Chapter 56. Treatment of Anxiety Disorders

Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

1 of 40

10/05/2009 16:36

Print Close Window

Jonathan R. T. Davidson, Kathryn M. Connor, Wei Zhang: Chapter 56. Treatment of Anxiety Disorders, in The American

Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff.

Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.424275. Printed

5/10/2009 from www.psychiatryonline.com

Textbook of Psychopharmacology >

Chapter 56. Treatment of Anxiety Disorders

TREATMENT OF ANXIETY DISORDERS: INTRODUCTION

Over the past decade and a half, there has been substantial progress in our understanding of the

anxiety disorders. Particularly fruitful has been the search to develop new treatments for the six

major anxiety disorders: obsessive-compulsive disorder (OCD), panic disorder, social phobia (social

anxiety disorder), specific phobia, generalized anxiety disorder (GAD), and posttraumatic stress

disorder (PTSD). In this chapter, we review the main findings from double-blind, and some

open-label, trials in each disorder. Both short-term and continuation/maintenance treatment

studies are included.

OBSESSIVE-COMPULSIVE DISORDER

When Kierkegaard wrote that “no grand inquisitor has in readiness such terrible tortures as has

anxiety, which never lets him escape,” he may well have been thinking of OCD, one of the few

conditions that has the capacity to produce a lifetime of psychological torture. Before the existence

of serotonin reuptake–inhibiting drugs, especially clomipramine, and selective serotonin reuptake

inhibitors (SSRIs), biological treatments generally had little effect, producing mild palliation at

best.

According to the Epidemiologic Catchment Area study (Myers et al. 1984; Robins et al. 1984), OCD

carries a lifetime prevalence of 2.5% in the United States and 6-month and 1-month prevalence

rates of 1.5% and 1.3%, respectively, although a more recent analysis from the National

Comorbidity Survey Replication (NCS-R) suggested slightly lower rates of 1.6% and 1.0% for the

lifetime and 12-month prevalence of OCD, respectively (Kessler et al. 2005a, 2005b). Its economic

toll is also substantial (Hollander et al. 1997). OCD has been recognized as the tenth leading cause

of disability worldwide (Murray and Lopez 1996). Treatment can be grouped broadly into

psychosocial and psychopharmacological approaches, the latter being our focus here. First, we

present information on monotherapy with serotonin reuptake–inhibiting drugs, followed by

management of partial responders or nonresponders, and we conclude with comments on less

frequently used treatments.

The chief rating scale for treatment studies of OCD remains the Yale-Brown Obsessive Compulsive

Scale (Y-BOCS; Goodman et al. 1989), a 10-item observer-rated measure. Self-ratings are of less

importance in the OCD literature and have traditionally received little weight.

Monotherapy

In 1967, Fernandez-Cordoba and Lopez-Ibor reported beneficial effects of the nonselective

serotonin reuptake inhibitor (SRI) tricyclic antidepressant (TCA) clomipramine in treating OCD.

Following this important insight, a series of placebo-controlled studies were completed in the late

1980s and the early 1990s, leading eventually to the first approved treatment of OCD in the United

States and other countries (Clomipramine Collaborative Study Group 1991). Clomipramine differs

from other tricyclic drugs in that it has a particularly potent serotonin reuptake–inhibiting effect.

The drug is not selective for serotonin, however, in that its demethylated metabolite is a

norepinephrine reuptake inhibitor. The anti-OCD effect of clomipramine correlates with the plasma

level of the parent drug, which is an SRI, suggesting that reuptake inhibition of serotonin is the

critical factor underlying the drug’s benefit. Moreover, some studies have shown lack of effect for

selective norepinephrine reuptake–inhibiting drugs, such as nortriptyline and desipramine, in OCDPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

2 of 40

10/05/2009 16:36

(Leonard et al. 1988; Thoren et al. 1980). An interesting aspect of the pharmacokinetics of

clomipramine is the ability of fluvoxamine to inhibit its demethylation, thereby increasing the

amount of clomipramine relative to desmethylclomipramine, which can produce a potentiating

effect in partial responders.

In the influential Clomipramine Collaborative Study Group (1991) trial, the Y-BOCS score was

reduced by about 40% in patients taking the drug as compared with 5% in patients receiving

placebo, bearing out findings by Mavissakalian et al. (1990) that OCD has a remarkably low placebo

response rate. At one point, it was thought that clomipramine may have a larger effect size than

SSRIs in the treatment of OCD (Greist et al. 1995b), but subsequently this finding has been

interpreted as more likely to have been due to sampling differences between studies. In general, it

is held that clomipramine and SSRI drugs are equivalent in the treatment of OCD (Koran et al.

1996). Nonetheless, clomipramine still may be a drug to consider in SSRI nonresponders. For the

most part, in view of its greater side effects and risks, as well as dose-related risks of seizures,

clomipramine would be regarded as a second-line treatment.

Today, SSRIs are considered first-line treatments for OCD, particularly the SSRIs fluvoxamine,

fluoxetine, sertraline, and paroxetine, all of which have a U.S. Food and Drug Administration (FDA)

indication for the treatment of OCD (Greist et al. 1995a, 1995b; Tollefson et al. 1994).

Clomipramine, fluvoxamine, fluoxetine, and sertraline also have been shown to be effective in

treating OCD in children, with an indication for treatment in such patients (Flament et al. 1985;

Liebowitz et al. 2002; March et al. 1998; Riddle et al. 2001). Escitalopram is also efficacious in OCD

at a daily dose of 20 mg on all main measures of efficacy, while 10 mg of escitalopram and 40 mg of

paroxetine were superior to placebo on some measures but took longer to work (D. J. Stein et al.

2007).

Paroxetine and fluoxetine appear to be more effective at higher doses, whereas no clear relation

between dose and effect was seen with sertraline, although a paradoxical finding of lesser efficacy

at 100 mg/day was most likely an artifact. The results for escitalopram suggest that possibly a

higher does of 20 mg is preferred, although 10 mg is somewhat effective. Recent results (Ninan et

1. 2006) suggest additional benefit for increasing the dosage of sertraline up to 400 mg/day in

nonresponders. Thus, when an SSRI drug is to be used in the treatment of OCD, not only may it

need to be given in higher doses, but also it may take a longer time to work effectively. Most people

believe that treatment should be long term to reduce the chance of relapse (Pato et al. 1990),

although the dosage might be lowered without loss of benefit (Ravizza et al. 1996).

Long-Term Treatment and Relapse Prevention

Long-term pharmacological treatments of OCD have suggested sustained response of an effective

medication beyond the acute treatment phase. In addition, clomipramine, paroxetine, sertraline,

and most recently, escitalopram all have been shown to be more effective than placebo in

preventing relapse in OCD (Fineberg et al. 2005, 2007). SSRIs appear to be well tolerated in these

studies.

Augmentation, Combination, and Other Strategies

Up to 60% of individuals with OCD show a response to SSRIs according to a conventional and

conservative criterion, full remission is rare, and response is often no more than partial. Relapse

can occur even while patients continue taking an SSRI, and comorbidity is often a complicating

factor in managing the disorder. The following augmentation, combination, and other novel

strategies have been reported as offering benefit:

Combining fluvoxamine with clomipramine (Szegedi et al. 1996) and the intravenous use of

clomipramine as monotherapy (Fallon et al. 1992; Koran et al. 1997) are both approaches to consider

in individuals who have shown a partial response to clomipramine. The rationale for combining

fluvoxamine with clomipramine was explained in the previous section, but some caution is in order

given the possibility of increased side effects and risk of seizure. Monitoring of plasma levels and

electrocardiograms is important with this combination. The use of intravenous clomipramine derivesPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

3 of 40

10/05/2009 16:36

from the fact that first-pass metabolism is avoided, and there is some suggestion that side effects are

less severe.

The benzodiazepine clonazepam has been added to clomipramine with mixed benefits (Pigott et al.

1992) and to sertraline with no added benefit (Crockett et al. 1999). Each of these findings was based

on a double-blind, placebo-controlled trial.

Patients with OCD refractory to SRI treatments may benefit from additional antipsychotic

augmentation. A meta-analysis of double-blind, randomized trials demonstrated significant benefits of

haloperidol and risperidone over placebo augmentation for OCD patients who failed to show treatment

response after an adequate trial of SRI, whereas evidence for the efficacy of olanzapine and quetiapine

is less conclusive (Bloch et al. 2006). Despite the fact that this approach appeared to benefit only a

limited number of subjects (although it was more beneficial among subjects who suffered from

comorbid tic disorders), any increased chance of improvement is worth striving for.

Greist and Jefferson (1998) have reported four studies in which SSRI and behavior therapy approaches

were compared and/or combined. Three of these studies gave some modest support to the idea that

combined treatment produces an enhanced effect. Also, rates of relapse after discontinuing behavior

therapy are considerably lower than those after discontinuing drug therapy. Other studies of SRI and

cognitive-behavioral therapy (CBT) using exposure and ritual prevention techniques have yielded

inconsistent results as to the benefits of combining drug and CBT over CBT alone (Cottraux et al. 1993;

Foa et al. 2005).

The addition of lithium, buspirone, desipramine, or gabapentin has produced very limited benefits in

studies to date, although there may be occasional patients for whom such combinations are helpful.

Other Approaches

One report suggested that St. John’s wort (Hypericum perforatum) produced some improvement

after 12 weeks of treatment in 12 patients with OCD (Taylor and Kobak 2000). The promise of this

early finding has been dampened by failure of the same group to establish efficacy for St. John’s

wort in a subsequent and adequately powered placebo-controlled study (Kobak et al. 2005).

A double-blind trial of intravenous clomipramine suggested greater benefit than oral loading (Koran

et al. 1997). Inositol, a naturally occurring second-messenger precursor, led to greater

improvement than placebo at a dosage of 18 g/day for 6 weeks (Fux et al. 1996).

Neurosurgical approaches, wherein either cingulotomy or anterior capsulotomy are carried out, can

be helpful for refractory OCD. Between 25% and 30% of the subjects show marked improvement,

and the side-effect burden of this procedure is small (Baer et al. 1995; Jenike et al. 1991). Limited

but promising studies also suggested other potential approaches such as deep brain stimulation for

severely treatment-refractory OCD patients (B. D. Greenberg et al. 2006; Nuttin et al. 1999).

CBT is well established for treating OCD, and evidence for efficacy is strong (e.g., Eddy et al. 2004;

Foa et al. 2005). In most types of CBT for this disorder, exposure with response prevention is used.

CBT is a first-choice option for OCD.

PANIC DISORDER

Panic disorder is a chronic and costly (P. E. Greenberg et al. 1999) condition that affects

approximately 1%–3% of the population (Alonso et al. 2004; Kessler et al. 2005b). It often

presents as a medical emergency and is associated with substantial comorbidity and increased

suicidal risks (Roy-Byrne et al. 2000). Effective treatment results in reduced emergency

department and laboratory resource utilization (Roy-Byrne et al. 2001).

Five core areas of the disorder require treatment: 1) full and limited symptom panic attacks, 2)

anticipatory anxiety, 3) phobias related to panic, 4) general well-being, and 5) disability (Ballenger

et al. 1998a). Treatment outcome can be comprehensively and succinctly measured with the Panic

Disorder Severity Scale (PDSS), which can be administered both as a clinician-rated and as a

self-rated scale (Shear et al. 1997).The PDSS contains seven domains relevant to panic disorder

and agoraphobia. Other widely used measures include the Sheehan Panic and Anticipatory Anxiety

Scale (PAAS; Sheehan 1986) and the self-rated Marks-Matthews Fear Questionnaire (FQ; Marks and Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

4 of 40

10/05/2009 16:36

Matthews 1979). Ideally, as with all of the anxiety disorders, the desired endpoint is full remission.

However, this is not always attainable.

The earliest groups of drugs to show robust efficacy relative to placebo were the TCAs and the

monoamine oxidase inhibitors (MAOIs) (Mavissakalian and Perel 1989; Sheehan et al. 1980).

However, even before any randomized clinical trials had been published to support the use of SSRI

drugs, the experts who were convened for the International Psychopharmacology Algorithm Project

(Jobson et al. 1995) indicated that their preferred first-line approach was to use an SSRI. The other

main approach would be to use benzodiazepine drugs, such as alprazolam or clonazepam (Lydiard

et al. 1992; Rosenbaum et al. 1997; Tesar et al. 1991). Initial drug selection, to be based on

discussion between the patient and the physician, would take into account issues of prior response,

proneness to abuse of medication, tolerability, safety, comorbidity, and presenting clinical picture

(e.g., degree of agitation).

First-Line Drug Treatments

Selective Serotonin Reuptake Inhibitors

In 1995, Boyer reported that SSRI drugs were more effective than imipramine and alprazolam in

treating panic disorder, although a recent meta-analysis by Otto et al. (2001) failed to confirm

these findings. Evidence is now available in support of citalopram (Wade et al. 1997), escitalopram

(Stahl et al. 2003), fluoxetine (Michelson et al. 1998, 2001), fluvoxamine (Asnis et al. 2001; Black

et al. 1993), paroxetine (Ballenger et al. 1998b; Oehrberg et al. 1995; Sheehan et al. 2005), and

sertraline (Londborg et al. 1998). In addition, clomipramine has been shown to have efficacy in

panic disorder (Lecrubier et al. 1997). Fluoxetine, paroxetine, and sertraline have been approved by

the FDA for treatment of panic disorder.

Although SSRI drugs are favored as first-line treatment, the following points need to be kept in

mind. Patients with panic disorder are often extremely sensitive to activating effects of

antidepressants and have poor tolerance of symptoms such as palpitations, sweating, and tremor.

It is therefore not uncommon for them to quickly lose faith and discontinue treatment or even drop

out without a full discussion having taken place. This problem can almost always be obviated,

either by coprescribing a benzodiazepine or by starting with extremely low doses of an SSRI and

gradually building up as tolerated. Also, perhaps of most importance is the availability of the

physician and thorough and reassuring preparation of patients ahead of time. Other problems of

SSRIs to be concerned about in panic disorder are those common to all other conditions for which

SSRIs are used (e.g., problems associated with weight gain, sexual dysfunction, impairment of

sleep, and potential drug–drug interactions). Discontinuation of treatment can be a significant

concern in panic disorder. Besides the obvious issue of relapse, SSRIs, with the exception of

fluoxetine, may sometimes produce troublesome discontinuation symptoms. Many of these

symptoms mimic panic disorder itself and can be quite distressing. Gradual dosage reduction is

usually recommended, along with adequate patient education and physician availability. Coping

strategies, including behavior therapy (Otto et al. 1993), are an option. Switching to an SSRI such

as fluoxetine also may be considered because this drug has a slow built-in taper. One also might

consider using serotonin2 (5-HT2) or serotonin3 (5-HT3) receptor antagonists, such as mirtazapine,

nefazodone, and ondansetron, to limit some of the symptoms that are mediated through these

pathways (e.g., insomnia, agitation, gastrointestinal distress).

Benzodiazepines

In the late 1980s, alprazolam received an FDA indication for treatment of panic disorder, making it

the first product so licensed. An important byproduct of this indication was raising general

awareness of the condition as well as helping to differentiate panic disorder with agoraphobia from

other kinds of anxiety. Several trials showed that alprazolam was more effective than placebo.

These included the Cross-National Collaborative Panic Study (1992), wherein imipramine and

alprazolam were both more effective than placebo. Lydiard et al. (1992) reported that alprazolam 2

mg/day was more effective than placebo, and benefit for alprazolam was shown in other trials.Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

5 of 40

10/05/2009 16:36

Efficacy for clonazepam was also demonstrated in panic disorder (Davidson and Moroz 1998;

Rosenbaum et al. 1997; Tesar et al. 1991).

Although alprazolam has been widely used for panic disorder, it is now regarded more as a

second-line treatment. Problems include the need for frequent administration, tendency to produce

sedation at higher doses, abuse liability, and discontinuation-related distress. Lesser et al. (1992)

showed that higher plasma levels (i.e., >70 ng/mL) were associated with greater likelihood of

response as compared with lower levels (in the 20–40 ng/mL range). Thus, higher doses may have

an advantage, particularly in managing phobic avoidance, but often at the price of more side effects

or discontinuation difficulty. Comparable efficacy and tolerability have been demonstrated for the

sustained-release formulation of alprazolam (Pecknold et al. 1994; Schweizer et al. 1993).

Clonazepam, which is also FDA approved for panic disorder, has an advantage over alprazolam in

that its half-life is considerably longer and the drug can be dosed once or twice a day. However, it

shares the usual class effects of benzodiazepines and can produce sedation, depression, and

discontinuation syndrome. A particular concern with benzodiazepines is their use in the elderly. The

elderly are not only more prone to developing side effects, including sedation and falls that result in

fractures and potential head injury, but also more likely to experience problems upon

discontinuation of the drug. In a fixed-dose study, clonazepam 1 mg/day was more effective than

placebo on nearly all major measures; however, clonazepam 0.5 mg/day was ineffective except on

the Hamilton Anxiety Scale (Ham-A; Hamilton 1959). In general, escalating the dosage up to 4

mg/day did not provide greater benefit, suggesting that such higher dosages should be reserved for

patients who are refractory to treatment at lower dosages. In the clonazepam studies, ratings of

actual panic attacks tended to be the least likely to detect drug and placebo differences. As pointed

out by Bandelow et al. (1995), overreliance on reduction of panic attacks as the principal outcome

measure is an unsatisfactory marker of overall treatment benefit. Despite the almost universal

unhappiness with this measure, it continues to be chosen as a primary outcome for regulatory

studies.

One interesting and important finding to emerge from the studies of clonazepam in panic disorder is

its substantial benefits on quality of life and work productivity. A broad-spectrum effect was noted

on all five measures of mental health–related quality of life. During a 6-week clinical trial, patients

moved from the seventh percentile for all adult Americans with regard to mental health component

score (MCS) of the Short Form–36 (SF-36) to the seventeenth percentile. By contrast, the placebo

group moved only from the eighth to the twelfth percentile during this time. With respect to work

productivity, the difference between the effects of clonazepam and placebo during a 6-week

treatment period amounted to an additional 6 hours of full productivity during a 40-hour workweek

(Jacobs et al. 1997).

Other Pharmacological Approaches

Tricyclic Antidepressants

Several studies have reported benefit for clomipramine and imipramine in the treatment of panic

disorder (Andersch et al. 1991; Cross-National Collaborative Panic Study 1992; Fahy et al. 1992;

Lecrubier et al. 1997; Mavissakalian and Perel 1989; Modigh et al. 1992). The norepinephrine

reuptake inhibitor desipramine also was more effective than placebo (Lydiard et al. 1993).

