Chapter 33. Generalized Anxiety Disorder

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Rudolf Hoehn-Saric, Thomas D. Borkovec, Kenneth Belzer: Chapter 33. Generalized Anxiety Disorder, in Gabbard’s

Treatments of Psychiatric Disorders, 4th Edition. Edited by Glen O. Gabbard. Copyright ©2009 American Psychiatric

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Gabbard’s Treatments of Psychiatric Disorders > Part VI. Anxiety Disorders, Dissociative Disorders, and Adjustment

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Chapter 33. Generalized Anxiety Disorder

INTRODUCTION

Generalized anxiety disorder (GAD) is not as sharply delineated as DSM nomenclature makes it

appear to be (Noyes and Hoehn-Saric 1998) but is a heterogeneous disorder; patients differ in

onset, the type and intensity of worries, the degree of hyperarousal, and their physical

manifestations. Worries may be generalized or focused on certain situations; hyperarousal may

lead to insomnia or be only present during certain times of the day. Physical complaints tend to

cluster to different degrees around muscular, cardiovascular, or gastrointestinal symptoms. In the

presence of medical comorbidity, anxiety may crystallize around the physical state. Personality

traits influence patients’ behavioral responses and can significantly modify the clinical picture.

Finally, GAD has a high comorbidity with affective and other anxiety disorders, which, when

present, necessitates the formulation of comprehensive treatment plans. Therefore, each patient

must be considered individually, according to the type, severity, and chronicity of symptoms;

triggers that elicit or aggravate the symptoms; life stressors; coping ability; learning potentials;

specific personality traits; and, above all, motivation to change. In most cases, GAD is a chronic

condition, but the severity of symptoms may depend greatly on the present degree of stress.

The management of GAD almost always requires psychological interventions and frequently, but not

invariably, pharmacotherapy. Mild forms respond to simple psychological interventions consisting

of assurance, explanation of somatic symptoms, clarification of conflicts, and exploration of coping

mechanisms. More complex patients may need cognitive-behavioral therapy (CBT), which is

particularly suited for the person who worries excessively and avoids anxiety-inducing situations.

PSYCHOLOGICAL TREATMENTS

Most developments in the psychological treatment of GAD have taken place within the context of

CBT. We first describe psychodynamic interventions for GAD, however, because they are often used

in clinical practice.

Psychodynamic Psychotherapy

Because psychodynamic therapy is a widely practiced treatment in the community (Jensen et al.

1990), many patients with GAD often receive this form of treatment. Luborsky’s (1984)

supportive-expressive psychodynamic approach was specifically adapted to the treatment of GAD

within an interpersonal-psychodynamic orientation (Crits-Christoph et al. 2004). This model

hypothesizes that dangerous or traumatic experiences at any phase of life can lead to inaccurate

beliefs (schemas) about oneself, others, and one’s ability to successfully satisfy one’s needs in

interpersonal relationships. In GAD, these schemas might involve concerns about obtaining love,

security, stability, or protection from others. At times, the schemas are connected to feelings of fear

that are so strong that the patient is motivated to not think about the concerns in order to reduce

the fear. However, the troubling emotional issues continue to influence the individual, as seen in

the symptoms of worry and in repetitive maladaptive relationships. The focus of treatment is on

understanding the anxiety symptoms in the context of interpersonal and intrapsychic conflicts.

Through examining past and current relationship patterns with others (including the therapist), the

conflicts contributing to anxiety symptoms are worked through, and better ways of coping with

feelings, expressing one’s needs, and responding to others are explored.

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Therapeutic Strategies

Self-Monitoring

The foundation of behavioral and cognitive therapies resides in self-monitoring, whereby patients

learn to observe their anxious experience and to detect the initial onset of anxious responses. Such

learning is facilitated in therapy by discussions with patients about their past anxious experiences

as well as through brief inductions of anxious states via using imagery and having patients worry.

They are then asked to practice identifying as early as possible any incipient anxiety cues in their

daily life.

Relaxation Techniques

Given that part of the patient’s problem resides in chronic, diffuse anxiety, a well-learned

relaxation response used throughout the day and whenever anxiety is experienced would

reasonably provide relief for at least the somatic aspects of the anxiety.

Abbreviated progressive muscle relaxation

Jacobson (1938) developed progressive muscle relaxation, a technique which Wolpe (1958)

abbreviated and incorporated into his systematic desensitization for phobias. In its later adaptation

to GAD, relaxation became a central strategy for reducing anxiety, taught as a generalized coping

response specifically targeting physiological hyperactivity. Training involves systematic tensing and

releasing tension in 16 muscle groups to create deep relaxation while the patient attends to the

feelings of tension and relaxation that occur. Over training sessions, muscle groups are combined,

and eventually the patient learns to produce relaxed states by merely focusing on a muscle group

and letting go of detected tension. The patient formally practices relaxation twice a day to

strengthen the ability to produce relaxation and is encouraged to apply the relaxation response

whenever anxiety is detected during the day.

Biofeedback

Biofeedback for relaxation typically uses frontalis electromyography to teach the patient to reduce

tension. Biofeedback equipment is expensive and rarely available to therapists, and empirical

evidence (Rice and Blanchard 1982) indicates that alternative relaxation methods are as effective

for producing general relaxation skills.

