are effective nonpharmacologic therapies in children.55,65 Placebo-controlled and open-label trials have provided evidence of efficacy of pharmacotherapy with an SSRI or SNRI in children 6 to 17 years of age.55,65 Children and adolescents prescribed an SSRI or SNRI for social anxiety (or for other purposes) should be closely monitored for increased risk of suicidal ideation. Headache, nausea, drowsiness, insomnia, jitteriness, and stomachaches were reported in children receiving antidepressants.55,65

Benzodiazepines should be reserved as the last-line agents in children with SAD.55,65 If prescribed, they should be used for the shortest time period possible. The adverse effects of benzodiazepines in children include drowsiness, oppositional behavior, disinhibition, and fatigue.

Approximately one-fifth of patients with SAD also suffer from an alcohol use disorder. Many people with SAD report that they use alcohol to cope with anxiety. Paroxetine significantly reduced social anxiety and the frequency and severity of alcohol use in patients with SAD and an alcohol use disorder.66 MAOIs and benzodiazepines are not appropriate therapy for patients with SAD and alcohol use disorder. SSRIs are the drugs of choice.

Personalized Pharmacotherapy

Despite the availability of effective treatments for social anxiety, most adults in the United States with social anxiety do not receive mental healthcare for their symptoms. Often the symptoms that patients desire to relieve interfere with the ability to seek treatment. Patients often feel embarrassed of what others might think or say about them. It is important to develop an alliance with the patient and offer reassurance throughout the treatment process.

Certain complications may influence the choice of first-line pharmacotherapy. Comorbid depression or suicidal ideation requires careful evaluation and close monitoring. Patients with comorbid substance abuse on presentation may require postponing pharmacotherapy until after detoxification and avoidance of use of benzodiazepines as part of treatment.

Patient-specific education about treatment is important. Patients should be instructed about the gradual onset of effect, when to expect full therapeutic benefit, and that long-term therapy is required. When drug therapy is discontinued, the dosage needs to be gradually decreased over several months, and the patient should be seen more frequently to monitor for signs and symptoms of relapse or withdrawal.

It is important to remember that although pharmacotherapy usually leads to improvement in social and occupational functioning, most patients do not achieve a full remission. Many patients require additional treatment, often in the form of CBT.

There is little evidence available to predict response to pharmacotherapy for social anxiety. Variation in a functional polymorphism known to influence 5-HT reuptake is associated with SSRI response in patients with generalized SAD. In a trial that evaluated whether variation in the 5-HT transporter gene promoter (5HTTLPR) influences the efficacy of SSRIs, a trend was seen for a linear association between 5HTTLPR genotype and likelihood of response to SSRI.67 Reduction in social anxiety symptoms during SSRI treatment was significantly associated with 5HTTLPR genotype using either the diallelic or triallelic classification.67

Evaluation of Therapeutic Outcomes

Images The pharmacotherapy of SAD can be monitored in three principal domains: SAD symptoms (e.g., fears and physical symptoms), functionality, and well-being or overall improvement.25,26,63 Response to pharmacotherapy in SAD is defined as a stable, clinically meaningful improvement; patients no longer have the full range of symptoms but typically continue to experience more than minimal symptoms.25,26,63

During the acute phase of treatment, patients should be seen weekly while the drug dosage is titrated. Once the patient responds and the dosage is stabilized, the patient can be seen monthly. Many patients report improvement during the first 4 weeks of therapy, but more than one quarter of those who do not have a response at week 8 may have a response at 12 weeks. At each visit, the patient should be asked about adverse effects and improvement in symptoms. The patient should be instructed to keep a diary to record fear levels, physical symptoms, cognitions, and anxious behaviors in actual exposures to social situations. The LSAS is a clinician-rated scale of clinical severity and change in SAD for monitoring response.29 Patients can use the Social Phobia Inventory for self-assessment of SAD symptoms.29 Full remission is a complete resolution of symptoms across the three SAD domains that is maintained for 3 months or a LSAS score of less than or equal to 30 points.29


Specific Phobia

Specific phobia is considered unresponsive to drug therapy, although highly responsive to CBT. The use of benzodiazepines or paroxetine in patients who failed CBT is supported by limited data. Benzodiazepines can be detrimental in patients with specific phobias treated with CBT.22


Anxiety disorders are common in the population and occur concurrently with other psychiatric disorders. The proper management of anxiety disorders begins with the correct diagnosis; not all patients should receive antianxiety agents. Nonpharmacologic interventions often are effective alone or when combined with drug therapy.

There are several subtypes of anxiety disorders, and the diagnosis determines the type of drug and nonpharmacologic intervention selected. Although benzodiazepines remain the drugs of choice for situational anxiety, antidepressants have emerged as first-line therapy for GAD, panic disorder, and SAD. Benzodiazepines are reserved for use in situations requiring immediate anxiety relief during the first 2 to 4 weeks of therapy with a long-term agent such as an antidepressant. Antidepressants, including the SSRIs and SNRIs, and the benzodiazepines clonazepam and alprazolam are used extensively in patients with GAD, panic disorder, and SAD.

The long-term goal of therapy for GAD, panic disorder, and SAD is remission of core anxiety symptoms with no impairment in functionality, minimal anxiety, and no depressive symptoms. Augmentation with anticonvulsants and atypical antipsychotics show some promise in treatment-resistant cases.





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