TCAs are second-line treatments for panic disorder at best. They are certainly effective, but the

associated autonomic side effects, cardiovascular problems, weight gain, and potential lethality in

overdose are all matters of concern. Dosing with TCAs may be critical. Mavissakalian and Perel

(1995), for example, found that phobic symptoms responded best if the plasma level of imipramine

and desmethylimipramine was in the range of 110–140 ng/mL, whereas control of panic attacks

tended to occur at lower plasma levels. As with SSRIs, low starting dosages in the range of 10–25

mg/day are in order, with gradual titration thereafter in accordance with patient tolerance.

Monoamine Oxidase InhibitorsPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

6 of 40

10/05/2009 16:36

Sheehan et al. (1980) found that phenelzine, along with imipramine, was more effective than

placebo in the treatment of panic disorder with agoraphobia, which they referred to as

“endogenous anxiety.” Lydiard and Ballenger (1987) expressed the opinion that MAOIs may be

superior to TCAs. Although these debates were fruitful in the 1980s, MAOIs have been swept aside

by the remorseless tide of history, as have TCAs to some degree. These drugs now have been

relegated to a lower echelon. Although for some patients MAOIs may still be the best treatment,

their overall role in managing anxiety disorders is now fairly small. The role of the safer reversible

inhibitor of monoamine oxidase A (RIMA) in panic disorder is unclear. Brofaromine and

moclobemide have shown comparable efficacy and tolerability to clomipramine (Bakish et al. 1993;

Kruger and Dahl 1999) and moclobemide also to fluoxetine for up to 1 year (Tiller et al. 1999);

however, the significance of these findings is questionable in the absence of a placebo control.

When compared with CBT and placebo, the effect of moclobemide was no different from placebo

and failed to enhance the effect of CBT (Loerch et al. 1999).

Other Drugs

The extended-release (XR) formulation of venlafaxine, a serotonin–norepinephrine reuptake

inhibitor (SNRI), has demonstrated greater efficacy than placebo in patients with panic disorder

(Bradwejn et al. 2005) and has received FDA approval for the treatment of panic disorder.

Following 10 weeks of treatment, patients receiving venlafaxine XR (mean dosage = 163 mg/day)

experienced fewer panic attacks, greater freedom from limited symptom attacks (but not full

symptom attacks), improvement in anticipatory anxiety and avoidance, and higher rates of

response and remission compared with placebo. The drug was well tolerated, with an

adverse-effect profile comparable with that of the drug in depression and other anxiety disorders.

Mirtazapine, a noradrenergic and specific serotonergic antidepressant, has also demonstrated

anxiolytic activity. Possible benefit in panic disorder has been reported for the drug (Boshuisen et

1. 2001; Ribeiro et al. 2001; Sarchiapone et al. 2003); however, double-blind, placebo-controlled

trials have yet to be conducted. It is noteworthy that mirtazapine has been associated with the

induction of panic attacks in depressed patients undergoing dose escalation and discontinuation

(Berigan 2003; Klesmer et al. 2000).

Reboxetine, a selective reuptake inhibitor of norepinephrine, has been found to produce greater

benefit than placebo in patients with panic disorder (Versiani et al. 2002). At dosages of 6–8

mg/day, the drug produced greater improvement in the number of panic attacks and phobic

symptoms, as well as reduction in score on the Hamilton Rating Scale for Depression (Ham-D;

Hamilton 1960), the Hopkins Symptom Checklist–90, and the Sheehan Disability Scale. It also

produced significantly higher levels of dry mouth than placebo but in general was well tolerated. In

a more recent randomized, single-blind study comparing reboxetine with paroxetine, paroxetine

was more effective on panic attacks, but no differences were noted between the treatments on

anticipatory anxiety and avoidance (Bertani et al. 2004). These findings suggest perhaps different

roles of norepinephrine and serotonin in the treatment of panic disorder. In those countries where

reboxetine has been approved for depression and is therefore available, it might be a useful backup

drug for use in SSRI and benzodiazepine nonresponders. Given its antidepressant properties, it

might be advantageous over benzodiazepines. However, the selective noradrenergic reuptake

inhibitor maprotiline appears to be ineffective in panic disorder (Den Boer and Westenberg 1988),

while the data for bupropion are inconclusive (Sheehan et al. 1983; Simon et al. 2003).

Trazodone was less effective than imipramine and alprazolam in the treatment of panic disorder

(Charney et al. 1986). Buspirone, a 5-HT1A partial agonist, was ineffective in panic disorder

(Sheehan et al. 1990). The anticonvulsant gabapentin was also generally ineffective in panic

disorder, though post hoc analyses suggest an anxiolytic effect in more severely ill patients (Pande

et al. 2000). Possible benefit has been reported for other anticonvulsant drugs, including

levetiracetam, tiagabine, and valproic acid (Keck et al. 1993; Papp 2006; Zwanzger et al. 2001), but

double-blind trials have not been undertaken. Preliminary data suggest improvement in refractory

panic disorder when atypical antipsychotics are prescribed to augment an SSRI (risperidone: SimonPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

7 of 40

10/05/2009 16:36

et al. 2006; olanzapine: Sepede et al. 2006) or at higher doses as monotherapy (olanzapine:

Hollifield et al. 2005); however, double-blind, placebo-controlled trials are needed. Metabotropic

glutamate type 2 receptor agonists have shown promise in preclinical models of anxiety but have

yet to demonstrate clinical efficacy in panic disorder (Bergink and Westenberg 2005). Similarly, the

effect of a cholecystokinin-B receptor antagonist was no different from placebo in patients with

panic disorder (Pande et al. 1999a).

Combination Pharmacotherapy

The activating side effects of SSRIs can be quite troublesome for anxiety patients, particularly

when beginning pharmacotherapy in patients with panic disorder. Coadministration of a long-acting

benzodiazepine for the first several weeks of treatment may help improve SSRI tolerability and

provide more rapid stabilization of panic symptoms than SSRI treatment alone (Goddard et al.

2001; Pollack et al. 2003).

Long-Term Management

Maintenance treatment is recommended for at least 12–24 months, if not longer. The long-term

treatment of panic disorder has been reviewed elsewhere (Davidson 1998). In a controlled trial of

paroxetine, clomipramine, and placebo, 84% of the paroxetine-treated patients eventually became

panic free over the 9-month period (Lecrubier and Judge 1997). In a 4-year naturalistic follow-up

study of 367 patients with panic disorder, greater improvements in panic attacks, phobic avoidance,

and daily functioning were observed in those who received continuation treatment for 4 years,

compared with 1 year (Katschnig et al. 1995), suggesting that recovery continues over several

years.

Long-term randomized, controlled trials have reported efficacy for citalopram (Lepola et al. 1998),

clomipramine (Fahy et al. 1992), fluoxetine (Michelson et al. 1999), paroxetine (Lecrubier and

Judge 1997; Lydiard et al. 1998), and sertraline (Rapaport et al. 2001). In a relapse prevention trial

following 3 months of successful open-label treatment with the drug, Ferguson et al. (2007)

showed that over the course of 7 months, relapse on placebo was 50%, whereas relapse among

those remaining on venlafaxine XR was 22%.

From an early long-term study of imipramine (Mavissakalian and Perel 1992), it appeared that

relapse may diminish with the passage of time, provided effective psychopharmacological cover has

been provided, but a later trial by the same group failed to confirm this (Mavissakalian and Perel

2002).

Discontinuation

Even though there is some similarity between symptoms of relapse and symptoms of drug

withdrawal, the existence of discontinuation symptoms from stopping medication is unarguable. If

poorly managed, discontinuation can be fraught with problems. Some strategies are likely to make

withdrawal of medication more tolerable. The first strategy is a slow taper. Indeed, for some

benzodiazepines, it may be necessary to taper the drug over many weeks or even months. Second,

timing of the taper may be important. This is best accomplished when other variables in a patient’s

life are as stable as possible. Switching to a longer-acting benzodiazepine, such as clonazepam,

also may be helpful. Some authors (Pages and Ries 1998) have advocated consideration of

anticonvulsants, such as carbamazepine and valproate. Otto et al. (1993) also found behavior

therapy to be helpful in this regard.

Various elaborations of CBT, including self-help books, and telephone- and Internet-delivered

therapy, have demonstrated efficacy on a consistent basis for panic disorder, with the common

elements being education, cognitive strategies, and exposure to feared sensations and situations

(Clum and Surls 1993; Royal Australian and New Zealand College of Psychiatrists Clinical Practice

Guidelines Team for Panic Disorder and Agoraphobia 2003). CBT is a first-line choice, and even

when pharmacotherapy is given as main treatment, principles of CBT should be incorporated into

the management plan. As noted, it can be of benefit during the process of drug discontinuation, andPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

8 of 40

10/05/2009 16:36

perhaps in lessening the chance of relapse afterwards.

SOCIAL PHOBIA

Social phobia, also referred to as social anxiety disorder, can be grouped into generalized and

nongeneralized types. Generalized social phobia is more commonly seen in clinical settings, is

usually more disabling, and is associated with greater levels of comorbidity and genetic loading

than nongeneralized social phobia. Most of our knowledge about pharmacotherapy for social phobia

derives from generalized social phobia, and the literature suggests that different medication

approaches may be called for in treating the two subtypes.

Comprehensive treatment of social phobia requires that the symptoms of fear, avoidance, and

physiological distress are brought under control, comorbidity is treated, disability and impairment

are improved, and quality of life is enhanced. Furthermore, evidence from maintenance and relapse

prevention studies has confirmed the value of long-term therapy in treatment responders.

Instruments commonly used to measure treatment change in social phobia include the clinician

and self-rated Liebowitz Social Anxiety Scale (LSAS; Liebowitz 1987), which assesses 24

performance or interpersonal situations for fear and avoidance. A score of 30 or less is considered

to equate with remission. The Social Phobia Inventory (SPIN) is a useful 17-item self-rating

instrument that assesses fear, avoidance, and physiological distress (Connor et al. 2000) and, like

the LSAS, is able to detect treatment differences on all its subscales.

Pharmacotherapy

Most clinicians consider SSRI drugs as the first choice for generalized social phobia, with either

-blockers or benzodiazepines being the first choice for nongeneralized social phobia. Second-line

drugs for generalized social phobia comprise the benzodiazepines, perhaps venlafaxine (an SNRI),

and maybe other antidepressants, including nefazodone and mirtazapine. MAOIs also have a role.

Bupropion and TCAs have been generally disappointing.

Serotonergic Drugs

Fluvoxamine has been widely studied and has the longest track record of success in the treatment

of social phobia. In 1994, van Vliet et al. showed superiority for fluvoxamine over placebo, with

response rates of 46% and 7%, respectively. M. B. Stein et al. (1999) later confirmed the efficacy

of fluvoxamine relative to placebo on all symptom domains of social phobia (i.e., fear, avoidance,

and physiological arousal). Studies have also looked at the controlled-released (CR) form of

fluvoxamine and found it to be superior to placebo (Davidson et al. 2004c; Westenberg et al. 2004).

In the study by Davidson et al. (2004c), baseline symptom severity was higher than in most other

clinical trials, yet drug therapy was still effective. In addition to these studies conducted in the

United States or Europe, a more recent study in Japan also found fluvoxamine to be effective

compared to placebo in reducing symptoms and associated psychosocial disability among Japanese

patients with generalized social anxiety disorder (Asakura et al. 2007).

Sertraline also has been studied (Blomhoff et al. 2001; Katzelnick et al. 1995; Liebowitz et al. 2003;

Van Ameringen et al. 2001; Walker et al. 2000). In the study by Van Ameringen et al. (2001), 53%

responded to sertraline as compared with 29% to placebo. As with the fluvoxamine study of M. B.

Stein et al. (1999), the Brief Social Phobia Scale was a primary outcome measure, and in both

instances, the drug was shown to produce benefit on all three symptom domains. In a primary care

setting, Haug et al. (2000) showed that cognitive therapy and sertraline could be effectively

delivered, although the combination did not really show any superiority over treatment with drug

alone.

Effectiveness for paroxetine was shown relative to placebo in both short-term efficacy and relapse

prevention. In the short-term studies by M. B. Stein et al. (1998), Allgulander (1999), and Baldwin

et al. (1999), rates of response to paroxetine were 55%, 70%, and 66%, respectively, as compared

with placebo response rates of 24%, 8%, and 32%. These differences are substantial and suggest a

marked effect for paroxetine in social phobia. All subjects in the paroxetine trials fulfilled criteriaPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

9 of 40

10/05/2009 16:36

for generalized social phobia and showed benefit on the primary measure, the LSAS. Between 2 and

4 weeks was required for paroxetine to show significant superiority.

Fluoxetine, while superior to placebo on primary outcomes in one study (Davidson et al. 2004c),

failed to separate from placebo in another (Kobak et al. 2002). In the latter study, placebo seemed

to yield a greater response (30%) than most other studies of SSRIs in social phobia. Another study

comparing cognitive therapy, fluoxetine plus self-exposure, and placebo plus self-exposure in social

phobia found cognitive therapy to be superior to fluoxetine plus self-exposure and placebo plus

self-exposure on measures of social phobia, with no difference between the latter two groups (D.

1. Clark et al. 2003). Interestingly, another serotonergic agent, nefazodone, also failed to separate

from placebo on most outcome measures in a recent report of Canadian outpatients with social

phobia (Van Ameringen et al. 2007).

Placebo-controlled data with citalopram have not been presented for social phobia. However, trials

with escitalopram have shown superiority over placebo in short-term, long-term, and relapse

prevention studies of generalized social phobia (Kasper et al. 2005; Lader et al. 2004; Montgomery

et al. 2005). Venlafaxine XR has also shown superiority over placebo in two double-blind trials of

generalized social phobia (Allgulander et al. 2004; Liebowitz et al. 2005). A double-blind,

placebo-controlled trial of mirtazapine in women showed statistically significant superiority for

drug over placebo (Muehlbacher et al. 2005).

Paroxetine, sertraline, and venlafaxine XR are currently the only FDA-approved drugs for the

treatment of social phobia, although the controlled-release form of fluvoxamine is likely to be

approved for social anxiety disorder in the near future.

Benzodiazepines

Three major placebo-controlled trials have shown efficacy for benzodiazepines in social phobia.

First, Gelernter et al. (1991) showed a very modest effect for alprazolam over placebo and a

generally inferior picture for alprazolam relative to phenelzine. The response rate with alprazolam,

at a mean daily dose of 4.2 mg, was 38%, a rate significantly better than the 20% response rate to

placebo. Davidson et al. (1993) conducted a moderately large trial in 75 patients taking clonazepam

or placebo and found a substantial 70% response rate to clonazepam compared with a 20%

response rate to placebo. Clonazepam worked rapidly and effectively and had a broad-spectrum

effect in the disorder. Bromazepam also has been found to work more effectively than placebo

(Versiani et al. 1997). A magnetic resonance spectroscopy study of clonazepam in social phobia has

shown that even when clonazepam is effective, there are no changes in the extent of

N-acetylaspartate, choline, and myo-inositol, suggesting that these particular changes within the

central nervous system are not state dependent.

Some benzodiazepines (clonazepam and bromazepam) provide a marked response yet do not find

favor as first-line drugs because of their more limited spectrum of action, as well as potential

withdrawal difficulties. However, they work rapidly, are well tolerated, and may be particularly

useful for individuals with periodic performance-related social anxiety.

Anticonvulsants

Gabapentin and pregabalin produce significant effects in social phobia. Pande et al. (1999b) found a

superior effect for gabapentin over placebo, with response rates of 39% and 17%, respectively.

Baseline symptom scores were comparatively high and overall response rates relatively low,

suggesting a degree of treatment resistance in the population. A flexible dosage of gabapentin was

used, ranging from 900 to 3,600 mg, with 2,100 mg/day being the most commonly chosen final

dosage. The newer anticonvulsant drug pregabalin has shown benefit in generalized social phobia.

Although 150 mg/day of pregabalin was no different from placebo, 600 mg/day produced greater

effects than placebo, with response rates of 43% and 22%, respectively. At 600 mg/day,

pregabalin produces a relatively high rate of side effects, and it is probably necessary to explore

lower dosages for social phobia. Further work with anticonvulsants is called for because they are

generally well tolerated, safe, and less likely to produce difficulties during discontinuation thanPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

10 of 40

10/05/2009 16:36

many SSRIs and benzodiazepines.

Reversible Inhibitors of Monoamine Oxidase

Moclobemide initially appeared to be a safer and very promising alternative to older MAOIs. A study

by Versiani et al. (1992) showed that moclobemide worked almost as effectively as phenelzine and

significantly better than placebo but that it was slower to take effect compared with phenelzine.

Response rates to moclobemide and placebo in the study were 65% and 15%, respectively, with a

fairly high dosage of moclobemide being attained (581 mg/day). However, these exciting early

findings have not been borne out by subsequent studies. For instance, Noyes et al. (1997) reported

no significant advantage for moclobemide at several dosages as compared with placebo. Schneier

et al. (1998) showed a poor effect for the drug in a single-center trial, and the International

Multicenter Clinical Trial Group on Moclobemide in Social Phobia (1997) found a modestly greater

response rate (47%) for moclobemide at 600 mg/day than for placebo (34%). Based on the two

positive trials, moclobemide has received a license in some countries but is not available in the

United States. Another RIMA, brofaromine, has shown promise in three trials, with response rates

of 78%, 50%, and 73%, respectively, compared with placebo response rates of 23%, 19%, and 0%

(Fahlen et al. 1995; Lott et al. 1997; van Vliet et al. 1992).

Irreversible Inhibitors of Monoamine Oxidase

Phenelzine has been studied in four double-blind, placebo-controlled trials and showed positive

benefit in all cases (Gelernter et al. 1991; Heimberg et al. 1998; Liebowitz et al. 1992; Versiani et

1. 1992). Response rates to phenelzine were 69%, 85%, 64%, and 65%, respectively, as

compared with 20%, 15%, 23%, and 33%, respectively, to placebo. Even though phenelzine is so

consistently effective, perhaps as a result of its combined noradrenergic, dopaminergic, and

serotonergic effects, its poor tolerance, as well as greater risks, makes it an unsuitable choice for

most patients. However, it should not be completely ignored and may make a major difference in

the lives of some patients whose symptoms do not respond to other drugs.