Relaxing imagery

Pleasant, calming images can be used to elicit relaxation. Patients develop detailed scenes that

describe soothing environments and that elicit physical and affective responses such as warmth,

happiness, and tranquility. Such imagery may be particularly useful for GAD patients because

imaginal activity can disrupt their pervasive tendency to engage in worrisome thinking.

Meditation

Meditational methods commonly have patients focus their attention on their breathing while

repeating a single word (“calm” or “relax”) with each exhalation. Similar to relaxing imagery, such

a focusing device can be very helpful for directing the patient’s attention away from worrisome

thinking and negative emotional states.

Slowed diaphragmatic breathing

Slowed diaphragmatic breathing involves shifting from shallow, rapid thoracic breathing to slowed

breathing from the diaphragm. It can be taught rather quickly, and patients are encouraged to use

this brief relaxation intervention upon detecting incipient anxiety.

Applied relaxation

Once relaxation techniques have been taught to the patient, systematic methods for applying the

relaxation response in daily living are incorporated (Öst 1987). For example, therapists interruptPrint: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

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patients during a session to point out observable signs of increased tension or anxiety and instruct

them to briefly “relax away” detected anxiety. Over sessions, the patient is expected to do this

without therapist prompting. Between sessions, patients choose cues in their environments (e.g.,

posted notes, telephone ringing, change in activity, every half-hour) to serve as frequent reminders

to identify extant anxiety and to relax so that it goes away.

Exposure Methods

Many GAD patients show subtle anxiety-motivated avoidance to various situations. Questions about

activities that the patient would like to do but does not and observation of any hesitancies in

talking about certain topics or engaging in certain activities are useful for identifying areas of

avoidance. Gradual, repeated in vivo exposures to such situations can then occur. Relaxation coping

responses are used beforehand to provide greater comfort in anticipation of exposure, during

exposure to minimize anxiety, and immediately after exposure to facilitate recovery. Such in vivo

exposure combined with relaxation has often been called anxiety management training (Suinn and

Richardson 1971).

GAD patients become anxious about many things. Once anxiety begins, its internal sensations

function as additional cues that lead to further anxiety. Repeated exposure to the anxiety

symptoms themselves would thus be useful. The most common approach of this type (self-control

desensitization [Goldfried 1971]) involves imagery methods to generate the patient’s most typical

anxiety symptoms. This is followed by the rehearsal of coping responses (both relaxation and

perspective shifts created during cognitive therapy) upon symptom occurrence in order to reduce or

eliminate the generated anxiety. An image is repeated until the patient can rapidly reduce extant

anxiety, before proceeding to another representative image involving additional situations and

internal anxiety cues. Following the same method, the patient can also be instructed to begin

worrying. Once the worry process is initiated, the patient uses coping responses to terminate the

process.

Cognitive Therapy

Cognitive therapy has long been viewed as a treatment relevant to GAD, given that the thought

system is so much a part of the nature of worry (Borkovec et al. 2004). The most common cognitive

therapy approach for GAD has been derived from Beck and Emery’s (1985) treatment of anxiety

disorders wherein the role of unrealistic, nonadaptive thinking and beliefs in generating anxiety is

emphasized, and the targeting of these cognitions for change becomes the focus of therapy.

Cognitive therapy methods involve identifying characteristic cognitive responses contributing to the

patient’s anxiety (e.g., thoughts, interpretations, meanings, predictions, and beliefs about the

world and the self) and teaching the patient to question whether these cognitions are accurate.

Thoughts and their underlying beliefs are examined to see whether they are logical or based on

actual evidence. If a thought is found to be inaccurate, the patient and therapist generate rational

and evidence-based alternative thoughts to substitute whenever the patient becomes anxious. Such

alternative perspectives are rehearsed along with relaxation responses during self-control

desensitization, and they are used in daily life whenever anxiety or worries are detected.

Throughout this process, the therapist uses Socratic dialogue extensively; the therapist asks

questions that lead the patient, by his or her own knowledge and resulting responses, to more

accurate thoughts and beliefs. Daily behavioral experiments are also used to obtain evidence for

testing old and new perspectives and to provide opportunities to apply the new perspectives.

Patients also monitor their daily worries, noting what they fear will happen and then observing the

actual outcome. By so doing, patients use natural daily experiences to obtain their own empirical

evidence on which to base new ways of thinking and perceiving.

The same notion of flexible and multiple coping responses used in relaxation is recommended for

developing cognitive coping resources: Patients are encouraged to generate several adaptive

perspectives for each area of concern. Decatastrophizing is particularly useful with GAD patients,

because they rarely think through their fears. For a worry, the therapist asks the patient whatPrint: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

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feared outcome is predicted. Having determined this, the therapist asks what would be bad about

that outcome, should it actually occur, and then what would be bad about that, and so forth, until

all underlying fears are made explicit and/or the worst possible feared outcome is identified.

Merely engaging in this process often allows patients to realize either that there is less to be feared

than they thought or that they would be able to cope. The customary use of logical analysis, search

for evidence, and generation of alternative perspectives then proceeds for each underlying fear.

Controlled Outcome Trials

Although outcome studies have varied widely in design, methodology, and measurement, the GAD

treatment outcome literature is substantial enough to draw the following conclusions (see

meta-analyses by Borkovec and Ruscio [2001], Borkovec and Whisman [1996], and Gould et al.

[1997, 2004] for further details): Behavioral therapies and CBT have consistently shown superiority

over no treatment. CBT produces the greatest degree of improvement relative to behavior therapy

alone, cognitive therapy alone, or nonspecific interventions, and these gains are maintained at

follow-up. Medication use commonly declines by follow-up. Dropout rates have typically been low.