Other Drugs

Olanzapine yielded greater improvement than placebo in a preliminary double-blind,

placebo-controlled monotherapy trial of social anxiety disorder (Barnett et al. 2002), suggesting

atypical antipsychotics may deserve further investigation in this area of research. Ondansetron,

while producing a statistically significant effect relative to placebo, seems to be of very limited

benefit (Bell and DeVeaugh-Geiss 1994; Davidson et al. 1997b), but it might be a useful backup or

adjunct in some cases. Its cost is a major problem. Buspirone was ineffective in a double-blind trial,

producing only a 7% response rate (van Vliet et al. 1997).

Despite their intuitive appeal, -blockers have shown poor effect in treating generalized social

phobia. For example, atenolol failed to separate from placebo in two trials (Liebowitz et al. 1992;

Turner et al. 1994). -Blockers do show some value in performance social anxiety, perhaps by

virtue of their ability to reduce peripheral autonomic arousal and block negative feedback.

Nefazodone, bupropion, and selegiline have not shown impressive results in open-label reports

(Emmanuel et al. 1991; Simpson et al. 1998; Van Ameringen et al. 1999).

A novel therapeutic approach is suggested by the findings of Hofmann et al. (2006), who

administered a single dose of D-cycloserine or placebo to patients with social anxiety disorder

treated with CBT. The drug was given prior to each CBT session and enhanced the benefit of CBT to

a greater extent than did placebo. The postulated mechanism of action relates to drug-facilitated

extinction of learned fear via glutamatergic pathways.

Treatment in Children and Adolescents

One interesting placebo-controlled trial of fluvoxamine in children ages 6–17 years showed that it

was superior to placebo in social phobia, GAD, or the combination: 76% of the fluvoxamine group

responded, as compared with 19% of the placebo group (Research Unit on Pediatric

Psychopharmacology Anxiety Study Group 2001). Double-blind trials of paroxetinePrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

11 of 40

10/05/2009 16:36

immediate-release (IR) (Wagner et al. 2004) and venlafaxine XR (March et al. 2007) have

produced positive results in children and adolescents with generalized social anxiety disorder.

Response rates for paroxetine and placebo were 78% and 38%, respectively; in the venlafaxine

study, they were 56% and 37%. An open-label trial by Compton et al. (2001) suggested some value

for sertraline in children and adolescents with social phobia, but we are unaware of any published

placebo-controlled trials.

Duration of Treatment

Because social phobia is a chronic illness, treatment is generally recommended for years.

Sutherland et al. (1996) reported that at 2-year follow-up, subjects who had received an active

drug rather than placebo in a double-blind trial were doing better. Relatively few relapse

prevention studies have been done. In a 12-month trial with clonazepam, Connor et al. (1998)

showed a 20% relapse rate in those switched to placebo compared with 0% in those who continued

taking clonazepam. On other measures, there was an upward drift in fear and phobia scores in

subjects who were withdrawn from clonazepam. However, in the study with its very slow taper, it

was encouraging that withdrawal symptoms were rare and not problematic. M. B. Stein et al.

(1996) reported that 62% of the subjects relapsed when switched double-blind from paroxetine to

placebo after 12 weeks, compared with only 12% who relapsed during maintenance treatment with

paroxetine.

Other Issues

CBT is efficacious in social anxiety disorder, being comparable to pharmacotherapy (Davidson et al.

2004b; Fedoroff and Taylor 2001), but little is known as to whether adding CBT to medication

lowers the relapse rate, and so far the limited evidence does not suggest any potentiating effects

when the treatments are combined (Davidson et al. 2004b). It does appear as if exposure

consistently produces gain, but adding cognitive elements does not confer further benefit (Haug et

1. 2003; Hofmann 2004). In a comparative study of drug and psychotherapy, Heimberg et al.

(1998) showed that phenelzine and CBT were approximately similar, although phenelzine had an

edge in more severely symptomatic patients. On the other hand, when subjects who had

discontinued treatment were followed up, rates of relapse tended to be lower in those who had

received CBT than in those who had taken phenelzine. Turner et al. (1994) found that atenolol was

not as good as social skills training, and D. B. Clark and Agras (1991) showed a relatively poor

response with buspirone over exposure therapy in performance social phobia.

Despite the obvious benefits of drug therapy in social phobia, medication often falls short of

producing remission, and a pressing need remains to find better drugs, better combinations, and

the ways in which drug therapy and psychosocial treatments might be most productively used,

whether in sequence, simultaneously, or according to some other formula. Nevertheless, compared

with the situation 15 years ago, prospects for recovery from social phobia are perhaps better than

they have ever been.

SPECIFIC PHOBIA

Specific phobia is among the most common psychiatric disorders, with a lifetime prevalence of

8%–12.5% (Alonso et al. 2004; Kessler et al. 2005b) and 12-month prevalence of 3.5%–9%

(Alonso et al. 2004; Kessler et al. 2005a). While the disorder is characterized by an early age of

onset (median age at onset is 7 years) (Kessler et al. 2005b), most of those with the disorder are

unimpaired by their symptoms; hence, few individuals actually seek treatment for their specific

phobia (Magee et al. 1996; Stinson et al. 2007; Zimmerman and Mattia 2000). However, for a

minority of individuals, specific phobia causes significant disability and requires treatment. The

generally accepted treatment of choice is exposure therapy, which is uniformly and rapidly

effective, with techniques including virtual reality or in vivo exposure, and muscle tension exercises

(for blood–injury phobia) (Swinson et al. 2006). Few studies have evaluated the efficacy of

pharmacological approaches, and no drug has yet been approved by the FDA for treating specific

phobia. No standard ratings exist for this disorder, although the Marks-Matthews FQ is quitePrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

12 of 40

10/05/2009 16:36

suitable for blood–injury phobia and some other fears. A modification of this scale, the

Marks-Sheehan Main Phobia Severity Scale (MSMPSS; Sheehan 1986) can be recommended.

Serotonergic drugs have shown efficacy in treating symptoms of fear and avoidance in a variety of

anxiety disorders and thus would seem logical choices in treating specific phobias. It is therefore

not surprising that studies of pharmacological treatments for specific phobia have focused on

serotonergic agents. In a double-blind, controlled trial, 11 subjects were treated for 4 weeks with

either paroxetine (up to 20 mg/day) or placebo (Benjamin et al. 2000). As measured by the

Marks-Matthews FQ and the Ham-A, 60% of the subjects (3 of 5), compared with 17% taking

placebo (1 of 6), responded to treatment with paroxetine. A more recent randomized, double-blind

pilot trial compared the effects of escitalopram versus placebo over 12 weeks in 12 adults with

specific phobia (Alamy et al. 2008). While no difference was observed on the primary outcome,

response based on a Clinical Global Impression Scale (CGI) Improvement score of 1 or 2 was noted

in 60% of subjects who received escitalopram, compared with 29% on placebo (effect size = 1.13).

The findings from these two small trials suggest promise for the SSRIs in specific phobia; however,

larger controlled trials are needed. In contrast, in a controlled trial of the serotonergic and

noradrenergic drug imipramine in 218 phobic subjects (agoraphobic, mixed phobic, or simple

phobic) receiving 26 weeks of behavior therapy, no difference was observed between imipramine

and placebo (Zitrin et al. 1983). Intermittent use of benzodiazepines also may be helpful in the

acute treatment of the somatic anxiety that accompanies specific phobia, although this usage has

not been an area of active investigation.

In a long-term controlled study of clonazepam in social phobia, Davidson et al. (1994) observed

that clonazepam was superior in reducing symptoms of anxiety related to blood–injury phobia as

measured by changes in the blood–injury phobia subscale of the Marks-Matthews FQ. Some caution

should be used with these drugs, however, because there is risk of physiological dependence.

Using a novel approach, Ressler et al. (2004) investigated the effect of a cognitive enhancer,

D-cycloserine, as an adjunct to psychotherapy, hypothesizing that the drug would accelerate the

associative learning processes that contribute to ameliorating psychopathology. D-Cycloserine is a

N-methyl-D-aspartate (NMDA) receptor partial agonist that has demonstrated improvement in

extinction in rodents. Subjects with acrophobia (n = 28) were randomized to receive a single dose

of D-cycloserine or placebo prior to each of two virtual reality exposure therapy sessions. The

combination of D-cycloserine and exposure therapy was associated with greater improvement in the

virtual-reality setting, as well as on a variety of anxiety domains. These changes were noted early

in treatment and were maintained at 3-month follow-up.

Specific phobia tends to be a chronic condition. Although psychotherapeutic approaches can be

beneficial in the short term, evidence suggests that the initial gains noted with treatment may not

be sustained over the long term (Lipsitz et al. 1999). Pharmacological augmentation may help to

extend the benefits of exposure therapy over time. It also has been hypothesized that specific

phobia may represent a phenomenological marker for a vulnerability to developing other anxiety

disorders that are characterized by more general avoidance (Goisman et al. 1998). As such,

perhaps early recognition and treatment in individuals at risk could reduce the occurrence of more

severe anxiety disorders in this population. Further study of these hypotheses is needed.

GENERALIZED ANXIETY DISORDER

GAD is a common anxiety disorder, with a lifetime prevalence of 5%–6% (Wittchen and Hoyer

2001) and is the most prevalent anxiety disorder in primary care, with rates that exceed 8%

(Goldberg and Lecrubier 1995). GAD tends to be a chronic and disabling condition with lifetime

rates of comorbidity as high as 90% (Wittchen et al. 1994), particularly depression (prevalence

rate greater than 60%) (Wittchen et al. 1994), which can increase the severity and burden of the

disorder.

GAD is characterized by persistent and excessive worry that is difficult to control and is

accompanied by symptoms of anxiety, tension, and autonomic arousal. Effective treatments includePrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

13 of 40

10/05/2009 16:36

anxiolytic drugs, such as benzodiazepines and azapirones. These drugs can be helpful for symptoms

of anxiety, but they are not generally considered satisfactory in the treatment of depression. In

addition, the side-effect profile of benzodiazepines and potential for physiological dependence limit

their use in many patients and have resulted in growing interest in the search for alternative

treatments. In recent years, growing evidence supports the role for antidepressants in treating

GAD, especially in patients with comorbid depression.

The goals of pharmacotherapy for GAD include treatment of the symptoms of worry, anxiety,

tension, somatic distress, and autonomic arousal. Ideally, treatments will have a rapid onset of

action in reducing these core symptoms; will be effective in treating the associated disability,

psychosocial impairment, and comorbidity; and will be safe for longer-term use in chronic GAD.

Assessment of response in almost all pharmacotherapy trials of GAD has involved use of the

clinician-administered Ham-A (Hamilton 1959), which measures psychic (i.e., psychological) and

somatic symptoms of anxiety and broadly maps onto the clinical features of GAD. Remission is

usually defined as a Ham-A score of 7 or less. The Hospital Anxiety and Depression Scale (HADS;

Zigmond and Snaith 1983) is also widely used and is capable of detecting differences in treatment

efficacy. An advantage of the HADS lies in the fact that its items are independent from the

confounding influence of psychotropic drug side effects. It also has widely established population

norms.

Anxiolytics

Benzodiazepines

Benzodiazepines have been widely used to treat acute and chronic anxiety since their introduction

in the 1960s. Their activity is mediated through potentiation of the inhibitory neurotransmitter

-aminobutyric acid (GABA) at the GABAA receptor. The efficacy and relative safety of

benzodiazepines in short-term use, over several weeks or months, are well established (Rickels et

1. 1983; Shader and Greenblatt 1993). However, the use of these drugs over longer periods is more

controversial, and long-term use can be associated with the development of tolerance, physiological

dependence, and withdrawal (if abruptly discontinued), as well as troublesome side effects,

including ataxia, sedation, motor dysfunction, and cognitive impairment. Furthermore, these drugs

should be avoided in patients with a history of substance use disorders, and long-term use may

infrequently lead to the development of major depression (Lydiard et al. 1987).

Benzodiazepines have been shown to be effective in GAD, as reported by Rickels et al. (1993) in an

8-week study of diazepam in patients with DSM-III (American Psychiatric Association

1980)–diagnosed GAD. The appeal of these drugs lies in their rapid onset of action, ease of use,

tolerability, and relative safety. However, few controlled data support their use over the long term

in GAD. Findings from several 6- to 8-month trials of maintenance treatment for chronic anxiety

have indicated continued efficacy of benzodiazepines over time (Rickels et al. 1983, 1988a, 1988b;

Schweizer et al. 1993). Because GAD tends to be a chronic disorder, many patients may need to

continue pharmacotherapy with benzodiazepines or other drugs for many years.

Estimates suggest that approximately 70% of patients with GAD will respond to an adequate trial of

a benzodiazepine (Greenblatt et al. 1983). An adequate treatment trial corresponds to the

equivalent of a 3- to 4-week treatment course of up to 40 mg/day of diazepam or 4 mg/day of

alprazolam (Schweizer and Rickels 1996). If a decision is made to discontinue treatment, the drug

should be tapered slowly to minimize the effects of withdrawal, the development of rebound

anxiety, and the potential for relapse. Some evidence suggests that benzodiazepines may be more

effective in treating particular GAD symptoms, such as autonomic arousal and somatic symptoms,

but less effective for the psychic symptoms of worry and irritability (Rickels et al. 1982; Rosenbaum

et al. 1984).

As our understanding of the phenomenology of GAD has grown and as the diagnostic criteria have

evolved from DSM-III to DSM-IV (American Psychiatric Association 1994), there has been a greaterPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

14 of 40

10/05/2009 16:36

emphasis on the psychic component of the disorder, with de-emphasis of the autonomic and

somatic components. Given these changes, along with the high rates of comorbid depression in GAD

and the anxiolytic activity of many of the newer classes of antidepressants, the utility of

benzodiazepines as a primary treatment for GAD is uncertain. However, even though somatic

symptoms are no longer featured as diagnostic criteria, they are frequently seen as presenting

clinical symptoms in practice. A degree of uncertainty still hangs over the most appropriate way to

classify GAD. Even as DSM-IV was being crafted, debate centered around the extent to which GAD

could be separated from mood disorders, such as dysthymia and major depression (Moras et al.

1996). This question has never been well resolved, and it is possible that with so much in common

between GAD and depressive disorders, its classification primarily as an anxiety disorder may

change in DSM-V.

Azapirones

The azapirones are structurally distinct from the benzodiazepines and are believed to exert their

anxiolytic effect through partial agonism of 5-HT1A receptors. Several trials have indicated that

buspirone is superior to placebo and comparable to benzodiazepines in treating GAD, with fewer

side effects and without concerns for abuse, dependence, and withdrawal (Cohn et al. 1986;

Enkelmann 1991; Petracca et al. 1990; Rickels et al. 1988b; Strand et al. 1990), although other

studies have reported conflicting results (Fontaine et al. 1987; Olajide and Lader 1987; Ross and

Matas 1987). Buspirone appears more effective in treating the psychic component of anxiety

(Rickels et al. 1982) and possibly anxiety with mixed depressive symptoms (Rickels et al. 1991)

than the somatic and autonomic symptoms of anxiety (Schweizer and Rickels 1988; Sheehan et al.

1990). An adequate trial of buspirone in GAD would be 3–4 weeks of treatment at a dosage of up to

60 mg/day, in divided doses. Treatment-limiting effects of the drug include greater potential for

side effects at higher dosages, slower onset of action, more variable antidepressant effect, and

possibly reduced effectiveness in patients with a prior favorable response to benzodiazepines

(Schweizer et al. 1986).

Tricyclic Antidepressants

Retrospective studies of subjects with “anxiety neurosis” suggested that TCAs may be effective in

treating anxiety states similar to GAD (Cohn et al. 1986; Johnstone et al. 1980). Data in support of

these findings come from controlled studies of imipramine and trazodone in GAD (Hoehn-Saric et al.

1988; Rickels et al. 1993). In a 6-week trial comparing imipramine and alprazolam, similar

improvement was observed with both treatments by week 2; however, imipramine appeared to be

more effective in treating the psychic anxiety associated with GAD, whereas alprazolam was more

effective in attenuating somatic symptoms (Hoehn-Saric et al. 1988). In an 8-week double-blind,

placebo-controlled trial of imipramine, trazodone, and diazepam (Rickels et al. 1993), early onset of

effect was noted with diazepam by week 2, with effect primarily on somatic symptoms. Over the

next 6 weeks, however, symptoms of psychic anxiety were more responsive to treatment with the

antidepressants. Overall, imipramine was more efficacious than diazepam, whereas the effect of

trazodone was comparable to that of diazepam, and all treatments were superior to placebo. In a

controlled trial comparing imipramine, paroxetine, and 2′-chlordesmethyldiazepam, early onset of

action was again noted with the benzodiazepine by week 2, but overall greater improvement was

noted with the antidepressants by week 4, with particular benefit noted in psychic symptoms

(Rocca et al. 1997).

Potential advantages of the TCAs over the benzodiazepines include their ability to treat symptoms

of both anxiety and depression, the absence of potential for abuse and physiological dependence,

and their effectiveness in the management of discontinuation of long-term benzodiazepine therapy

(Rickels et al. 2000a). TCAs, however, can be accompanied by a variety of troublesome side effects

related to pharmacological blockade of histamine1 (H1), 1-adrenergic, and muscarinic receptors,

and these effects can limit their use. Frequently reported adverse effects include weight gain,

orthostatic hypotension, edema, urinary retention, blurred vision, dry mouth, and constipation.

Sedation is also commonly noted; for some patients this is an adverse event, whereas for others itPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

15 of 40

10/05/2009 16:36

is of therapeutic benefit. The utility of the TCAs is also limited by their cardiotoxic potential and

lethality in overdose.

Selective Serotonin Reuptake Inhibitors and Serotonin–Norepinephrine

Reuptake Inhibitors

A number of SSRIs are effective in GAD. Paroxetine IR at 20–50 mg per day has been shown to be

as effective as imipramine and more effective than 2′-chlordesmethyldiazepam, with the

antidepressants again demonstrating greatest effect on symptoms of psychic anxiety (Rocca et al.

1997). Compared with placebo, a similar dosage range of paroxetine IR was associated with

significant reduction in anxiety after 8 weeks of treatment (Bellew et al. 2000; Pollack et al. 2001),

with an improvement in psychic anxiety as measured by reduction in the anxious mood item of the

Ham-A scale, observed as early as 1 week after initiating treatment (Pollack et al. 2001).

Paroxetine IR also improves social functioning in patients with GAD (Bellew et al. 2000). Rickels et

1. (2003) have reported superior benefit of paroxetine IR in GAD, relative to placebo.

Three 8-week placebo-controlled trials have found efficacy for escitalopram in a 10- to 20-mg dose

range on a variety of measures, of both anxiety symptoms and disability or quality of life (Davidson

et al. 2004a; Goodman et al. 2005). In a 6-month trial, Bielski et al. (2005) found equivalent benefit

for paroxetine IR and escitalopram. In a larger placebo-controlled trial of three doses of

escitalopram and 20 mg paroxetine IR, 10 mg escitalopram demonstrated superiority over 20 mg

paroxetine, 10 and 20 mg escitalopram were superior to placebo, while 5 mg escitalopram and 20

mg paroxetine IR were superior on some secondary outcomes (Baldwin et al. 2006). A relapse

prevention study found that sustained treatment with escitalopram 20 mg/day up to 74 weeks

reduced the rate of relapse relative to placebo substitution (Allgulander et al. 2006). Relapse rates

were for 19% for escitalopram versus 56% for placebo.

Two studies have shown benefit for sertraline over placebo in GAD (Allgulander et al. 2004;

Brawman-Mintzer et al. 2006).

Several placebo-controlled trials have confirmed the short-term efficacy of venlafaxine XR in GAD

over 8 weeks, with improvement noted in both the psychic and the somatic symptoms of the

disorder. In one trial, 365 adult outpatients received treatment with venlafaxine XR (75 mg/day or

150 mg/day), buspirone (30 mg/day), or placebo (Davidson et al. 1999). The adjusted mean scores

on the Ham-A anxious mood and tension items were significantly improved at both dosages of

venlafaxine XR compared with placebo; however, the adjusted mean Ham-A total score failed to

distinguish between the groups. Venlafaxine XR was superior to buspirone on the Anxiety subscale

of the HADS. In a second trial, 541 outpatients were given either venlafaxine XR (37.5 mg/day, 75

mg/day, or 150 mg/day) or placebo (Allgulander et al. 2001). By the end of the study, the 75-mg

and 150-mg doses of venlafaxine showed superior efficacy to placebo on all primary outcome

measures, whereas the 37.5-mg dose was superior on only one measure (the Anxiety subscale of

the HADS). Significant improvement was noted in symptoms of psychic anxiety by week 2 of

treatment with venlafaxine, with reduction of somatic symptoms noted a bit later, following 4–8

weeks of treatment. A third trial evaluated fixed dosages of venlafaxine XR at 75 mg/day, 150

mg/day, and 225 mg/day (Rickels et al. 2000b). Venlafaxine XR was superior to placebo on all

outcome measures, although the most robust effects were observed with 225 mg/day. In addition,

venlafaxine XR significantly reduced psychic anxiety but was no different from placebo in treating

somatic symptoms of anxiety.

Venlafaxine XR also has shown long-term efficacy in GAD. In two 6-month controlled trials of fixed

(37.5 mg, 75 mg, 150 mg/day) (Allgulander et al. 2001) and flexible (75–225 mg/day) (Gelenberg

et al. 2000) doses of venlafaxine XR, significant improvement in anxiety was observed as early as 1

week, and efficacy was sustained over the 28-week treatment period. In the fixed-dose study, the

greatest effect was observed with the 150-mg/day dose. In addition, significant improvement in

social functioning was noted at the two higher doses by week 8 and sustained over the 6 months of

the trial.Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

16 of 40

10/05/2009 16:36

Venlafaxine XR is also effective in treating GAD with comorbid depression (Silverstone and Salinas

2001). After 12 weeks of treatment with venlafaxine XR (75–225 mg/day), fluoxetine, or placebo,

significant reduction was observed in both anxiety and depression, as measured by the Ham-A and

the Ham-D, respectively, only in subjects receiving venlafaxine XR. The response was delayed

somewhat in subjects with comorbid GAD and depression, as compared with those with depression

alone, suggesting that those with comorbidity may benefit from a longer course of treatment.

The traditional treatment goal for GAD and many other psychiatric disorders has been attainment of

response, defined as 50% improvement relative to baseline. There is a growing consensus in the

field, however, that this goal is not sufficient for many patients and that the goal of treatment

should instead be remission, defined as 70% or greater improvement from baseline and/or minimal

or absent symptoms (i.e., Ham-A score 7). Pooled analysis of data from the two long-term studies

noted above has determined that remission is attainable in GAD (Meoni and Hackett 2000). By 2

months, approximately 40% of those receiving venlafaxine responded to treatment (response

defined as 50% reduction in Ham-A score from baseline), and 42% attained remission (defined as

a Ham-A score 7). By 6 months, the proportion of those in remission increased to almost 60%,

whereas responders declined to 20%, in contrast to a remission rate of less than 40% with placebo.

Venlafaxine XR has some advantages over the benzodiazepines—notably, antidepressant activity,

lack of potential for abuse and dependence, and efficacy in treating symptoms of psychic anxiety.

Nonetheless, venlafaxine can be associated with some adverse effects, even though the incidence

of these effects diminishes markedly with long-term treatment. Adverse events may be noted with

long-term therapy, however, and include sexual dysfunction and blood pressure elevation in some

patients. In addition, abrupt discontinuation of treatment can be associated with unpleasant side

effects, most commonly dizziness, light-headedness, tinnitus, nausea, vomiting, and loss of

appetite, and the discontinuation syndrome is worse if one abruptly stops from higher dosage levels

(Allgulander et al. 2001).

Duloxetine, also an SNRI antidepressant, has shown superior efficacy to placebo in GAD

(Allgulander et al. 2007; Rynn et al. 2008) in the range of 60–120 mg per day, as well as lessening

the chance of relapse during maintenance therapy.

Noradrenergic and Specific Serotonergic Antidepressants (Mirtazapine,

Bupropion)

The antidepressant mirtazapine also has demonstrated anxiolytic properties (Ribeiro et al. 2001).

However, published reports of its effect in GAD are limited to a small open-label study in major

depression and comorbid GAD (Goodnick et al. 1999). Although the results were encouraging, data

from controlled trials are needed to adequately assess a possible role for mirtazapine in GAD.

One double-blind trial, published in abstract form, found that bupropion XL produced a higher

remission rate than escitalopram, as well as better coping skills (Bystritsky et al. 2005).

Notwithstanding these intriguing findings, the body of clinical evidence for now supports the use of

serotonergic drugs, or dual serotonergic/noradrenergic reuptake inhibitors, before agents that are

primarily noradrenergic in action. However, the Bystritsky et al. findings suggest the potential

importance of noradrenergic mechanisms in GAD and its therapeutics.

Hydroxyzine

Hydroxyzine, a drug that blocks both H1 and muscarinic receptors, has been studied in GAD. In one

controlled study, hydroxyzine was superior to placebo following 1 week of treatment, and this

difference was maintained over a 4-week trial (Ferreri and Hantouche 1998). In a larger controlled

multicenter trial, hydroxyzine was compared with buspirone over 4 weeks (Lader and Scotto 1998).

Changes in the Ham-A from baseline to day 28 indicated that hydroxyzine was superior to placebo,

with no difference observed between buspirone and placebo. Of note, both hydroxyzine and

buspirone were more efficacious than placebo on the secondary outcomes. Llorca et al. (2002)

found that hydroxyzine 50 mg/day was superior to placebo and comparable to bromazepam in a

12-week trial.Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

17 of 40

10/05/2009 16:36

Other Drugs

The 2 calcium channel antagonist pregabalin was superior to placebo in four studies of GAD

(Feltner et al. 2003; Pande et al. 2003; Pohl et al. 2005; Rickels et al. 2005). Efficacy was noted

early in treatment, but the ability of this drug to successfully treat some of the comorbid disorders

found with GAD is unknown. The GABA reuptake inhibitor tiagabine failed to separate from placebo

on key measures in one multicenter trial (Pollack et al. 2005).

Evidence for antipsychotic monotherapy in GAD is limited. An open-label trial suggested benefit for

ziprasidone (Snyderman et al. 2005). Flupenthixol is approved for the use of depression in some

countries but is also widely used to treat GAD-like states. One controlled study showed that

flupenthixol was superior to amitriptyline, clotiazepam, and placebo among subjects with refractory

GAD (Wurthmann et al. 1995). Sulpiride is also used in similar situations (Bruscky et al. 1974; Chen

et al. 1994). Use of antipsychotic drugs carries some concern about their tolerability and safety

profile.

Riluzole, a presynaptic glutamate release inhibitor, has shown promise in a small open-label study

at a daily dose of 100 mg (Mathew et al. 2005).

Complementary treatments, such as homeopathy and the herbal remedy kava kava, are ineffective

in GAD (Bonne et al. 2003; Connor and Davidson 2002).

A meta-analysis of GAD studies by Hidalgo et al. (2007) showed that the effect sizes (in diminishing

order from strongest to weakest) for each drug or drug group versus placebo were as follows:

pregabalin, 0.50; hydroxyzine, 0.45; venlafaxine XR, 0.42; benzodiazepines, 0.38; SSRIs, 0.36;

buspirone, 0.17; and homeopathy and herbal treatment, –0.31.

Drugs that have been approved in the United States for treating GAD or historical forerunners of the

disorder include a large number of benzodiazepines, buspirone, paroxetine IR, escitalopram,

venlafaxine XR, and duloxetine.

There is also convincing evidence in favor of efficacy for CBT in GAD, with sustained benefit over 2

years of follow-up. These findings have been well reviewed by Swinson et al. (2006). There are no

clinically informative studies to compare, or combine, CBT and pharmacotherapy in GAD, but on

pragmatic grounds, one may consider their combination in patients who have shown only a partial

response to a thorough course of either CBT or medication alone.

POSTTRAUMATIC STRESS DISORDER

PTSD is a chronic and disabling disorder, with a lifetime prevalence of about 7% (Kessler et al.

2005a). The direct and indirect consequences of the disorder inflict an enormous burden on society,

leading PTSD to be the primary cost driver in the annual $42 billion cost of anxiety disorders in the

late 1990s (P. E. Greenberg et al. 1999).

Treatment of PTSD should target a range of presenting features. Clearly, effective therapy needs to

reduce the core symptoms of the disorder. Treatment also should focus on improving resilience and

coping with daily stress, improving quality of life, and reducing comorbidity and disability. For

some, medication may serve to help seal over the distress and pain of the event and allow a return

to normal daily activities. For others, medication may help them to engage in a treatment plan that

involves uncovering the distress and allows for resolution of the traumatic experience.

Instruments that have been widely used in trials of pharmacotherapy comprise the DSM-IV

criteria–linked Clinician-Administered PTSD Scale (CAPS; Weathers et al. 2001) and the more

globally oriented Short PTSD Rating Instrument (SPRINT; Connor and Davidson 2001). Self-rating

scales include the Davidson Trauma Scale (DTS; Davidson et al. 1997a), a 17-item, two-part

assessment of the major DSM-IV symptoms of PTSD, and the SPRINT, which also has been

validated as a self-rating. Most studies to date have evaluated monotherapy, but a growing number

are examining augmentation approaches.

AntidepressantsPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

18 of 40

10/05/2009 16:36

The TCAs and MAOIs were among the first pharmacological agents studied in controlled trials of

PTSD. More recently, findings from several controlled multicenter trials have shown efficacy for the

SSRI and SNRI drugs. With the documented antidepressant and anxiolytic effects of these

noradrenergic and serotonergic agents, and the high rates of comorbid depression in PTSD (Kessler

et al. 1995), antidepressants would seem like a logical choice for treatment of PTSD.

Tricyclic Antidepressants

Positive evidence for the efficacy of TCAs has been found in two controlled trials involving male

combat veterans with PTSD defined by DSM-III criteria. In one study, 46 World War II and Vietnam

War veterans were given amitriptyline (50–300 mg/day) or placebo for 8 weeks. Greater

improvement was noted with amitriptyline than with placebo; 50% of those receiving amitriptyline

showed much or very much global improvement, compared with 17% of those receiving placebo

(Davidson et al. 1990). A second study examined imipramine (50–300 mg/day) and placebo in 60

veterans of the Vietnam era. Greater reduction in symptoms was noted in subjects receiving

imipramine, with a 25% reduction in Impact of Event Scale (IES; Horowitz et al. 1979) score from

baseline for imipramine compared with 5% for placebo. Global improvement also was superior with

imipramine (65%) compared with placebo (28%) (Kosten et al. 1991). Together, these studies

showed that TCAs are more effective than placebo in the short-term treatment of PTSD in male

combat veterans.

Monoamine Oxidase Inhibitors

In a study of male combat veterans, Kosten et al. (1991) compared phenelzine (15–75 mg/day)

with placebo and found a 45% decrease in IES score from baseline for phenelzine, compared with a

5% decrease for placebo, but no improvement was noted in depressive symptoms with either

treatment. The RIMA brofaromine has been assessed in two controlled trials of PTSD: a U.S. sample

composed predominantly of combat veterans (n = 114) (Baker et al. 1995) and a civilian European

sample with few veterans (n = 68) (Katz et al. 1994). The U.S. study failed to show a difference

between the treatments. Findings from the European study also were mixed, depending on the

measure used to assess change. Finally, the RIMA moclobemide was assessed in 20 subjects with

PTSD meeting DSM-III-R (American Psychiatric Association 1987) criteria (Neal et al. 1997).

Following 12 weeks of treatment, 11 subjects no longer met the full PTSD criteria, providing a

signal that the drug might be effective in PTSD.

Selective Serotonin Reuptake Inhibitors

Three controlled trials support the efficacy of fluoxetine in PTSD. In these studies, fluoxetine was

administered at dosages of 20–80 mg/day for 5–12 weeks in samples including both civilians and

combat veterans with PTSD meeting DSM-III-R (Connor et al. 1999; van der Kolk et al. 1994) or

DSM-IV (Martenyi et al. 2002a) criteria. Significant differences were observed in favor of

fluoxetine, as measured by changes in clinician-rated structured interviews from baseline to the

end of treatment. In the study by Connor et al. (1999), fluoxetine also was associated with a

significant improvement in resilience, as measured by a reduction in stress vulnerability, and in

disability. Martenyi et al. (2002a) showed that at a mean dosage of 57 mg/day, fluoxetine was

associated with significant reduction in PTSD symptoms from baseline as early as week 6 and at

week 12, in a sample predominantly made up of male combat veterans.

Two studies of maintenance therapy with fluoxetine over a period of 1 year have shown reductions

in the rate of relapse, as compared with placebo substitution (Davidson et al. 2005; Martenyi et al.

2002b).

Two studies have shown efficacy for sertraline in PTSD (Brady et al. 2000; Davidson et al. 2001). At

a mean dosage of approximately 150 mg/day, sertraline was more effective than placebo in

reducing overall PTSD symptoms and avoidance; symptoms of arousal improved with sertraline in

one study (Brady et al. 2000; Davidson et al. 2001), but no differences were noted in intrusive

symptoms. Based on a response definition of a greater than 30% reduction in CAPS (Blake et al.

1995) score from baseline and a CGI score of 1 or 2 (much or very much improvement), responsePrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

19 of 40

10/05/2009 16:36

rates for sertraline ranged from 53% to 60%, compared with 32%–38% for placebo. A pooled

analysis of these data showed the broad-spectrum effect of the drug, particularly on psychological

symptoms of the disorder, with an early modulation of anger at 1 week preceding improvement in

other symptoms (Davidson et al. 2002). This finding is of particular interest, given that angry

temperament can be associated with impulsivity and violence and a greater risk for cardiac events

(Williams et al. 2001), as well as increased heart rate and blood pressure, in PTSD (Beckham et al.

2002). Other short-term studies of sertraline in PTSD have been negative (Brady et al. 2005;

Davidson et al. 2006b; Friedman et al. 2007) or inconclusive (Zohar et al. 2002).

Continued treatment with sertraline over 9 months was associated with sustained improvement in

more than 90% of the subjects (Londborg et al. 2001). In those with more severe PTSD who did not

improve with acute treatment over 12 weeks, more than 50% were likely to respond with continued

treatment (Londborg et al. 2001). Over 15 months of treatment, improvement was sustained, with

relapse rates of 5% with sertraline and 26% with placebo, thereby suggesting that the drug

provides prophylactic protection against relapse (Davidson et al. 2001). Sertraline is also effective

in improving quality of life and reducing functional impairment, with rapid improvement noted with

acute treatment and more than 55% of patients functioning at levels within 10% of the general

population. These gains are maintained with long-term treatment, and continued improvement can

be noted, whereas treatment discontinuation is more likely to lead to deteriorating function,

although not to levels observed prior to treatment (Rapaport et al. 2002).

The efficacy of paroxetine in PTSD has been shown in two 12-week controlled multicenter trials,

including flexible-dose (n = 307; paroxetine 20–50 mg) (Tucker et al. 2001) and fixed-dose (n =

451; paroxetine 20 or 40 mg) (Marshall et al. 2001) regimens. Compared with placebo, paroxetine

produced significant improvement in overall PTSD symptomatology, individual symptom clusters,

and functional impairment. Response rates ranged from 54% to 62% for paroxetine compared with

37% to 40% for placebo.

Findings from two open-label studies of fluvoxamine, at dosages of 100–250 mg/day, have been

reported, including those from an 8-week study in civilians (n = 15) and a 10-week study in combat

veterans (n = 10) (Davidson et al. 1998; Marmar et al. 1996), in which the drug was effective in

treating symptoms of PTSD. Treatment with fluvoxamine (mean = 194 mg/day) also has been

associated with significant improvement in autonomic reactivity, with reductions in heart rate and

blood pressure on exposure to trauma cues to levels that are indistinguishable from those of control

subjects without PTSD (Tucker et al. 2000). These findings are encouraging, but larger controlled

trials are needed to determine the efficacy of the drug in PTSD.

Two large multicenter studies have established efficacy for venlafaxine XR up to 300 mg per day, in

one case for as long as 6 months. Rates of remission exceeded 50% in the longer-term trial, and

resilience was significantly improved in one of the two studies (Davidson et al. 2006a, 2006b).

In summary, the SSRIs are efficacious in the treatment of PTSD, with two drugs, paroxetine IR and

sertraline, approved for treatment of PTSD. SSRIs and SNRIs show a broad spectrum of activity,

with significant reduction in some symptoms as early as 1–2 weeks after treatment initiation. SSRI

and SNRI drugs not only improve symptoms with acute treatment but also result in sustained and

continued improvement, and in some cases remission, with long-term treatment up to 15 months.