Evidence thus suggests that psychological treatment is indeed effective for immediate

posttreatment and long-term follow-up improvement in GAD and that the combination of cognitive

therapy with behavioral methods (e.g., applied relaxation and/or exposure procedures) has

produced the greatest degree of enduring change.

Three significant issues remain to be addressed, however. First, many patients continue to

experience significant anxiety (up to 50%), failing to fully recover. Second, whether the

combination or sequencing of medication and psychological treatment would further enhance

overall efficacy remains to be determined. Conclusions concerning combined treatments based on

early work by Power et al. (1989), (1990) are limited by the use of fixed low-dose regimens of

benzodiazepines. Third, statistically significant differences between combined CBT and one of its

elements (e.g., relaxation training or cognitive therapy) often have not been found on all measures

at all assessment moments. Thus, the active mechanisms and the nature and process of change in

the effective psychological treatment of GAD remain to be identified.

Predictors of Outcome

Four reviews of GAD outcome studies have evaluated a variety of factors for their ability to predict

immediate and long-term outcomes (Gould et al. 1997, 2004; Durham 2006; Newman et al. 2006).

Some tentative conclusions about who benefits from psychotherapy and who does less well are

possible. The reviewed predictor studies involved CBT conditions, except where noted otherwise.

The effectiveness of therapy is not influenced by gender, group versus individual treatment format,

number of sessions administered, or presence of medications. The majority of studies suggest that

longer duration of the disorder, presence of Axis I comorbidity, lower levels of patient expectancy

for improvement and/or belief in the therapy (also found for supportive-expressive therapy), and

history of prior psychiatric treatment predict poorer outcome. The most consistent results indicate

that greater anxiety severity and more significant interpersonal problems (true also for

supportive-expressive therapy) prior to therapy predict lessened clinical improvement.

Employment status, cognitive impairment in the elderly, and ethnicity have not been found to relate

to outcome, whereas low socioeconomic status and low self-esteem predict poorer improvement.

Mixed results also suggest the possibility that poorer treatment response will occur for patients

with higher pretherapy depression, Axis II comorbidity, presence of relaxation-induced anxiety

during relaxation training, and low frequency of practicing newly learned coping skills.

Summary of Clinical Guidelines for Cognitive-Behavioral Treatment of

Generalized Anxiety Disorder

Based on clinical experience and research on treatment efficacy and predictors of therapeutic

response, the following are recommendations for the psychological treatment of GAD:

1. Patients should monitor their anxiety to identify its earliest occurrence. In-session inductions of worryPrint: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

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and anxiety and between-session practice in detecting cognitive and somatic cues can facilitate this

learning.

Multiple relaxation strategies should be taught (brief methods such as slowed diaphragmatic breathing,

meditation, and pleasant imagery to more thorough progressive muscle relaxation). Patients should

experiment with these methods to determine which are most useful under each circumstance.

2.  

The success of relaxation will depend on the frequency of application. Patients should develop reminders

to apply their relaxation skills often during the day and in response to incipient anxiety.

3.  

Graduated in vivo exposure is useful when explicit or subtle avoidance of environmental situations

exists. Relaxation will help patients to minimize the anxiety before, during, and after exposures.

4.  

Likelihood of application of relaxation skills can be increased in therapy sessions by imagery exposure

methods: Patients induce incipient cognitive (especially worrisome) and somatic anxiety and repeatedly

rehearse coping responses to reduce the anxiety.

5.  

Cognitive therapy, when combined with the above behavioral interventions, may be particularly

effective. The technique involves identification and logical analysis of inaccurate anxiety-provoking

thoughts and beliefs that underlie perceptions of threat; generation of accurate alternative cognitions;

and frequent substitution of more adaptive perspectives when anxiety is detected. Decatastrophizing,

behavioral experiments to obtain evidence for or against old and new thoughts and beliefs, emphasis on

generating multiple adaptive perspectives, and rehearsal of new cognitions during imagery methods can

further facilitate cognitive reorganization.

6.  

Positive expectations about the usefulness of the techniques should be encouraged when a patient is

beginning therapy.

7.  

Recent studies suggest that interventions to help patients resolve interpersonal difficulties may provide

therapeutic benefits in addition to those generated by the coping skills learned in CBT (Borkovec 2002).

8.  

PHARMACOTHERAPY

Benzodiazepines

In the past, benzodiazepines were the most frequently prescribed drugs for GAD and were usually

obtained from family physicians (Beardsley et al. 1988). They still play an important role in the

treatment of GAD. Benzodiazepines cause sedation, muscle relaxation, anxiety reduction, and

increased seizure threshold (Tallman et al. 1980). Benzodiazepines have the most pronounced

effects on arousal; they lower hypervigilance, inducing relaxation and, at higher doses, somnolence.

Psychic symptoms are less affected by benzodiazepines (Hoehn-Saric et al. 1988; Rickels et al.

1993). In clinical doses, benzodiazepines only slightly decrease a person’s tendency to worry, to

ruminate, or to be hypersensitive in interpersonal relationships.

The anxiolytic effects of benzodiazepines, given over a short time, are well documented (Hollister

et al. 1993). Tolerance to the sedative properties of benzodiazepines occurs when they are taken

regularly (McLeod et al. 1988). There is little evidence of tolerance to anxiolytic effects of

benzodiazepines, however (Nutt 2005). Patients who persistently demand dose increases are

suspected of seeking euphoria rather than anxiety reduction. Because tolerance rapidly develops to

euphoria, such patients constantly crave higher doses.

Many benzodiazepines are available to the clinician. Benzodiazepines differ little in their

pharmacodynamic properties; however, they differ in their speed of absorption in the brain and in

their half-lives (Greenblatt and Shader 1981). Quickly absorbed drugs, such as diazepam,

lorazepam, or alprazolam, are useful for fast relief of anxiety; however, because they tend to

produce a “high,” they have a greater addiction potential than, for instance, oxazepam, a

benzodiazepine with a slower absorption rate (Griffiths et al. 1984). Benzodiazepines with long

half-lives (such as chlordiazepoxide, diazepam, and flurazepam), prolonged in their activity by

active metabolites, are advantageous when regular administration is indicated because their

actions are smoother than those of benzodiazepines with short half-lives. However, they may

accumulate in patients with slow clearance, particularly in elderly patients and in patients with liver

diseases, and cause excessive sedation (Salzman et al. 1983). Asians also tend to have a slower

clearance of benzodiazepines (Lin et al. 1988).Print: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

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Benzodiazepines are compatible with most medications, but they enhance the effects of alcohol and

sedatives. Short-acting benzodiazepines, particularly triazolam, can produce significant

anterograde amnesia when taken in high doses or combined with alcohol (Brown et al. 1991).

The greatest drawback of benzodiazepines is their addiction potential (Marks 1983). Physical

dependency (i.e., difficulty in decreasing a therapeutic dose) can develop in patients using

medications in the therapeutic range. The severity of withdrawal symptoms depends on the dose,

the length of use, the patient’s personality, and, possibly, genetic factors. Patients with a history of

substance abuse and those with a positive family history of alcoholism are more prone to becoming

dependent on benzodiazepines (Ciraulo et al. 1989). Benzodiazepine withdrawal symptoms

resemble anxiety symptoms, which makes it difficult to determine whether patients who decrease

or discontinue benzodiazepines experience the reemergence of drug-suppressed anxiety,

withdrawal symptoms, or both. Because withdrawal symptoms vanish within 2 weeks, the

underlying anxiety levels can be assessed in patients within 3–4 weeks after the decrease or

discontinuation of medication.

In summary, benzodiazepines are very versatile drugs that can be taken in a single dose or on a

regular basis. Their beneficial effect on hyperarousal and the autonomic system renders them

particularly useful in the treatment of anxiety associated with somatic manifestations. Compared

with other tranquilizers and antidepressants, they are much safer if taken in an overdose. Their

main disadvantage is their addiction potential, which can be reduced considerably when

benzodiazepines are taken on a regular basis for only a short time or, when possible, on an

as-needed basis. Long-term use of benzodiazepines is usually reserved for cases that are resistant

to treatment with antidepressants.

Antidepressants With Serotonin Reuptake Inhibitory Properties

During the past decade, first-line treatment of GAD has shifted toward the use of antidepressants

with serotonin (5-hydroxytryptamine [5-HT]) reuptake inhibitory properties (Rynn and

Brawman-Mintzer 2004). Selective serotonin reuptake inhibitors (SSRIs) reduce primarily psychic

anxiety, including worries and obsessions. Having no effects on muscle tension or autonomic

responses, antidepressants are less effective in reducing somatic symptoms than are

benzodiazepines. However, with increased well-being, patients perceive a reduction in somatic

symptoms that can be, but not always is, accompanied by synchronic physiological changes

(McLeod and Hoehn-Saric 1993).

Tertiary tricyclic antidepressants (TCAs) (clomipramine, doxepin, amitriptyline, and imipramine)

are 5-HT and norepinephrine (NE) reuptake inhibitors, but only imipramine has undergone

controlled study in GAD (Rickels et al. 1993). Imipramine was found to have anxiolytic properties

that exceeded benzodiazepines after 2 weeks of treatment, affecting primarily psychic symptoms.

TCAs with antihistaminic sedative side effects can reduce hypervigilance. Their anticholinergic

effects can cause dry mouth, constipation, difficulty urinating, increased heart rate, increased

intraocular pressure, difficulties in visual accommodation, and cognitive disturbances (Preskorn

1993). TCAs also have quinidine-like action on the myocardium and cardiac conduction system, and

they are more toxic than newer antidepressants (Glassman and Bigger 1981). As a result, they are

less used today. However, in patients with irritable bowel syndrome, the anticholinergic effects

produce more feelings of well-being and reduce abdominal pain and dissatisfaction with bowel

movements (Rajagopalan et al. 1998). They are also useful in patients with comorbid migraine

headaches. Moreover, they are much less expensive than the newer antidepressants.

The SSRIs citalopram (Hoehn-Saric et al. 2004; Varia and Rauscher 2002), escitalopram (Davidson

et al. 2004), fluoxetine, fluvoxamine (Research Unit on Pediatric Psychopharmacology Anxiety

Study Group 2001), paroxetine (Sheehan and Mao 2003), and sertraline (Allgulander et al. 2004;

Ball et al. 2005), and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine (Meoni et

1. 2004; Sheehan 2001), have each been shown useful in the treatment of GAD, based on

placebo-controlled trials. Another SNRI, duloxetine, has not yet been tested in clinical trials for

effectiveness in GAD. Only escitalopram, paroxetine and venlafaxine, however, have official U.S.Print: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

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Food and Drug Administration (FDA) approval for the indication of GAD. Fluoxetine (Birmaher et al.