These drugs are generally well tolerated, although some adverse effects (e.g., sexual dysfunction,

sleep disturbances, and weight gain) may lead to treatment discontinuation.

Other Antidepressants

Results of one 8-week controlled trial of mirtazapine in 29 outpatients with PTSD have been

reported. A clinician-rated global assessment found response rates to mirtazapine of 65%

compared with response rates to placebo of 20%, with significant improvement on several

measures of PTSD as well as general anxiety (Davidson et al. 2003).

Six open-label studies of nefazodone in civilians and combat veterans with PTSD have been

reported (Hidalgo et al. 1999). Treatment with nefazodone (50–600 mg/day) over 6–12 weeks wasPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

20 of 40

10/05/2009 16:36

associated with significant reduction in severity of overall PTSD, as well as in each of the symptom

clusters. Of particular note was improvement in sleep, which is often disrupted in PTSD, and these

problems are frequently exacerbated by treatment with SSRIs. Davis et al. (2004) have

demonstrated superior efficacy for the drug, relative to placebo, in combat veterans.

Anxiolytics

Benzodiazepines are often prescribed to treat acute anxiety in the aftermath of a trauma. However,

findings have been disappointing. An open-label study of alprazolam and clonazepam in 13

outpatients with PTSD found reduced hyperarousal symptoms but no change in intrusion or

avoidance/numbing (Gelpin et al. 1996). In a crossover design, subjects received 5 weeks of

treatment with either alprazolam or placebo followed by 5 weeks of the alternative therapy (Braun

et al. 1990). Minimal improvement was observed in anxiety symptoms overall, with no

improvement in the core symptoms of PTSD. Clonazepam 2 mg was not different from placebo in

controlling nightmares in a 2-week single-blind crossover study, where the test drug was added to

preexisting treatment (Cates et al. 2004). Thus, the evidence does not yet support the use of

benzodiazepines in PTSD, even though they appear to be widely used (Mellman et al. 2003). Their

position in managing PTSD thus remains unclear.

Anticonvulsants

In the 1980s, Lipper et al. (1986) proposed that the pathophysiology of PTSD may involve

sensitization and kindling processes and, to this end, that anticonvulsants might be of therapeutic

benefit. In testing this hypothesis, these investigators found that 7 of 10 (70%) Vietnam War

veterans who received open-label carbamazepine (600–1,000 mg/day) for 5 weeks had “moderate”

or “very much” improvement with treatment, particularly in symptoms of intrusion and

hyperarousal. Three subsequent open-label studies have been performed, including two with

sodium valproate in combat veterans (R. D. Clark et al. 1999; Fesler 1991) and a study of

adjunctive topiramate in a civilian PTSD sample (Berlant and van Kammen 2002). The treatments

showed somewhat different effects, with sodium valproate (250–2,000 mg/day) improving

symptoms of arousal and intrusion in one study (Fesler 1991) and arousal and avoidance in the

other (R. D. Clark et al. 1999), whereas topiramate (15.5–500 mg/day) was most effective in

reducing symptoms of intrusion, particularly nightmares and flashbacks (Berlant and van Kammen

2002). The largest placebo-controlled trial of an anticonvulsant to date found no difference

between tiagabine, dosed up to 16 mg per day, and placebo in 232 patients in a 12-week

multicenter trial (Davidson et al. 2007). In a small placebo-controlled trial of lamotrigine (200–500

mg per day) in 15 outpatients (Hertzberg et al. 1999), a response rate of 50% was noted with

lamotrigine, compared with a placebo response rate of 25%.

Other Treatments

Antipsychotics

One placebo-controlled monotherapy trial of olanzapine has been published (Butterfield et al.

2001), in which 15 subjects were randomized 2:1 to treatment with olanzapine (up to 20 mg/day)

or placebo. No differences were observed between the treatments, although olanzapine was

associated with greater weight gain. It is difficult to interpret these findings in this small sample,

especially given the high placebo response rate (60%). Other reports of antipsychotics are based

on augmentation therapy in SSRI partial responders. Four placebo-controlled studies, mainly as

augmentation, have found superior efficacy for low-dose risperidone (Bartzokis et al. 2005; Hamner

et al. 2003; Monnelly et al. 2003; Reich et al. 2004) and olanzapine (M. B. Stein et al. 2002). In the

Monnelly study, particular benefit was noted for irritability and in the Hamner study, psychotic

symptoms were relieved. These antipsychotic studies in aggregate comprised 155 patients.

Prazosin and Guanfacine

Raskind et al. (2003) reported encouraging results for intractable PTSD-related nightmares in a

placebo-controlled crossover study of prazosin, an 1-adrenergic antagonist, at doses of up to 10Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

21 of 40

10/05/2009 16:36

mg/day. The investigators have confirmed their initial findings in a second and larger

placebo-controlled, double-blind augmentation trial conducted in combat veterans, using doses of

up to 15 mg daily; benefits were most apparent on nightmares and sleep quality, but the drug also

produced greater global improvement (Raskind et al. 2007). One possible mechanism of action may

lie in the ability of prazosin to reduce the output of corticotropin-releasing hormone. Suppression of

nightmare-generating non–rapid eye movement stage 1 sleep may be another explanation for this

intriguing finding. Standing in contrast is a negative placebo-controlled study of the 2-adrenergic

agonist guanfacine in patients who, unlike those in the prazosin studies, were not preselected for

having troublesome nightmares (Neylan et al. 2006).

Other Drugs

Given the prevalence of comorbid depression with PTSD and the effectiveness of triiodothyronine

(T3) augmentation in some individuals with treatment-refractory depression, it is possible that T3

augmentation also may be of benefit in PTSD. Five subjects with PTSD currently taking an SSRI

were treated with open-label T3 (25 g/day) for 8 weeks (Agid et al. 2001). Improvement was

noted as early as 2 weeks, and by the end of treatment, four of the five subjects showed at least

partial improvement in depressive symptoms and hyperarousal. The mechanism for these effects is

unknown, and further controlled studies of this augmentation strategy are therefore needed.

Cyproheptadine, an antihistaminic drug, was no more effective than placebo for nightmares over 2

weeks in a series of 69 combat veterans with PTSD (Jacobs-Rebhun et al. 2000). The naturally

occurring compound inositol was ineffective in a small placebo-controlled trial (Kaplan et al. 1996).

ACUTE STRESS DISORDER AND THE IMMEDIATE AFTERMATH OF TRAUMA

Acute stress disorder (ASD) is characterized by the development of a constellation of symptoms

shortly after a traumatic event and includes symptoms of dissociation and intrusive recollections,

avoidance, and hyperarousal. These symptoms persist for 2–28 days following the trauma and

cause significant distress and/or impairment. If the condition persists beyond 1 month, the

individual usually qualifies for a diagnosis of PTSD. ASD was first included in the diagnostic

nosology in DSM-IV, and little is known about the pharmacotherapy of this disorder. As noted

earlier, it has been suggested that early intervention for trauma survivors might help to alter the

course of PTSD, and this would imply early identification and treatment of those with or at risk for

ASD.

The effects of open-label treatment with risperidone have been reported in four inpatient survivors

of physical trauma with ASD; this drug showed possible benefit in flashback symptoms (Eidelman et

1. 2000). A controlled pilot study assessed the effects of low-dose imipramine compared with

choral hydrate in 25 pediatric burn patients with ASD (Robert et al. 1999a). After 1 week of

treatment, 38% of the subjects responded to treatment with placebo, compared with 83% to

imipramine, with an earlier report noting reduction in intrusion and hyperarousal symptoms

(Robert et al. 1999b). Another study evaluated the effects of -adrenergic blockade in reducing

subsequent PTSD following acute trauma (Pitman et al. 2002). Within 6 hours of the trauma,

subjects were treated with either propranolol (n = 18; 40 mg qid) or placebo (n = 23) for 10 days,

followed by a 9-day taper period. One month after the trauma, PTSD was noted in 30% of the

placebo group compared with 10% of the propranolol group. At 3-month follow-up, physiological

arousal was assessed using personal script-driven imagery of the event, and 43% of the placebo

group were physiological responders compared with 0% of the propranolol group. Although the

dropout rate was higher with propranolol (7 of 18; 39%) than with placebo (3 of 23; 13%), these

findings suggest that acute treatment with -adrenergic-blocking agents may be effective in

preventing the later development of PTSD, but further studies are needed. In one study of

temazepam versus placebo for ASD or subthreshold PTSD, coupled with at least moderate sleep

disturbance, there was no advantage for the drug, either during treatment or at follow-up 6 weeks

posttrauma (Mellman et al. 2002). Two promising studies have found greater long-term benefit for

short-term hydrocortisone versus placebo in high-risk subjects recovering from septic shock and

from cardiac surgery (Schelling et al. 2006). In subpopulations with critical illness–relatedPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

22 of 40

10/05/2009 16:36

corticosteroid insufficiency, this might be an attractive treatment approach for preventing PTSD.

One limitation of the authors’ work, however, has been the absence of baseline PTSD ratings before

administration of hydrocortisone.

CBT has been extensively studied in PTSD and shows efficacy in most cases (Bisson and Andrew

2005). Exposure is regarded as the key therapeutic principle in the numerous variants of CBT.

Modest preservation of gains is found at long-term follow-up (Bradley et al. 2005), but much

pathology remains. For this reason, it is unfortunate that there are almost no trials, either long or

short term, combining CBT with drugs. Shortened forms of CBT appear to be effective for acute

PTSD-like states, with persistence of gain at 4-year follow-up (Bryant et al. 1998, 2003).

CONCLUSION

Twenty years ago, few would have thought that one class of drugs, the SSRIs, which were all

introduced initially for depression, would have established primacy in five of the six major anxiety

disorder categories. Their position is based on solid category 1 randomized, controlled trial

evidence, and they are now first-line drugs for treatment of these disorders. To the extent that

studies have been conducted, SSRIs also offer some protection against relapse. However, they are

not 100% successful, they carry some limiting side effects, and they may require supplementation

with, or substitution by, drugs from other categories. We have reviewed what is known about these

other drugs and expect further progress in the pharmacotherapy of anxiety, with both established

drugs and novel categories (e.g., corticotropin-releasing hormone antagonist). Among many

unexplored areas, we need to know more about the treatment of resistant anxiety disorders and

comorbid anxiety disorder and the comparative efficacy, or contribution, of pharmacotherapy and

psychosocial treatment in anxiety.

The rationale for using drugs rests, in part, on the broad-based evidence that vulnerability to each

of the anxiety disorders includes shared and/or unique genetic risk factors, which usually coexist

with environmental factors in respect of explaining variance. High trait neuroticism is a genetic risk

factor for internalizing disorders as a whole and for comorbidity among the anxiety disorders and

depression (Hettema et al. 2006). A diagnostically nonspecific genetic vulnerability may underlie

fear proneness and amygdalar hyperreactivity (Hariri et al. 2005). Family and twin studies, as well

as other types of studies, support genetic risk factors for generalized anxiety, panic disorder,

phobias, and OCD (Hettema et al. 2001; Westenberg et al. 2007) and social anxiety disorder

(Mathew and Ho 2007), for which some candidate genes are beginning to emerge. For PTSD, the

evidence suggests a role for unique and shared genetic effects (Chantarujikapong et al. 2001; True

et al. 1993), including common genetic liability for PTSD and major depression (Koenen et al.

2008). While detailed consideration of genetics goes beyond the scope of this chapter, it is of

considerable interest to note the findings of M. B. Stein et al. (2006) and Denys et al. (2007), for

example, that drug response in social anxiety disorder and OCD, respectively, may be related to

genetic polymorphisms. These exciting findings may herald a time when we can more effectively

individualize pharmacotherapy for anxiety.

REFERENCES

Agid O, Shalev AY, Lerer B, et al: Triiodothyronine augmentation of selective serotonin reuptake

inhibitors in posttraumatic stress disorder. J Clin Psychiatry 62:169–173, 2001 [PubMed]

Alamy S, Zhang W, Varia I, et al: Escitalopram in specific phobia: results of a placebo-controlled

pilot trial. J Psychopharmacol 22:157–161, 2008 [PubMed]

Allgulander C: Paroxetine in social anxiety disorder: a randomized placebo-controlled study. Acta

Psychiatr Scand 100:193–198, 1999 [PubMed]

Allgulander C, Hackett D, Salinas E: Venlafaxine extended release (ER) in the treatment of

generalised anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Br J

Psychiatry 179:15–22, 2001 [PubMed]

Allgulander C, Dahl AA, Austin C, et al: Efficacy of sertraline in a 12-week trial for generalizedPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

23 of 40

10/05/2009 16:36

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

Allgulander C, Florea I, Huusom AK: Prevention of relapse in generalized anxiety disorder by

escitalopram treatment. Int J Neuropsychopharmacol 9:495–505, 2006 [PubMed]

Allgulander C, Hartford J, Russell J, et al: Pharmacotherapy of generalized anxiety disorder: results

of duloxetine treatment from a pooled analysis of three clinical trials. Curr Med Res Opin

23:1245–1252, 2007 [PubMed]

Alonso J, Angermeyer MC, Bernert S, et al: Sampling and methods of the European Study of the

Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl (420):8–20, 2004

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd

Edition. Washington, DC, American Psychiatric Association, 1980

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd

Edition, Revised. Washington, DC, American Psychiatric Association, 1987

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th

Edition. Washington, DC, American Psychiatric Association, 1994

Andersch S, Rosenberg NK, Kullingsjo H, et al: Efficacy and safety of alprazolam, imipramine and

placebo in treating panic disorder. A Scandinavian multicenter study. Acta Psychiatr Scand Suppl

365:18–27, 1991 [PubMed]

Asakura S, Tajima O, Koyama T: Fluvoxamine treatment of generalized social anxiety disorder in

Japan: a randomized double-blind, placebo-controlled study. Int J Neuropsychopharmacol

10:263–274, 2007 [PubMed]

Asnis GM, Hameedi FA, Goddard AW, et al: Fluvoxamine in the treatment of panic disorder: a

multi-center, double-blind, placebo-controlled study in outpatients. Psychiatry Res 103:1–14, 2001

[PubMed]

Baer L, Rauch SL, Ballantine HT Jr, et al: Cingulotomy for intractable obsessive-compulsive disorder.

Prospective long-term follow-up of 18 patients. Arch Gen Psychiatry 52:384–392, 1995 [PubMed]

Baker DG, Diamond BI, Gillette G, et al: A double-blind, randomized, placebo-controlled,

multi-center study of brofaromine in the treatment of post-traumatic stress disorder.

Psychopharmacology (Berl) 122:386–389, 1995 [PubMed]

Bakish D, Saxena BM, Bowen R, et al: Reversible monoamine oxidase-A inhibitors in panic disorder.

Clin Neuropharmacol 16 (suppl 2):S77–S82, 1993

Baldwin D, Bobes J, Stein DJ, et al: Paroxetine in social phobia/social anxiety disorder.

Randomised, double-blind, placebo-controlled study. Paroxetine Study Group. Br J Psychiatry

175:120–126, 1999 [PubMed]

Baldwin DS, Huusom AK, Maehlum E: Escitalopram and paroxetine in the treatment of generalised

anxiety disorder: randomised, placebo-controlled, double-blind study. Br J Psychiatry 189:264–272,

2006 [PubMed]

Ballenger JC, Davidson JR, Lecrubier Y, et al: Consensus statement on panic disorder from the

International Consensus Group on Depression and Anxiety. J Clin Psychiatry 59 (suppl 8):47–54,

1998a

Ballenger JC, Wheadon DE, Steiner M, et al: Double-blind, fixed-dose, placebo-controlled study of

paroxetine in the treatment of panic disorder. Am J Psychiatry 155:36–42, 1998b

Bandelow B, Hajak G, Holzrichter S, et al: Assessing the efficacy of treatments for panic disorder

and agoraphobia, I: methodological problems. Int Clin Psychopharmacol 10:83–93, 1995 [PubMed]

Barnett SD, Kramer ML, Casat CD, et al: Efficacy of olanzapine in social anxiety disorder: a pilot

study. J Psychopharmacol (Oxf) 16:365–368, 2002 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

24 of 40

10/05/2009 16:36

Bartzokis G, Lu PH, Turner J, et al: Adjunctive risperidone in the treatment of chronic

combat-related posttraumatic stress disorder. Biol Psychiatry 57:474–479, 2005 [PubMed]

Beckham JC, Vrana SR, Barefoot JC, et al: Magnitude and duration of cardiovascular responses to

anger in Vietnam veterans with and without posttraumatic stress disorder. J Consult Clin Psychol

70:228–234, 2002 [PubMed]

Bell J, DeVeaugh-Geiss J: Multicenter trial of a 5-HT antagonist, ondansetron, in social phobia.