2003) and fluvoxamine have been shown to be effective in placebo-controlled trials in children and

adolescents (Cheer and Figgitt 2002).

In the majority of SSRI studies, psychic symptoms were more responsive than somatic symptoms

(Rynn and Brawman-Mintzer 2004). A study using paroxetine (Stocchi et al. 2003) also

demonstrated that patients maintained on medication had a lower relapse rate than patients on

placebo. Similar to TCAs, venlafaxine and duloxetine induce 5-HT and NE reuptake inhibition

without the pronounced antihistaminic and anticholinergic side effects of the latter (Rynn and

Brawman-Mintzer 2004).

SSRIs are comparable in their clinical effects, except that fluoxetine’s long half-life makes it less

flexible in administration (Preskorn 1993). TCA, SSRIs, and SNRIs may worsen anxiety in the start

of therapy, but this effect can be avoided by starting with low doses or by adding anxiolytic

medications. SSRIs may cause headaches, diarrhea, nausea, and sexual dysfunction and may

interact with hepatic cytochrome P450 enzyme systems (Nemeroff et al. 1996). Discontinuation of

SSRIs should be gradual to avoid self-limited but often unpleasant withdrawal symptoms (Coupland

et al. 1996). Venlafaxine and duloxetine also may cause nausea, dizziness, and sexual dysfunction

and may interact with some hepatic cytochromes. Venlafaxine also can increase blood pressure in

some patients (Rynn and Brawman-Mintzer 2004).

The dose of antidepressants in the treatment of GAD can be lower than doses used in the treatment

of depression or panic disorder (Hoehn-Saric et al. 1988). The anxiolytic effects of antidepressants

manifest themselves gradually and increase over time, while the effects of benzodiazepines are

immediate but do not increase during subsequent weeks. The duration of treatment varies. Many

GAD patients see a physician while under stress and improve within a few weeks or months, after

which they do not need regular medications. A subgroup of patients need long-term treatment.

Antidepressants are useful when there are severe and lasting psychic symptoms present (Rickels

and Schweizer 1990).

Trazodone, which is also a serotonin reuptake inhibitor and a 5-HT2 receptor antagonist, was found

effective in the treatment of GAD (Rickels and Schweizer 1990; Rickels et al. 1993). Because of its

sedating properties, trazodone is frequently coadministered with a nonsedating antidepressant as a

sedative in the evening. Nefazodone, a compound closely related to trazodone, was found effective

in GAD in an open-label trial (Hedges et al. 1996). It is less sedating than trazodone but can cause

severe liver damage (Hedges et al. 1996; Rynn and Brawman-Mintzer 2004). Mirtazapine, an

antidepressant with a novel mechanism, has been found effective in an open-label study in GAD

with comorbid depression (Goodnick et al. 1999). It does not cause initial worsening of anxiety and

promotes sleep, but it is very sedating, increases appetite, and causes weight gain (Nutt 2005;

Rynn and Brawman-Mintzer 2004).

In summary, evidence is accumulating that antidepressants with serotonin reuptake–inhibiting

properties have anxiolytic effects on psychic symptoms. They are indicated in patients who have

difficulties coping with pathological fears and worries. The effect of antidepressants is not

immediate, and medications must be taken regularly for several weeks. The choice of the

antidepressant depends on how a patient tolerates side effects. Generally, the clinician should start

with a low dose to permit the body to adjust to the side effects and then increase the dose

gradually until a therapeutic effect is achieved or until poor tolerance necessitates a change in

medication. Tolerance to the anxiolytic effects does not develop, and there is no abuse potential.

Plasma levels are of little clinical help except to assess a lack of response caused by low levels or

toxic effects caused by excessive levels. However, despite good clinical improvement, many

patients dislike the necessity of taking medications regularly or stop taking the medications

because of undesirable side effects.

Anxiolytics With Serotonergic Properties

Azaspirones, of which only buspirone is currently available, are anxiolytics that are structurally andPrint: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

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pharmacologically unrelated to benzodiazepines. Buspirone is more effective in the treatment of

GAD than placebo but less effective than the antidepressant venlafaxine (Davidson et al. 1999). It

is not habit-forming; side effects of buspirone are mild and consist primarily of nausea and

headaches. To be fully effective, buspirone must be taken regularly for at least 2 weeks.

Antihistamines

Antihistamines induce drowsiness and sedation (Rickels et al. 1970). They have weaker anxiolytic

effects than benzodiazepines, and effective doses may produce marked side effects. However, the

drugs have no addictive potential. Because of their quick action, antihistamines can be

administered in single doses or as a regular prescription. They remain popular because they are not

habit-forming and can be given safely to people who are likely to abuse medications.

Antipsychotics

Several typical antipsychotics, including loxapine, trifluoperazine, and thioridazine, have shown

anxiolytic properties (Chou and Sussman 1988). The atypical antipsychotics olanzapine,

risperidone, and quetiapine are also used to reduce anxiety (Nutt 2005). However, because of

extrapyramidal symptoms caused by typical antipsychotics and potentiation of diabetes and weight

gain from atypical antipsychotics, these drugs should be reserved for the rare patient with GAD who

seems to respond selectively to such drugs.