Paper presented at the 33rd Annual Meeting of the American College of Neuropsychopharmacology,

San Juan, Puerto Rico, December 12–16, 1994

Bellew KM, McCafferty JP, Iyengar M: Short-term efficacy of paroxetine in generalized anxiety

disorder: a double-blind placebo-controlled trial (NR253). Paper presented at the 153rd Annual

Meeting of the American Psychiatric Association, Chicago, IL, May 13–18, 2000

Benjamin J, Ben-Zion IZ, Karbofsky E, et al: Double-blind placebo-controlled pilot study of

paroxetine for specific phobia. Psychopharmacology 149:194–196, 2000 [PubMed]

Bergink V, Westenberg HG: Metabotropic glutamate II receptor agonists in panic disorder: a double

blind clinical trial with LY354740. Int Clin Psychopharmacol 20:291–293, 2005 [PubMed]

Berigan TR: Panic attacks during escalation of mirtazapine. Primary Care Companion to the Journal

of Clinical Psychiatry 5:93, 2003 [PubMed]

Berlant J, van Kammen DP: Open-label topiramate as primary or adjunctive therapy in chronic

civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry 63:15–20, 2002

[PubMed]

Bertani A, Perna G, Migliarese G, et al: Comparison of the treatment with paroxetine and reboxetine

in panic disorder: a randomized, single-blind study. Pharmacopsychiatry 37:206–210, 2004

[PubMed]

Bielski RJ, Bose A, Chang CC: A double-blind comparison of escitalopram and paroxetine in the

long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry 17:65–69, 2005 [PubMed]

Bisson J, Andrew M: Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane

Database Syst Rev (2):CD003388, 2005

Black DW, Wesner R, Bowers W, et al: A comparison of fluvoxamine, cognitive therapy, and placebo

in the treatment of panic disorder. Arch Gen Psychiatry 50:44–50, 1993 [PubMed]

Blake DD, Weathers FW, Nagy LM, et al: The development of a clinician-administered PTSD scale. J

Trauma Stress 8:75–90, 1995 [PubMed]

Bloch MH, Landeros-Weisenberger A, Kelmendi B, et al: A systematic review: antipsychotic

augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry

11:622–632, 2006 [PubMed]

Blomhoff S, Haug TT, Hellstrom K, et al: Randomised controlled general practice trial of sertraline,

exposure therapy and combined treatment in generalised social phobia. Br J Psychiatry 179:23–30,

2001 [PubMed]

Bonne O, Shemer Y, Gorali Y, et al: A randomized, double-blind, placebo-controlled study of

classical homeopathy in generalized anxiety disorder. J Clin Psychiatry 64:282–287, 2003 [PubMed]

Boshuisen ML, Slaap BR, Vester-Blokland ED, et al: The effect of mirtazapine in panic disorder: an

open label pilot study with a single-blind placebo run-in period. Int Clin Psychopharmacol

16:363–368, 2001 [PubMed]

Boyer W: Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic

attacks: a meta-analysis. Int Clin Psychopharmacol 10:45–49, 1995 [PubMed]

Bradley R, Greene J, Russ E, et al: A multidimensional meta-analysis of psychotherapy for PTSD. AmPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

25 of 40

10/05/2009 16:36

J Psychiatry 162:214–227, 2005 [Full Text] [PubMed]

Bradwejn J, Ahokas A, Stein DJ, et al: Venlafaxine extended-release capsules in panic disorder:

flexible-dose, double-blind, placebo-controlled study. Br J Psychiatry 187:352–359, 2005 [PubMed]

Brady K, Pearlstein T, Asnis GM, et al: Efficacy and safety of sertraline treatment of posttraumatic

stress disorder: a randomized controlled trial. JAMA 283:1837–1844, 2000 [PubMed]

Brady KT, Sonne S, Anton RF, et al: Sertraline in the treatment of co-occurring alcohol dependence

and posttraumatic stress disorder. Alcohol Clin Exp Res 29:395–401, 2005 [PubMed]

Braun P, Greenberg D, Dasberg H, et al: Core symptoms of posttraumatic stress disorder

unimproved by alprazolam treatment. J Clin Psychiatry 51:236–238, 1990 [PubMed]

Brawman-Mintzer O, Knapp RG, Rynn M, et al: Sertraline treatment for generalized anxiety

disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 67:874–881, 2006

[PubMed]

Bruscky SB, Caldeira MV, Bueno JR: Clinical trials of sulpiride. Arq Neuropsiquiatr 32:234–239, 1974

[PubMed]

Bryant RA, Harvey AG, Dang ST, et al: Treatment of acute stress disorder: a comparison of

cognitive-behavioral therapy and supportive counseling. J Consult Clin Psychol 66:862–866, 1998

[PubMed]

Bryant RA, Moulds ML, Nixon RV, et al: Cognitive behaviour therapy of acute stress disorder: a

four-year follow-up. Behav Res Ther 41:489–494, 2003 [PubMed]

Butterfield MI, Becker ME, Connor KM, et al: Olanzapine in the treatment of post-traumatic stress

disorder: a pilot study. Int Clin Psychopharmacol 16:197–203, 2001 [PubMed]

Bystritsky A, Kerwin L, Eiduson S, et al: A pilot controlled trial of bupropion vs. escitalopram in

generalized anxiety disorder (GAD) [abstract]. Neuropsychopharmacology 30 (suppl 1):S101, 2005

Cates ME, Bishop MH, Davis LL, et al: Clonazepam for treatment of sleep disturbances associated

with combat-related posttraumatic stress disorder. Ann Pharmacother 38:1395–1399, 2004

[PubMed]

Chantarujikapong SI, Scherrer JF, Xian H, et al: A twin study of generalized anxiety disorder

symptoms, panic disorder symptoms and post-traumatic stress disorder in men. J Nerv Ment Dis

103:133–145, 2001 [PubMed]

Charney DS, Woods SW, Goodman WK, et al: Drug treatment of panic disorder: the comparative

efficacy of imipramine, alprazolam, and trazodone. J Clin Psychiatry 47:580–586, 1986 [PubMed]

Chen A, Zhao Y, Yu X: The clinical study of antianxiety and antidepressive effect of sulpiride. Chin J

Neurol Psychiatry 27:220–222, 1994

Clark DB, Agras WS: The assessment and treatment of performance anxiety in musicians. Am J

Psychiatry 148:598–605, 1991 [PubMed]

Clark DM, Ehlers A, McManus F, et al: Cognitive therapy versus fluoxetine in generalized social

phobia: a randomized placebo-controlled trial. J Consult Clin Psychol 71:1058–1067, 2003

[PubMed]

Clark RD, Canive JM, Calais LA, et al: Divalproex in posttraumatic stress disorder: an open-label

clinical trial. J Trauma Stress 12:395–401, 1999 [PubMed]

Clomipramine Collaborative Study Group: Clomipramine in the treatment of patients with

obsessive-compulsive disorder. Arch Gen Psychiatry 48:730–738, 1991

Clum GA, Surls R: A meta-analysis of treatments for panic disorder. J Consult Clin Psychol

61:317–326, 1993 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

26 of 40

10/05/2009 16:36

Cohn JB, Bowden CL, Fisher JG, et al: Double-blind comparison of buspirone and clorazepate in

anxious outpatients. Am J Med 80:10–16, 1986 [PubMed]

Compton SN, Grant PJ, Chrisman AK, et al: Sertraline in children and adolescents with social anxiety

disorder: an open trial. J Am Acad Child Adolesc Psychiatry 40:564–571, 2001 [PubMed]

Connor KM, Davidson JRT: SPRINT: a brief global assessment of post-traumatic stress disorder. Int

Clin Psychopharmacol 16:279–284, 2001 [PubMed]

Connor KM, Davidson JRT: A placebo-controlled study of kava kava in generalized anxiety disorder.

Int Clin Psychopharmacol 17:185–188, 2002 [PubMed]

Connor KM, Davidson JR, Potts NL, et al: Discontinuation of clonazepam in the treatment of social

phobia. J Clin Psychopharmacol 18:373–378, 1998 [PubMed]

Connor KM, Sutherland SM, Tupler LA, et al: Fluoxetine in post-traumatic stress disorder.

Randomised, double-blind study. Br J Psychiatry 175:17–22, 1999 [PubMed]

Connor KM, Davidson JRT, Churchill EL, et al: Psychometric properties of the Social Phobia

Inventory (SPIN). A new self-rating scale. Br J Psychiatry 176:379–386, 2000 [PubMed]

Cottraux J, Mollard E, Bouvard M, et al: Exposure therapy, fluvoxamine, or combination treatment in

obsessive-compulsive disorder: one-year follow-up. Psychiatry Res 49:63–75, 1993 [PubMed]

Crockett BA, Davidson JRT, Churchill LE: Treatment of obsessive-compulsive disorder with

clonazepam and sertraline versus placebo and sertraline. Paper presented at the 39th Annual

Meeting of the New Clinical Drug Evaluation Unit, Boca Raton, FL, June 1, 1999

Cross-National Collaborative Panic Study: Drug treatment of panic disorder. Comparative efficacy of

alprazolam, imipramine, and placebo. Br J Psychiatry 160:191–202, 1992

Davidson JRT: The long-term treatment of panic disorder. J Clin Psychiatry 59 (suppl 8):17–21,

1998

Davidson JRT, Moroz G: Pivotal studies of clonazepam in panic disorder. Psychopharmacol Bull

34:169–174, 1998 [PubMed]

Davidson JRT, Kudler H, Smith R, et al: Treatment of posttraumatic stress disorder with

amitriptyline and placebo. Arch Gen Psychiatry 47:259–266, 1990 [PubMed]

Davidson JRT, Hughes DL, George LK, et al: The epidemiology of social phobia: findings from the

Duke Epidemiological Catchment Area Study. Psychol Med 23:709–718, 1993 [PubMed]

Davidson JRT, Tupler LA, Potts NL: Treatment of social phobia with benzodiazepines. J Clin

Psychiatry 55 (suppl):28–32, 1994

Davidson JRT, Book SW, Colket JT, et al: Assessment of a new self-rating scale for post-traumatic

stress disorder. Psychol Med 27:153–160, 1997a

Davidson JRT, Miner CM, DeVeaugh-Geiss J, et al: The Brief Social Phobia Scale: a psychometric

evaluation. Psychol Med 27:161–166, 1997b

Davidson JRT, Weisler RH, Malik M, et al: Fluvoxamine in civilians with posttraumatic stress

disorder. J Clin Psychopharmacol 18:93–95, 1998 [PubMed]

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 JRT, Pearlstein T, Londborg P, et al: Efficacy of sertraline in preventing relapse of

posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study. Am J

Psychiatry 158:1974–1981, 2001 [Full Text] [PubMed]

Davidson JRT, Landerman LR, Farfel GM, et al: Characterizing the effects of sertraline inPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

27 of 40

10/05/2009 16:36

post-traumatic stress disorder. Psychol Med 32:661–670, 2002 [PubMed]

Davidson JRT, Weisler RH, Butterfield MI, et al: Mirtazapine vs. placebo in posttraumatic stress

disorder: a pilot trial. Biol Psychiatry 53:188–191, 2003 [PubMed]

Davidson JRT, 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, 2004a

Davidson JRT, Foa EB, Huppert JD, et al: Fluoxetine, comprehensive cognitive behavioral therapy

(CCBT) and placebo in generalized social phobia. Arch Gen Psychiatry 61:1005–1013, 2004b

Davidson JRT, Yaryura-Tobias J, DuPont R, et al: Fluvoxamine-controlled release formulation for the

treatment of generalized social anxiety disorder. J Clin Psychopharmacol 24:118–225, 2004c

Davidson JRT, Connor KM, Hertzberg MA, et al: Maintenance therapy with fluoxetine in

posttraumatic stress disorder: a placebo-controlled discontinuation study. J Clin Psychopharmacol

25:166–169, 2005 [PubMed]

Davidson JRT, Baldwin D, Stein DJ, et al: Treatment of posttraumatic stress disorder with

venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry

63:1158–1165, 2006a

Davidson JRT, Rothbaum BO, Tucker P, et al: Venlafaxine extended release in posttraumatic stress

disorder: a sertraline- and placebo-controlled study. J Clin Psychopharmacol 26:259–267, 2006b

Davidson JRT, Brady K, Mellman TA, et al: The efficacy and tolerability of tiagabine in adult patients

with post-traumatic stress disorder. J Clin Psychopharmacol 27:85–88, 2007 [PubMed]

Davis LL, Jewell ME, Ambrose S, et al: A placebo-controlled study of nefazodone for the treatment

of chronic posttraumatic stress disorder: a preliminary study. J Clin Psychopharmacol 24:291–297,

2004 [PubMed]

Den Boer JA, Westenberg HG: Effect of a serotonin and noradrenaline uptake inhibitor in panic

disorder; a double-blind comparative study with fluvoxamine and maprotiline. Int Clin

Psychopharmacol 3:59–74, 1988

Denys D, van Nieuwerburgh F, Deforce D, et al: Prediction of response to paroxetine and

venlafaxine by serotonin-related genes in obsessive-compulsive disorder in a randomized,

double-blind trial. J Clin Psychiatry 68:747–753, 2007 [PubMed]

Eddy K, Dutra L, Bradley R, et al: A multidimensional meta-analysis of psychotherapy and

pharmacotherapy for obsessive-compulsive disorder. Clin Psychol Rev 24:1–30, 2004

Eidelman I, Seedat S, Stein DJ: Risperidone in the treatment of acute stress disorder in physically

traumatized in-patients. Depress Anxiety 11:187–188, 2000 [PubMed]

Emmanuel NP, Lydiard RB, Ballenger JC: Treatment of social phobia with bupropion. J Clin

Psychopharmacol 11:276–277, 1991 [PubMed]

Enkelmann R: Alprazolam versus buspirone in the treatment of outpatients with generalized anxiety

disorder. Psychopharmacology (Berl) 105:428–432, 1991 [PubMed]

Fahlen T, Nilsson HL, Borg K, et al: Social phobia: the clinical efficacy and tolerability of the

monoamine oxidase-A and serotonin uptake inhibitor brofaromine. A double-blind

placebo-controlled study. Acta Psychiatr Scand 92:351–358, 1995 [PubMed]

Fahy TJ, O’Rourke D, Brophy J, et al: The Galway Study of Panic Disorder, I: clomipramine and

lofepramine in DSM-III-R panic disorder. A placebo controlled trial. J Affect Disord 25:63–75, 1992

[PubMed]

Fallon BA, Campeas R, Schneier FR, et al: Open trial of intravenous clomipramine in five

treatment-refractory patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci

4:70–75, 1992 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

28 of 40

10/05/2009 16:36

Fedoroff I, Taylor S: Psychological and pharmacological treatments of social phobia: a

meta-analysis. J Clin Psychopharmacol 21:311–324, 2001 [PubMed]

Feltner DE, Crockatt JG, Dubovsky SJ, et al: A randomized, double-blind, placebo-controlled,

fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin

Psychopharmacol 23:240–249, 2003 [PubMed]

Ferguson JM, Khan A, Mangano R, et al: Relapse prevention of panic disorder in adult outpatient

responders to treatment with venlafaxine extended release. J Clin Psychiatry 68:58–68, 2007

[PubMed]

Fernandez-Cordoba E, Lopez-Ibor JA: La monoclorimipramina en enfermos psiquitricos resistentes a

otrostratiamentos. Actas Luso-Espanolas de Neurologia, y Psiquiatria Ciencias Afines 26:119–147,

1967 [PubMed]

Ferreri M, Hantouche EG: Recent clinical trials of hydroxyzine in generalized anxiety disorder. Acta

Psychiatr Scand Suppl 393:102–108, 1998 [PubMed]

Fesler FA: Valproate in combat-related posttraumatic stress disorder. J Clin Psychiatry 52:361–364,

1991 [PubMed]

Fineberg NA, Sivakumaran T, Roberts A, et al: Adding quetiapine to SRI in treatment-resistant

obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol

20:223–226, 2005 [PubMed]

Fineberg NA, Tonnoir B, Lemming O, et al: Escitalopram prevents relapse of obsessive-compulsive

disorder. Eur Neuropsychopharmacol 17:430–439, 2007 [PubMed]

Flament MF, Rapoport JL, Berg CJ, et al: Clomipramine treatment of childhood obsessive-compulsive

disorder. A double-blind controlled study. Arch Gen Psychiatry 42:977–983, 1985 [PubMed]

Foa EB, Liebowitz MR, Kozak MJ, et al: Randomized, placebo-controlled trial of exposure and ritual

prevention, clomipramine, and their combination in the treatment of obsessive-compulsive

disorder. Am J Psychiatry 162:151–161, 2005 [Full Text] [PubMed]

Fontaine R, Beaudry P, Beauclair L, et al: Comparison of withdrawal of buspirone and diazepam: a

placebo controlled study. Prog Neuropsychopharmacol Biol Psychiatry 11:189–197, 1987 [PubMed]

Friedman MJ, Marmar CR, Baker DG, et al: Randomized double-blind comparison of sertraline and

placebo for posttraumatic stress disorder in a Department of Veterans Affairs setting. J Clin

Psychiatry 68:711–720, 2007 [PubMed]

Fux M, Levine J, Aviv A, et al: Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry

153:1219–1221, 1996 [Full Text] [PubMed]

Gelenberg AJ, Lydiard RB, Rudolph RL, et al: Efficacy of venlafaxine extended-release capsules in

nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial.

JAMA 283:3082–3088, 2000 [PubMed]

Gelernter CS, Uhde TW, Cimbolic P, et al: Cognitive-behavioral and pharmacological treatments of

social phobia. A controlled study. Arch Gen Psychiatry 48:938–945, 1991 [PubMed]

Gelpin E, Bonne O, Peri T, et al: Treatment of recent trauma survivors with benzodiazepines: a

prospective study. J Clin Psychiatry 57:390–394, 1996 [PubMed]

Goddard AW, Brouette T, Almai A, et al: Early coadministration of clonazepam with sertraline for

panic disorder. Arch Gen Psychiatry 58:681–686, 2001 [PubMed]

Goisman RM, Allsworth J, Rogers MP, et al: Simple phobia as a comorbid anxiety disorder. Depress

Anxiety 7:105–112, 1998 [PubMed]

Goldberg DP, Lecrubier Y: Form and frequency of mental disorders across centers, in Mental Illness

in General Health Care: An International Study. Edited by Üstürn TB, Sartorius N. New York, Wiley,Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

29 of 40

10/05/2009 16:36

1995, pp 323–334

Goodman WK, Price LH, Rasmussen SA, et al: The Yale-Brown Obsessive Compulsive Scale, II:

validity. Arch Gen Psychiatry 46:1012–1016, 1989 [PubMed]

Goodman WK, Bose A, Wang Q: Treatment of generalized anxiety disorder with escitalopram:

pooled results from double-blind, placebo-controlled trials. J Affect Disord 87:161–167, 2005

[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]

Greenberg BD, Malone DA, Friehs GM, et al: Three-year outcomes in deep brain stimulation for

highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 31:2384–2393, 2006

[PubMed]

Greenberg PE, Sisitsky T, Kessler RC, et al: The economic burden of anxiety disorders in the 1990s.

J Clin Psychiatry 60:427–435, 1999 [PubMed]

Greenblatt DJ, Shader RI, Abernethy DR: Drug therapy. Current status of benzodiazepines. N Engl J

Med 309:410–416, 1983 [PubMed]

Greist JH, Jefferson JW: Pharmacotherapy for obsessive-compulsive disorder. Br J Psychiatry Suppl

(35):64–70, 1998

Greist JH, Chouinard G, DuBoff E, et al: Double-blind parallel comparison of three dosages of

sertraline and placebo in outpatients with obsessive-compulsive disorder. Arch Gen Psychiatry

52:289–295, 1995a

Greist JH, Jefferson JW, Kobak KA, et al: Efficacy and tolerability of serotonin transport inhibitors in

obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 52:53–60, 1995b

Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 32:50–55, 1959

[PubMed]

Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62, 1960 [PubMed]

Hamner MB, Faldowski RA, Ulmer HG, et al: Adjunctive risperidone treatment in post-traumatic

stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms. Int Clin

Psychopharmacol 18:1–8, 2003 [PubMed]

Hariri AR, Drabant EM, Munoz KE, et al: A susceptibility gene for affective disorders and the

response of the human amygdala. Arch Gen Psychiatry 62:145–152, 2005

Haug TT, Hellstrom K, Blomhoff S, et al: The treatment of social phobia in general practice: is

exposure therapy feasible? Fam Pract 17:114–118, 2000 [PubMed]

Haug TT, Blomoff S, Hellstrom K, et al: Exposure therapy and sertraline in social phobia: 1-year

follow-up of a randomized controlled trial. Br J Psychiatry 182:312–318, 2003 [PubMed]

Heimberg RG, Liebowitz MR, Hope DA, et al: Cognitive behavioral group therapy vs phenelzine

therapy for social phobia: 12-week outcome. Arch Gen Psychiatry 55:1133–1141, 1998 [PubMed]

Hertzberg MA, Butterfield MI, Feldman ME, et al: A preliminary study of lamotrigine for the

treatment of posttraumatic stress disorder. Biol Psychiatry 45:1226–1229, 1999 [PubMed]

Hettema JM, Neale MC, Kendler KS: A review and meta-analysis of the genetic epidemiology of

anxiety disorders. Am J Psychiatry 158:1568–1578, 2001 [Full Text] [PubMed]

Hettema JM, Neale MC, Myers JM, et al: A population-based twin study of the relationship between

neuroticism and internalizing disorders. Am J Psychiatry 163:857–864, 2006 [Full Text] [PubMed]

Hidalgo R, Hertzberg MA, Mellman T, et al: Nefazodone in post-traumatic stress disorder: results

from six open-label trials. Int Clin Psychopharmacol 14:61–68, 1999 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

30 of 40

10/05/2009 16:36

Hidalgo RB, Tupler LA, Davidson JRT: An effect-size analysis of pharmacological treatments for

generalized anxiety disorder. J Psychopharmacol 21:864–872, 2007 [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]

Hofmann SG: Cognitive mediation of change in social phobia. J Consult Clin Psychol 72:393–399,

2004 [PubMed]

Hofmann SG, Meuret AE, Smits JA, et al: Augmentation of exposure therapy with D-cycloserine for

social anxiety disorder. Arch Gen Psychiatry 63:298–304, 2006 [PubMed]

Hollander E, Stein DJ, Kwon JH, et al: Psychosocial and economic costs of obsessive-compulsive

disorder. CNS Spectr 2:16–25, 1997

Hollifield M, Thompson PM, Ruiz JE, et al: Potential effectiveness and safety of olanzapine in

refractory panic disorder. Depress Anxiety 21:33–40, 2005 [PubMed]

Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom

Med 41:209–218, 1979 [PubMed]

International Multicenter Clinical Trial Group on Moclobemide in Social Phobia: Moclobemide in

social phobia. A double-blind, placebo-controlled clinical study. Eur Arch Psychiatry Clin Neurosci

247:71–80, 1997

Jacobs RJ, Davidson JR, Gupta S, et al: The effects of clonazepam on quality of life and work

productivity in panic disorder. Am J Manag Care 3:1187–1196, 1997 [PubMed]

Jacobs-Rebhun S, Schnurr PP, Friedman MJ, et al: Posttraumatic stress disorder and sleep difficulty.

Am J Psychiatry 157:1525–1526, 2000 [Full Text] [PubMed]

Jenike MA, Baer L, Ballantine T, et al: Cingulotomy for refractory obsessive-compulsive disorder. A

long-term follow-up of 33 patients. Arch Gen Psychiatry 48:548–555, 1991 [PubMed]

Jobson KO, Davidson JR, Lydiard RB, et al: Algorithm for the treatment of panic disorder with

agoraphobia. Psychopharmacol Bull 31:483–485, 1995 [PubMed]

Johnstone EC, Owens DG, Frith CD, et al: Neurotic illness and its response to anxiolytic and

antidepressant treatment. Psychol Med 10:321–328, 1980 [PubMed]

Kaplan Z, Amir M, Swartz M, et al: Inositol treatment of post-traumatic stress disorder. Anxiety

2:51–52, 1996 [PubMed]

Kasper S, Stein DJ, Loft H, et al: Escitalopram in the treatment of social anxiety disorder:

randomised, placebo-controlled, flexible-dosage study. Br J Psychiatry 186:222–226, 2005

[PubMed]

Katschnig H, Amering M, Stolk JM, et al: Long-term follow-up after a drug trial for panic disorder. Br

J Psychiatry 167:487–494, 1995 [PubMed]

Katz RJ, Lott MH, Arbus P, et al: Pharmacotherapy of post-traumatic stress disorder with a novel

psychotropic. Anxiety 1:169–174, 1994 [PubMed]

Katzelnick DJ, Kobak KA, Greist JH, et al: Sertraline for social phobia: a double-blind,

placebo-controlled crossover study. Am J Psychiatry 152:1368–1371, 1995 [Full Text] [PubMed]

Keck PE Jr, McElroy SL, Tugrul KC, et al: Antiepileptic drugs for the treatment of panic disorder.

Neuropsychobiology 27:150–153, 1993 [PubMed]

Kessler RC, Sonnega A, Bromet E, et al: Posttraumatic stress disorder in the National Comorbidity

Survey. Arch Gen Psychiatry 52:1048–1060, 1995 [PubMed]

Kessler RC, Berglund P, Demler O, et al: Lifetime prevalence and age-of-onset distributions ofPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

31 of 40

10/05/2009 16:36

DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593–602,

2005a

Kessler RC, Chiu WT, Demler O, et al: Prevalence, severity, and comorbidity of 12-month DSM-IV

disorders in the National Comorbidity Survey Replication.[see comment]. Arch Gen Psychiatry

62:617–627, 2005b

Klesmer J, Sarcevic A, Fomari V: Panic attacks during discontinuation of mirtazapine. Can J

Psychiatry 45:570–571, 2000 [PubMed]

Kobak KA, Greist JH, Jefferson JW, et al: Fluoxetine in social phobia: a double-blind,

placebo-controlled pilot study. J Clin Psychopharmacol 22:257–262, 2002 [PubMed]

Kobak KA, Taylor LV, Bystritsky A, et al: St. John’s wort versus placebo in obsessive-compulsive

disorder: results from a double-blind study. Int Clin Psychopharmacol 20:299–304, 2005 [PubMed]

Koenen KC, Fu QJ, Ertel K, et al: Common genetic liability to major depression and posttraumatic

stress disorder in men. J Affect Disord 105:109–115, 2008 [PubMed]

Koran LM, McElroy SL, Davidson JR, et al: Fluvoxamine versus clomipramine for

obsessive-compulsive disorder: a double-blind comparison. J Clin Psychopharmacol 16:121–129,

1996 [PubMed]

Koran LM, Sallee FR, Pallanti S: Rapid benefit of intravenous pulse loading of clomipramine in

obsessive-compulsive disorder. Am J Psychiatry 154:396–401, 1997 [Full Text] [PubMed]

Kosten TR, Frank JB, Dan E, et al: Pharmacotherapy for posttraumatic stress disorder using

phenelzine or imipramine. J Nerv Ment Dis 179:366–370, 1991 [PubMed]

Kruger MB, Dahl AA: The efficacy and safety of moclobemide compared to clomipramine in the

treatment of panic disorder. Eur Arch Psychiatry Clin Neurosci 249 (suppl 1):S19–S24, 1999

Lader M, Scotto JC: A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in

patients with generalized anxiety disorder. Psychopharmacology (Berl) 139:402–406, 1998

[PubMed]

Lader M, Stender K, Burger V, et al: Efficacy and tolerability of escitalopram in 12- and 24-week

treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixed-dose

study. Depress Anxiety 19:241–248, 2004 [PubMed]

Lecrubier Y, Judge R: Long-term evaluation of paroxetine, clomipramine and placebo in panic

disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand 95:153–160,

1997 [PubMed]

Lecrubier Y, Bakker A, Dunbar G, et al: A comparison of paroxetine, clomipramine and placebo in

the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr

Scand 95:145–152, 1997 [PubMed]

Leonard H, Swedo S, Rapoport JL, et al: Treatment of childhood obsessive compulsive disorder with

clomipramine and desmethylimipramine: a double-blind crossover comparison. Psychopharmacol

Bull 24:93–95, 1988 [PubMed]

Lepola UM, Wade AG, Leinonen EV, et al: A controlled, prospective, 1-year trial of citalopram in the

treatment of panic disorder. J Clin Psychiatry 59:528–534, 1998 [PubMed]

Lesser IM, Lydiard RB, Antal E, et al: Alprazolam plasma concentrations and treatment response in

panic disorder and agoraphobia. Am J Psychiatry 149:1556–1562, 1992 [PubMed]

Liebowitz MR: Social phobia. Mod Probl Pharmacopsychiatry 22:141–173, 1987 [PubMed]

Liebowitz MR, Schneier F, Campeas R, et al: Phenelzine vs atenolol in social phobia. A

placebo-controlled comparison. Arch Gen Psychiatry 49:290–300, 1992 [PubMed]

Liebowitz MR, Turner SM, Piacentini J, et al: Fluoxetine in children and adolescents with OCD: aPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

32 of 40

10/05/2009 16:36

placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 41:1431–1438, 2002 [PubMed]

Liebowitz MR, DeMartinis NA, Weihs K, et al: Efficacy of sertraline in severe generalized social

anxiety disorder: results of a double-blind, placebo-controlled study. J Clin Psychiatry 64:785–792,

2003 [PubMed]

Liebowitz MR, Mangano RM, Bradwejn J, et al: A randomized controlled trial of venlafaxine

extended release in generalized social anxiety disorder. J Clin Psychiatry 66:238–247, 2005

[PubMed]

Lipper S, Davidson JR, Grady TA, et al: Preliminary study of carbamazepine in post-traumatic stress

disorder. Psychosomatics 27:849–854, 1986 [PubMed]

Lipsitz JD, Mannuzza S, Klein DF, et al: Specific phobia 10–16 years after treatment. Depress

Anxiety 10:105–111, 1999 [PubMed]

Llorca PM, Spadone C, Sol O, et al: Efficacy and safety of hydroxyzine in the treatment of

generalized anxiety disorder: a 3-month double-blind study [see comment]. J Clin Psychiatry

63:1020–1027, 2002 [PubMed]

Loerch B, Graf-Morgenstern M, Hautzinger M, et al: Randomised placebo-controlled trial of

moclobemide, cognitive-behavioural therapy and their combination in panic disorder with

agoraphobia. Br J Psychiatry 174:205–212, 1999 [PubMed]

Londborg PD, Wolkow R, Smith WT, et al: Sertraline in the treatment of panic disorder. A multi-site,

double-blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 173:54–60, 1998

[PubMed]

Londborg PD, Hegel MT, Goldstein S, et al: Sertraline treatment of posttraumatic stress disorder:

results of 24 weeks of open-label continuation treatment. J Clin Psychiatry 62:325–331, 2001

[PubMed]

Lott M, Greist JH, Jefferson JW, et al: Brofaromine for social phobia: a multicenter,

placebo-controlled, double-blind study. J Clin Psychopharmacol 17:255–260, 1997 [PubMed]

Lydiard RB, Ballenger JC: Antidepressants in panic disorder and agoraphobia. J Affect Disord

13:153–168, 1987 [PubMed]

Lydiard RB, Laraia MT, Ballenger JC, et al: Emergence of depressive symptoms in patients receiving

alprazolam for panic disorder. Am J Psychiatry 144:664–665, 1987 [PubMed]

Lydiard RB, Lesser IM, Ballenger JC, et al: A fixed-dose study of alprazolam 2 mg, alprazolam 6 mg,

and placebo in panic disorder. J Clin Psychopharmacol 12:96–103, 1992 [PubMed]

Lydiard RB, Morton WA, Emmanuel NP, et al: Preliminary report: placebo-controlled, double-blind

study of the clinical and metabolic effects of desipramine in panic disorder. Psychopharmacol Bull

29:183–188, 1993 [PubMed]

Lydiard RB, Steiner M, Burnham D, et al: Efficacy studies of paroxetine in panic disorder.

Psychopharmacol Bull 34:175–182, 1998 [PubMed]

Magee WJ, Eaton WW, Wittchen HU, et al: Agoraphobia, simple phobia, and social phobia in the

National Comorbidity Survey. Arch Gen Psychiatry 53:159–168, 1996 [PubMed]

March JS, Biederman J, Wolkow R, et al: Sertraline in children and adolescents with

obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA 280:1752–1756,

1998 [PubMed]

March JS, Entsuah AR, Rynn M, et al: A randomized controlled trial of venlafaxine ER versus placebo

in pediatric social anxiety disorder. Biol Psychiatry 62:1149–1154, 2007 [PubMed]

Marks IM, Mathews AM: Brief standard self-rating for phobic patients. Behav Res Ther 17:263–267,

1979 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

33 of 40

10/05/2009 16:36

Marmar CR, Schoenfeld F, Weiss DS, et al: Open trial of fluvoxamine treatment for combat-related

posttraumatic stress disorder. J Clin Psychiatry 57 (suppl 8):66–70, 1996

Marshall RD, Beebe KL, Oldham M, et al: Efficacy and safety of paroxetine treatment for chronic

PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 158:1982–1988, 2001 [Full Text]

[PubMed]

Martenyi F, Brown EB, Zhang H, et al: Fluoxetine versus placebo in posttraumatic stress disorder. J

Clin Psychiatry 63:199–206, 2002a

Martenyi F, Brown EB, Zhang H, et al: Fluoxetine vs placebo in prevention of relapse in

post-traumatic stress disorder. Br J Psychiatry 181:315–320, 2002b

Mathew SJ, Ho S: Etiology and neurobiology of social anxiety disorder. J Clin Psychiatry 67 (suppl

12):9–13, 2007

Mathew SJ, Amiel JM, Coplan JD, et al: Open-label trial of riluzole in generalized anxiety disorder.

Am J Psychiatry 162:2379–2381, 2005 [Full Text] [PubMed]

Mavissakalian MR, Perel JM: Imipramine dose-response relationship in panic disorder with

agoraphobia. Preliminary findings. Arch Gen Psychiatry 46:127–131, 1989 [PubMed]

Mavissakalian M, Perel JM: Protective effects of imipramine maintenance treatment in panic

disorder with agoraphobia. Am J Psychiatry 149:1053–1057, 1992 [PubMed]

Mavissakalian MR, Perel JM: Imipramine treatment of panic disorder with agoraphobia: dose

ranging and plasma level-response relationships. Am J Psychiatry 152:673–682, 1995 [Full Text]

[PubMed]

Mavissakalian MR, Perel JM: Duration of imipramine therapy and relapse in panic disorder with

agoraphobia. J Clin Psychopharmacol 22:294–299, 2002 [PubMed]

Mavissakalian MR, Jones B, Olson S: Absence of placebo response in obsessive-compulsive disorder.

J Nerv Ment Dis 178:268–270, 1990 [PubMed]

Mellman TA, Bustamante V, David D, et al: Hypnotic medication in the aftermath of trauma. J Clin

Psychiatry 63:1183–1184, 2002 [PubMed]

Mellman TA, Clark RE, Peacock WJ: Prescribing patterns for patients with posttraumatic stress

disorder. Psychiatr Serv 54:1618–1621, 2003 [Full Text] [PubMed]

Meoni P, Hackett D: Characterization of the longitudinal course of long-term venlafaxine-ER

treatment of GAD. Paper presented at the 13th Annual Meeting of the European College of

Neuropsychopharmacology, Munich, Germany, September 11, 2000

Michelson D, Lydiard RB, Pollack MH, et al: Outcome assessment and clinical improvement in panic

disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine

Panic Disorder Study Group. Am J Psychiatry 155:1570–1577, 1998 [Full Text] [PubMed]

Michelson D, Pollack M, Lydiard RB, et al: Continuing treatment of panic disorder after acute

response: randomised, placebo-controlled trial with fluoxetine. The Fluoxetine Panic Disorder Study

Group. Br J Psychiatry 174:213–218, 1999 [PubMed]

Michelson D, Allgulander C, Dantendorfer K, et al: Efficacy of usual antidepressant dosing regimens

of fluoxetine in panic disorder: randomised, placebo-controlled trial. Br J Psychiatry 179:514–518,

2001 [PubMed]

Modigh K, Westberg P, Eriksson E: Superiority of clomipramine over imipramine in the treatment of

panic disorder: a placebo-controlled trial. J Clin Psychopharmacol 12:251–261, 1992 [PubMed]

Monnelly EP, Ciraulo DA, Knapp C, et al: Low-dose risperidone as adjunctive therapy for irritable

aggression in posttraumatic stress disorder. J Clin Psychopharmacol 23:193–196, 2003 [PubMed]

Montgomery SA, Nil R, Durr-Pal N, et al: A 24-week randomized, double-blind, placebo-controlledPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

34 of 40

10/05/2009 16:36

study of escitalopram for the prevention of generalized social anxiety disorder. J Clin Psychiatry

66:1270–1278, 2005 [PubMed]

Moras K, Borkovec TD, DiNardo PA, et al: Generalized anxiety disorder, in DSM-IV Sourcebook.