Beta-Adrenergic Blockers

Beta-blockers do not directly affect psychic anxiety (Tyrer 1976). They reduce the cardiac response

to anxiety by decreasing heart rate and reducing tremor, including that of vocal muscles, which

have a psychologically calming effect in some patients. Beta-blockers have a rapid clinical effect

and can be taken either in single doses or on a regular schedule.

CONCLUSION

The following considerations apply to the management of GAD symptoms:

Patients should be carefully assessed regarding the type, severity, and chronicity of symptoms; triggers

that elicit or aggravate symptoms; life stressors; coping ability; learning potential; specific personality

traits; and motivation to change. Clinicians must keep in mind that each patient is unique and that

treatment plans have to be tailored to meet specific needs.

1.  

If patients worry about their physical state, they should undergo a thorough physical examination, and

the results should be discussed with them to clarify which symptoms may be attributed to anxiety and

which symptoms to a potential physical illness.

2.  

Psychotherapy should be planned according to the need and expectation of the patients. Milder cases

may require only supportive therapy (Catalan et al. 1984). More severely ill patients may need CBT, with

greater emphasis on relaxation when physical symptoms predominate and with more emphasis on

cognitive aspects when strong psychic symptoms are present. Avoidant behavior requires active

encouragement to face feared situations. Psychodynamic therapy is indicated for characterological

problems.

3.  

Pharmacotherapy should be considered when symptoms are severe or when psychological interventions

are not feasible. A combination of psychotherapy and pharmacotherapy can enhance therapy outcomes

(Luborsky and Singer 1975). However, patients who undergo CBT may maintain treatment gains longer

than patients who receive only medications (Gould et al. 1997). Discontinuation of drug therapy may

have a negative effect on the maintenance of improvement. Patients who have become accustomed to

the anxiety-reducing effects of medications may become less tolerant of the discomforts caused by

anxiety than patients who have undergone drug-free psychological training and who have learned to

accept certain levels of anxiety as part of life.

4.  

Often, only short-term use of medications during times of heightened stress is necessary. In this case,

benzodiazepines or antihistamines are the medications of choice.

5.  

Chronic psychic symptoms respond better to antidepressants than to benzodiazepines or antihistamines.

Some patients may require combinations of medications, for instance, an antidepressant for excessive

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worries and (in addition) the occasional use of a benzodiazepine for insomnia or for the management of

stressful situations that cause hyperarousal and somatic symptoms.

The choice of the antidepressant depends on the age of the patient and on comorbidity. SSRIs and

SNRIs have less cardiovascular side effects than TCAs and are better tolerated by patients with

cardiovascular illnesses. Since these agents are less toxic, they are safer in potentially suicidal patients.

On the other hand, they frequently cause sexual dysfunction, may worsen an irritable bowel disorder,

and may aggravate migraine headache. For such patients, TCAs are better suited. SSRIs and SNRIs are

not sedating, and patients with tension or insomnia may need an additional benzodiazepine or a

sedative. Zaleplon, zolpidem, and eszopiclone are effective for sleep induction; trazodone is also

effective and not habit-forming, but it sometimes induces a hangover feeling.

7.  

All antidepressants need to be started in a low dose (to avoid unpleasant side effects or the initial

excitation experienced with most antidepressants) and gradually increased to an effective level. The

duration of treatment has to be individualized: Some patients improve within few months, while others

have to remain on medication indefinitely.

8.  

A number of medications not approved for treatment of anxiety, such as tiagabine and ondansetron,

have shown some anxiolytic effects. Pregabalin has been shown to be as effective as lorazepam, without

causing withdrawal effects after 4 weeks of administration (Pande et al. 2003).

9.  

The goal of treatment is to help patients become self-sufficient without the need for medication.

However, one must keep in mind that a minority of GAD patients need continuous pharmacotherapy,

including benzodiazepines. It would be shortsighted and insensitive to deny such patients medications

that could improve their quality of life.

10.  

REFERENCES

Allgulander C, Dahl AA, Austin C, et al: Efficacy of sertraline in a 12-week trial for generalized

anxiety disorder. Am J Psychiatry 161:1642–1649, 2004 [Full Text] [PubMed]

Ball SG, Kuhn A, Wall D, et al: Selective serotonin reuptake inhibitor treatment for generalized

anxiety disorder: a double-blind, prospective comparison between paroxetine and sertraline. J Clin

Psychiatry 66:94–99, 2005 [PubMed]

Beardsley RS, Gardocki GJ, Larson DB, et al: Prescribing of psychotropic medication by primary care

physicians and psychiatrists. Arch Gen Psychiatry 45:1117–1119, 1988 [PubMed]

Beck AT, Emery G: Anxiety Disorders and Phobias: A Cognitive Perspective. New York, Basic Books,

1985

Birmaher B, Axelson DA, Monk K, et al: Fluoxetine for the treatment of childhood anxiety disorders.

J Am Acad Child Adolesc Psychiatry 42:415–423, 2003 [PubMed]

Borkovec TD: Clinical and psychophysiological outcomes from cognitive behavioral therapy for

generalized anxiety disorder and the potential importance of targeting interpersonal behavior.

Keynote address, annual meeting of the European Association of Behavioural and Cognitive

Therapy, Maastricht, Netherlands, September 2002

Borkovec TD, Ruscio A: Psychotherapy for generalized anxiety disorder. J Clin Psychiatry 62:37–45,

2001 [PubMed]

Borkovec TD, Whisman MA: Psychosocial treatment for generalized anxiety disorder, in Long-Term

Treatments of Anxiety Disorders. Edited by Mavissakalian M, Prien RF. Washington, DC, American

Psychiatric Publishing, 1996, pp 171–199

Borkovec TD, Alcaine O, Behar E: Avoidance theory of worry and generalized anxiety disorder, in

Generalized Anxiety Disorder: Advances in Research and Practice. Edited by Heimberg RG, Turk CL,

Mennin DS. New York, Guilford, 2004, pp 77–108

Brown CS, Rakel RE, Wells BG, et al: A practical update on anxiety disorders and their

pharmacological treatment. Arch Intern Med 15:873–884, 1991

Catalan J, Gath D, Edmonds G, et al: The effects of nonprescribing of anxiolytics in general practice,Print: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

10 of 12

10/05/2009 17:23

I: controlled evaluation of psychiatric and social outcome. Br J Psychiatry 144:593–602, 1984

[PubMed]

Cheer SM, Figgitt DP: Spotlight on fluvoxamine in anxiety disorders in children and adolescents.

CNS Drugs 16:139–144, 2002 [PubMed]

Chou JC, Sussman N: Neuroleptics in anxiety. Psychiatric Annals 18:172–175, 1988

Ciraulo DA, Barnhill JG, Ciraulo AM, et al: Parental alcoholism as a risk factor in benzodiazepine

abuse: a pilot study. Am J Psychiatry 146:1333–1335, 1989 [PubMed]

Coupland NJ, Bell CJ, Potokar J: Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol

16:356–362, 1996 [PubMed]

Crits-Christoph P, Gibbons MB, Losardo D, et al: Who benefits from brief psychodynamic therapy for

generalized anxiety disorder? Canadian Journal of Psychoanalysis 12:301–324, 2004

Davidson JRT, DuPont RL, Hedges D, et al: Efficacy, safety, and tolerability of venlafaxine extended

release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry

60:528–535, 1999 [PubMed]

Davidson JR, Bose A, Korotzer A, et al: Escitalopram in the treatment of generalized anxiety

disorder: double-blind, placebo controlled, flexible-dose study. Depress Anxiety 19:234–240, 2004

[PubMed]

Durham RC: Predictors of treatment outcome, in Worry and Psychological Disorders: Theory,

Assessment, and Treatment. Edited by Davey GCL, Wells A. New York, Wiley, 2006, pp 379–397

Glassman AH, Bigger JT: Cardiovascular effects of therapeutic doses of tricyclic antidepressants.

Arch Gen Psychiatry 38:815–820, 1981 [PubMed]

Goldfried MR: Systematic desensitization as training in self-control. J Consult Clin Psychol

37:228–234, 1971 [PubMed]

Goodnick PJ, Puig A, DeVane CL, et al: Mirtazapine in major depression with comorbid generalized

anxiety disorder. J Clin Psychiatry 60:446–448, 1999 [PubMed]

Gould RA, Otto MW, Pollack MH, et al: Cognitive behavioral and pharmacological treatment of

generalized anxiety disorder: a preliminary meta-analysis. Behav Ther 28:285–305, 1997

Gould RA, Safren SA, Washington DO, et al: A meta-analytic review of cognitive-behavioral

treatments, in Generalized Anxiety Disorder: Advances in Research and Practice. Edited by

Heimberg RG, Turk CL, Mennin DS. New York, Guilford, 2004, pp 248–264

Greenblatt DJ, Shader RI: Clinical use of the benzodiazepines. Ration Drug Ther 15(10):1–6, 1981

[PubMed]

Griffiths RR, McLeod DR, Bigelow GE, et al: Relative abuse liability of diazepam and oxazepam:

behavioral and subjective dose effects. Psychopharmacology 84:147–154, 1984 [PubMed]

Hedges DW, Reimherr FW, Strong RE, et al: An open trial of nefazodone in adult patients with

generalized anxiety disorder. Psychopharmacol Bull 32:671–676, 1996 [PubMed]

Hoehn-Saric R, McLeod DR, Zimmerli WD: Differential effects of alprazolam and imipramine in

generalized anxiety disorder: somatic versus psychic symptoms. J Clin Psychiatry 49:293–301,

1988 [PubMed]

Hoehn-Saric R, Schlund MW, Wong SHY: Effect of citalopram on worry and brain activation in

patients with generalized anxiety disorder. Psychiatry Res Neuroimaging 131:11–21, 2004

[PubMed]

Hollister LE, Muller-Oerlinghausen B, Rickels K, et al: Clinical uses of benzodiazepines. J Clin

Psychopharmacol 13 (suppl 1):1S–169S, 1993Print: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

11 of 12

10/05/2009 17:23

Jacobson E: Progressive Relaxation. Chicago, IL, University of Chicago Press, 1938

Jensen JP, Bergin AE, Greaves DW: The meaning of eclecticism: new survey and analysis of

components. Professional Psychology: Research and Practice 21:124–130, 1990

Lin KM, Lau JK, Smith R, et al: Comparison of alprazolam plasma levels in normal Asian and

Caucasian male volunteers. Psychopharmacology 96:365–369, 1988 [PubMed]

Luborsky L: Principles of Psychoanalytic Psychotherapy: A Manual for Supportive-Expressive

Treatment. New York, Basic Books, 1984

Luborsky L, Singer B: Comparative studies of psychotherapies. Is it true that “everyone has won

and all must have prizes”? Arch Gen Psychiatry 32:995–1008, 1975 [PubMed]

Marks J: The benzodiazepines—for good or evil. Neuropsychobiology 10:115–126, 1983 [PubMed]

McLeod DR, Hoehn-Saric R, Labib AS, et al: Six weeks of diazepam treatment in normal women:

effects on psychomotor performance and psychophysiology. J Clin Psychopharmacol 8:83–99, 1988

[PubMed]

McLeod DR, Hoehn-Saric R: Perception of physiological change in normal and pathological anxiety,

in Biology of Anxiety Disorders. Edited by Hoehn-Saric R, McLeod DR. Washington, DC, American

Psychiatric Press, 1993, pp 223–243

Meoni P, Hackett D, Lader M: Pooled analysis of venlafaxine XR efficacy on somatic and psychic

symptoms of anxiety in patients with generalized anxiety disorder. Depress Anxiety 19:127–132,

2004 [PubMed]

Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am

J Psychiatry 153:311–320, 1996 [Full Text] [PubMed]

Newman MG, Crits-Christoph P, Connelly MB, et al: Participant factors in the treatment of anxiety

disorders, in Effective Principles of Change. Edited by Castonguay LG, Beutler LE. New York, Oxford

University Press, 2006, pp 121–154

Noyes RJ, Hoehn-Saric R: The Anxiety Disorders. Cambridge, UK, Cambridge University Press, 1998

Nutt DJ: Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectrums 10:49–56,

2005 [PubMed]

Öst L: Applied relaxation: description of a coping technique and review of controlled studies. Behav

Res Ther 25:397–409, 1987

Pande AC, Crockatt JG, Feltner DE, et al: Pregabalin in generalized anxiety disorder: a

placebo-controlled trial. Am J Psychiatry 160:533–540, 2003 [Full Text] [PubMed]

Power KG, Jerrom DW, Simpson RJ, et al: A controlled comparison of cognitive behavior therapy,

diazepam and placebo in the management of generalized anxiety. Behavioural Psychotherapy

17:1–14, 1989

Power KG, Simpson MB, Swanson V, et al: A controlled comparison of cognitive-behavior therapy,

diazepam, and placebo, alone and in combination, for the treatment of generalized anxiety disorder.

Journal of Anxiety Disorders 4:267–292, 1990

Preskorn SH: Pharmacokinetics of antidepressants: why and how are they relevant to treatment. J

Clin Psychiatry 54 (9 suppl):14–34, 1993

Rajagopalan M, Kurian G, John E: Symptom relief with amitriptyline in the irritable bowel syndrome.

J Gastroenterol Hepatol 13:738–741, 1998 [PubMed]

Research Unit on Pediatric Psychopharmacology Anxiety Study Group: Fluvoxamine for the

treatment of anxiety disorders in children and adolescents. N Engl J Med 344:1279–1285, 2001

Rice KM, Blanchard EB: Biofeedback in the treatment of anxiety disorders. Clin Psychol RevPrint: Chapter 33. Generalized Anxiety Disorder http://www.psychiatryonline.com/popup.aspx?aID=258993&print=yes…

12 of 12

10/05/2009 17:23

2:557–577, 1982

Rickels K, Schweizer E: The clinical course and long-term management of generalized anxiety

disorder. J Clin Psychopharmacol 10:101–109, 1990

Rickels K, Gordon PE, Zamostien BB, et al: Hydroxyzine and chlordiazepoxide in anxious neurotic

outpatients: a collaborative controlled study. Compr Psychiatry 11:457–474, 1970 [PubMed]

Rickels K, Downing R, Schweizer E, et al: Antidepressants for the treatment of generalized anxiety

disorder: a placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen

Psychiatry 50:884–895, 1993 [PubMed]

Rynn MA, Brawman-Mintzer O: Generalized anxiety disorder: acute and chronic treatment. CNS

Spectrums 9:716–723, 2004 [PubMed]

Salzman C, Shader RI, Greenblatt DJ, et al: Long vs. short half-life benzodiazepines in the elderly.

Arch Gen Psychiatry 40:293–297, 1983 [PubMed]

Sheehan D: Attaining remission in generalized anxiety disorder: venlafaxine extended release

comparative data. J Clin Psychiatry 62 (suppl 19):26–31, 2001

Sheehan DV, Mao CG: Paroxetine treatment of generalized anxiety disorder. Psychopharmacol Bull

37 (suppl 1):64–75, 2003

Stocchi F, Nordera G, Jakinen R, et al: Efficacy and tolerability of paroxetine for long-term

treatment of generalized anxiety disorder. J Clin Psychiatry 64:250–258, 2003 [PubMed]

Suinn RM, Richardson F: Anxiety management training: a nonspecific behavior therapy program for

anxiety control. Behav Ther 2:498–510, 1971

Tallman JH, Paul SM, Skolnick P: Receptors for the age of anxiety: pharmacology of the

benzodiazepines. Science 207:274–281, 1980 [PubMed]

Tyrer P: The Role of Bodily Feelings in Anxiety. London, Oxford University Press, 1976

Varia I, Rauscher F: Treatment of generalized anxiety disorder with citalopram. Clin

Psychopharmacol 17:103–107, 2002 [PubMed]

Wolpe J: Psychotherapy by Reciprocal Inhibition. Stanford, CA, Stanford University Press, 1958

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