Edited by Widiger TA, Frances AJ, Pincus HA, et al. Washington, DC, American Psychiatric

Association, 1996, pp 607–621

Muehlbacher M, Nickel MK, Nickel C, et al: Mirtazapine treatment of social phobia in women: a

randomized, double-blind, placebo controlled trial. J Clin Psychopharmacol 25:580–583, 2005

[PubMed]

Murray CJL, Lopez AD: The Global Burden of Disease. Cambridge, MA, Harvard School of Public

Health, 1996

Myers JK, Weissman MM, Tischler GL, et al: Six-month prevalence of psychiatric disorders in three

communities 1980 to 1982. Arch Gen Psychiatry 41:959–967, 1984 [PubMed]

Neal LA, Shapland W, Fox C: An open trial of moclobemide in the treatment of post-traumatic stress

disorder. Int Clin Psychopharmacol 12:231–237, 1997 [PubMed]

Neylan TC, Lenoci M, Samuelson KW, et al: No improvement of posttraumatic stress disorder

symptoms with guanfacine treatment. Am J Psychiatry 163:2186–2188, 2006 [Full Text] [PubMed]

Ninan PT, Koran LM, Kiev A, et al: High-dose sertraline strategy for nonresponders to acute

treatment for obsessive-compulsive disorder: a multicenter double-blind trial. J Clin Psychiatry

67:15–22, 2006 [PubMed]

Noyes R Jr, Moroz G, Davidson JR, et al: Moclobemide in social phobia: a controlled dose-response

trial. J Clin Psychopharmacol 17:247–254, 1997 [PubMed]

Nuttin B, Cosyns P, Demeulemeester H, et al: Electrical stimulation in anterior limbs of internal

capsules in patients with obsessive-compulsive disorder. Lancet 354:1526, 1999 [PubMed]

Oehrberg S, Christiansen PE, Behnke K, et al: Paroxetine in the treatment of panic disorder. A

randomised, double-blind, placebo-controlled study. Br J Psychiatry 167:374–379, 1995 [PubMed]

Olajide D, Lader M: A comparison of buspirone, diazepam, and placebo in patients with chronic

anxiety states. J Clin Psychopharmacol 7:148–152, 1987 [PubMed]

Otto MW, Pollack MH, Sachs GS, et al: Discontinuation of benzodiazepine treatment: efficacy of

cognitive-behavioral therapy for patients with panic disorder. Am J Psychiatry 150:1485–1490,

1993 [Full Text] [PubMed]

Otto MW, Tuby KS, Gould RA, et al: An effect-size analysis of the relative efficacy and tolerability of

serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry 158:1989–1992, 2001

[Full Text] [PubMed]

Pages KP, Ries RK: Use of anticonvulsants in benzodiazepine withdrawal. Am J Addict 7:198–204,

1998 [PubMed]

Pande AC, Davidson JR, Jefferson JW, et al: Treatment of social phobia with gabapentin: a

placebo-controlled study. J Clin Psychopharmacol 19:341–348, 1999a

Pande AC, Greiner M, Adams JB, et al: Placebo-controlled trial of the CCK-B antagonist, CI-988, in

panic disorder. Biol Psychiatry 46:860–862, 1999b

Pande AC, Pollack MH, Crockatt J, et al: Placebo-controlled study of gabapentin treatment of panic

disorder. J Clin Psychopharmacol 20:467–471, 2000 [PubMed]

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]

Papp LA: Safety and efficacy of levetiracetam for patients with panic disorder: results of an

open-label, fixed-flexible dose study. J Clin Psychiatry 67:1573–1576, 2006 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

35 of 40

10/05/2009 16:36

Pato MT, Hill JL, Murphy DL: A clomipramine dosage reduction study in the course of long-term

treatment of obsessive-compulsive disorder patients. Psychopharmacol Bull 26:211–214, 1990

[PubMed]

Pecknold J, Luthe L, Munjack D, et al: A double-blind, placebo-controlled, multicenter study with

alprazolam and extended-release alprazolam in the treatment of panic disorder. J Clin

Psychopharmacol 14:314–321, 1994 [PubMed]

Petracca A, Nisita C, McNair D, et al: Treatment of generalized anxiety disorder: preliminary clinical

experience with buspirone. J Clin Psychiatry 51 (suppl):31–39, 1990

Pigott T, L’Hereux F, Rubinstein CS: A controlled trial of clonazepam augmentation in OCD patients

with clomipramine or fluoxetine (NR82). Paper presented at the 145th Annual Meeting of the

American Psychiatric Association, May 2–7, 1992

Pitman RK, Sanders KM, Zusman RM, et al: Pilot study of secondary prevention of posttraumatic

stress disorder with propranolol. Biol Psychiatry 51:189–192, 2002 [PubMed]

Pohl RB, Feltner DE, Fieve RR, et al: Efficacy of pregabalin in the treatment of generalized anxiety

disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin

Psychopharmacol 25:151–158, 2005 [PubMed]

Pollack MH, Zaninelli R, Goddard A, et al: Paroxetine in the treatment of generalized anxiety

disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 62:350–357, 2001

[PubMed]

Pollack MH, Simon NM, Worthington JJ, et al: Combined paroxetine and clonazepam treatment

strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol (Oxf)

17:276–282, 2003 [PubMed]

Pollack MH, Roy-Byrne PP, Van Ameringen M, et al: The selective GABA reuptake inhibitor tiagabine

for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Clin

Psychiatry 66:1401–1408, 2005 [PubMed]

Rapaport MH, Wolkow R, Rubin A, et al: Sertraline treatment of panic disorder: results of a

long-term study. Acta Psychiatr Scand 104:289–298, 2001 [PubMed]

Rapaport MH, Endicott J, Clary CM: Posttraumatic stress disorder and quality of life: results across

64 weeks of sertraline treatment. J Clin Psychiatry 63:59–65, 2002 [PubMed]

Raskind MA, Peskind ER, Kanter ED, et al: Reduction of nightmares and other PTSD symptoms in

combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry 160:371–373, 2003 [Full

Text] [PubMed]

Raskind MA, Peskind ER, Hoff DJ, et al: A parallel group placebo controlled study of prazosin for

trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder.

Biol Psychiatry 61:928–934, 2007 [PubMed]

Ravizza L, Barzega G, Bellino S, et al: Drug treatment of obsessive-compulsive disorder (OCD):

long-term trial with clomipramine and selective serotonin reuptake inhibitors (SSRIs).

Psychopharmacol Bull 32:167–173, 1996 [PubMed]

Reich DB, Winternitz S, Hennen J, et al: A preliminary study of risperidone in the treatment of

posttraumatic stress disorder related to childhood abuse in women. J Clin Psychiatry

65:1601–1606, 2004 [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

Ressler KJ, Rothbaum BO, Tannenbaum L, et al: Cognitive enhancers as adjuncts to psychotherapy:

use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry

61:1136–1144, 2004 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

36 of 40

10/05/2009 16:36

Ribeiro L, Busnello JV, Kauer-Sant’Anna M, et al: Mirtazapine versus fluoxetine in the treatment of

panic disorder. Braz J Med Biol Res 34:1303–1307, 2001 [PubMed]

Rickels K, Weisman K, Norstad N, et al: Buspirone and diazepam in anxiety: a controlled study. J

Clin Psychiatry 43:81–86, 1982 [PubMed]

Rickels K, Case WG, Downing RW, et al: Long-term diazepam therapy and clinical outcome. JAMA

250:767–771, 1983 [PubMed]

Rickels K, Fox IL, Greenblatt DJ, et al: Clorazepate and lorazepam: clinical improvement and

rebound anxiety. Am J Psychiatry 145:312–317, 1988a

Rickels K, Schweizer E, Csanalosi I, et al: Long-term treatment of anxiety and risk of withdrawal.

Prospective comparison of clorazepate and buspirone. Arch Gen Psychiatry 45:444–450, 1988b

Rickels K, Amsterdam JD, Clary C, et al: Buspirone in major depression: a controlled study. J Clin

Psychiatry 52:34–38, 1991 [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]

Rickels K, DeMartinis N, Garcia-Espana F, et al: Imipramine and buspirone in treatment of patients

with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Am J

Psychiatry 157:1973–1979, 2000a

Rickels K, Pollack MH, Sheehan DV, et al: Efficacy of extended-release venlafaxine in nondepressed

outpatients with generalized anxiety disorder. Am J Psychiatry 157:968–974, 2000b

Rickels K, Zaninelli R, McCafferty J, et al: Paroxetine treatment of generalized anxiety disorder: a

double-blind, placebo-controlled study. Am J Psychiatry 160:749–756, 2003 [Full Text] [PubMed]

Rickels K, Pollack MH, Feltner DE, et al: Pregabalin for treatment of generalized anxiety disorder: a

4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen

Psychiatry 62:1022–1030, 2005 [PubMed]

Riddle MA, Reeve EA, Yaryura-Tobias JA, et al: Fluvoxamine for children and adolescents with

obsessive-compulsive disorder: a randomized, controlled, multicenter trial. J Am Acad Child Adolesc

Psychiatry 40:222–229, 2001 [PubMed]

Robert R, Blakeney PE, Villarreal C, et al: Imipramine treatment in pediatric burn patients with

symptoms of acute stress disorder: a pilot study. J Am Acad Child Adolesc Psychiatry 38:873–882,

1999a

Robert R, Meyer WJ 3rd, Villarreal C, et al: An approach to the timely treatment of acute stress

disorder. J Burn Care Rehabil 20:250–258, 1999b

Robins LN, Helzer JE, Weissman MM, et al: Lifetime prevalence of specific psychiatric disorders in

three sites. Arch Gen Psychiatry 41:949–958, 1984 [PubMed]

Rocca P, Fonzo V, Scotta M, et al: Paroxetine efficacy in the treatment of generalized anxiety

disorder. Acta Psychiatr Scand 95:444–450, 1997 [PubMed]

Rosenbaum JF, Woods SW, Groves JE, et al: Emergence of hostility during alprazolam treatment.

Am J Psychiatry 141:792–793, 1984 [PubMed]

Rosenbaum JF, Moroz G, Bowden CL: Clonazepam in the treatment of panic disorder with or without

agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic

Disorder Dose-Response Study Group. J Clin Psychopharmacol 17:390–400, 1997 [PubMed]

Ross CA, Matas M: A clinical trial of buspirone and diazepam in the treatment of generalized anxiety

disorder. Can J Psychiatry 32:351–355, 1987 [PubMed]

Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team forPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

37 of 40

10/05/2009 16:36

Panic Disorder and Agoraphobia: Australian and New Zealand clinical practice guidelines for the

treatment of panic disorder and agoraphobia. Aust N Z J Psychiatry 37:641–656, 2003

Roy-Byrne PP, Stang P, Wittchen HU, et al: Lifetime panic-depression comorbidity in the National

Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J

Psychiatry 176:229–235, 2000 [PubMed]

Roy-Byrne PP, Clary CM, Miceli RJ, et al: The effect of selective serotonin reuptake inhibitor

treatment of panic disorder on emergency room and laboratory resource utilization. J Clin

Psychiatry 62:678–682, 2001 [PubMed]

Rynn M, Russell JM, Erickson J, et al: Efficacy and safety of duloxetine in the treatment of

generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial.

Depress Anxiety 25:182–189, 2008 [PubMed]

Sarchiapone M, Amore M, De Risio S, et al: Mirtazapine in the treatment of panic disorder: an

open-label trial. Int Clin Psychopharmacol 18:35–38, 2003 [PubMed]

Schelling G, Roozendaal B, Krauseneck T, et al: Efficacy of hydrocortisone in preventing

posttraumatic stress disorder following critical illness and major surgery. Ann N Y Acad Sci

1071:46–53, 2006 [PubMed]

Schneier FR, Goetz D, Campeas R, et al: Placebo-controlled trial of moclobemide in social phobia. Br

J Psychiatry 172:70–77, 1998 [PubMed]

Schweizer E, Rickels K: Buspirone in the treatment of panic disorder: a controlled pilot comparison

with clorazepate. J Clin Psychopharmacol 8:303, 1988 [PubMed]

Schweizer E, Rickels K: Pharmacological treatment for generalized anxiety disorder, in Long-term

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

Psychiatric Press, 1996, pp 201–220

Schweizer E, Rickels K, Lucki I: Resistance to the anti-anxiety effect of buspirone in patients with a

history of benzodiazepine use. N Engl J Med 314:719–720, 1986 [PubMed]

Schweizer E, Patterson W, Rickels K, et al: Double-blind, placebo-controlled study of a once-a-day,

sustained-release preparation of alprazolam for the treatment of panic disorder. Am J Psychiatry

150:1210–1215, 1993 [Full Text] [PubMed]

Sepede G, De Berardis D, Gambi F, et al: Olanzapine augmentation in treatment-resistant panic

disorder: a 12-week, fixed-dose, open-label trial. J Clin Psychopharmacol 26:45–49, 2006 [PubMed]

Shader RI, Greenblatt DJ: Use of benzodiazepines in anxiety disorders. N Engl J Med

328:1398–1405, 1993 [PubMed]

Shear MK, Brown TA, Barlow DH, et al: Multicenter collaborative panic disorder severity scale. Am J

Psychiatry 154:1571–1575, 1997 [Full Text] [PubMed]

Sheehan DV: The Anxiety Disease. Bantam Books, New York, 1986

Sheehan DV, Ballenger J, Jacobsen G: Treatment of endogenous anxiety with phobic, hysterical, and

hypochondriacal symptoms. Arch Gen Psychiatry 37:51–59, 1980 [PubMed]

Sheehan DV, Davidson J, Manschreck T, et al: Lack of efficacy of a new antidepressant (bupropion)

in the treatment of panic disorder with phobias. J Clin Psychopharmacol 3:28–31, 1983 [PubMed]

Sheehan DV, Raj AB, Sheehan KH, et al: Is buspirone effective for panic disorder? J Clin

Psychopharmacol 10:3–11, 1990 [PubMed]

Sheehan DV, Burnham DB, Iyengar MK, et al: Efficacy and tolerability of controlled-release

paroxetine in the treatment of panic disorder. J Clin Psychiatry 66:34–40, 2005 [PubMed]

Silverstone PH, Salinas E: Efficacy of venlafaxine extended release in patients with major

depressive disorder and comorbid generalized anxiety disorder. J Clin Psychiatry 62:523–529, 2001Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

38 of 40

10/05/2009 16:36

[PubMed]

Simon NM, Emmanuel N, Ballenger J, et al: Bupropion sustained release for panic disorder.

Psychopharmacol Bull 37:66–72, 2003 [PubMed]

Simon NM, Hoge EA, Fischmann D, et al: An open-label trial of risperidone augmentation for

refractory anxiety disorders. J Clin Psychiatry 67:381–385, 2006 [PubMed]

Simpson HB, Schneier FR, Marshall RD, et al: Low dose selegiline (L-deprenyl) in social phobia.

Depress Anxiety 7:126–129, 1998 [PubMed]

Snyderman SH, Rynn MA, Rickels K: Open-label pilot study of ziprasidone for refractory generalized

anxiety disorder. J Clin Psychopharmacol 25:497–499, 2005 [PubMed]

Stahl SM, Gergel I, Li D: Escitalopram in the treatment of panic disorder: a randomized,

double-blind, placebo-controlled trial. J Clin Psychiatry 64:1322–1327, 2003 [PubMed]

Stein DJ, Andersen EW, Tonnoir B, et al: Escitalopram in obsessive-compulsive disorder: a

randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study. Curr Med Res

Opin 23:701–711, 2007 [PubMed]

Stein MB, Chartier MJ, Hazen AL, et al: Paroxetine in the treatment of generalized social phobia:

open-label treatment and double-blind placebo-controlled discontinuation. J Clin Psychopharmacol

16:218–222, 1996 [PubMed]

Stein MB, Liebowitz MR, Lydiard RB, et al: Paroxetine treatment of generalized social phobia (social

anxiety disorder): a randomized controlled trial. JAMA 280:708–713, 1998 [PubMed]

Stein MB, Fyer AJ, Davidson JR, et al: Fluvoxamine treatment of social phobia (social anxiety

disorder): a double-blind, placebo-controlled study. Am J Psychiatry 156:756–760, 1999 [Full Text]

[PubMed]

Stein MB, Kline NA, Matloff JL: Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a

double-blind, placebo-controlled study. Am J Psychiatry 159:1777–1779, 2002 [Full Text] [PubMed]

Stein MB, Seedat S, Gelernter J: Serotonin transporter gene promoter polymorphism predicts SSRI

response in generalized social anxiety disorder. Psychopharmacology (Berl) 187:168–172, 2006

Stinson FS, Dawson DA, Patricia Chou S, et al: The epidemiology of DSM-IV specific phobia in the

USA: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychol

Med 37:1047–1059, 2007 [PubMed]

Strand M, Hetta J, Rosen A, et al: A double-blind, controlled trial in primary care patients with

generalized anxiety: a comparison between buspirone and oxazepam. J Clin Psychiatry 51

(suppl):40–45, 1990

Sutherland SM, Tupler LA, Colket JT, et al: A 2-year follow-up of social phobia. Status after a brief

medication trial. J Nerv Ment Dis 184:731–738, 1996 [PubMed]

Swinson RP, Antony MM, Bleau P, et al: Clinical practice guidelines. Management of anxiety

disorders. Can J Psychiatry 51 (suppl 2):1–92, 2006

Szegedi A, Wetzel H, Leal M, et al: Combination treatment with clomipramine and fluvoxamine: drug

monitoring, safety, and tolerability data. J Clin Psychiatry 57:257–264, 1996 [PubMed]

Taylor LH, Kobak KA: An open-label trial of St John’s wort (Hypericum perforatum) in

obsessive-compulsive disorder. J Clin Psychiatry 61:575–578, 2000 [PubMed]

Tesar GE, Rosenbaum JF, Pollack MH, et al: Double-blind, placebo-controlled comparison of

clonazepam and alprazolam for panic disorder. J Clin Psychiatry 52:69–76, 1991 [PubMed]

Thoren P, Asberg M, Cronholm B, et al: Clomipramine treatment of obsessive-compulsive disorder,

I: a controlled clinical trial. Arch Gen Psychiatry 37:1281–1285, 1980 [PubMed]Print: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

39 of 40

10/05/2009 16:36

Tiller JW, Bouwer C, Behnke K: Moclobemide and fluoxetine for panic disorder. International Panic

Disorder Study Group. Eur Arch Psychiatry Clin Neurosci 249 (suppl 1):S7–S10, 1999

Tollefson GD, Rampey AH Jr, Potvin JH, et al: A multicenter investigation of fixed-dose fluoxetine in

the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 51:559–567, 1994 [PubMed]

True WR, Rice J, Eisen SA, et al: A twin study of genetic and environmental contributions to liability

for posttraumatic stress symptoms. Arch Gen Psychiatry 50:257–264, 1993 [PubMed]

Tucker P, Smith KL, Marx B, et al: Fluvoxamine reduces physiologic reactivity to trauma scripts in

posttraumatic stress disorder. J Clin Psychopharmacol 20:367–372, 2000 [PubMed]

Tucker P, Zaninelli R, Yehuda R, et al: Paroxetine in the treatment of chronic posttraumatic stress

disorder: results of a placebo-controlled, flexible-dosage trial. J Clin Psychiatry 62:860–868, 2001

[PubMed]

Turner SM, Beidel DC, Jacob RG: Social phobia: a comparison of behavior therapy and atenolol. J

Consult Clin Psychol 62:350–358, 1994 [PubMed]

Van Ameringen M, Mancini C, Oakman JM: Nefazodone in social phobia. J Clin Psychiatry 60:96–100,

1999

Van Ameringen MA, Lane RM, Walker JR, et al: Sertraline treatment of generalized social phobia: a

20-week, double-blind, placebo-controlled study. Am J Psychiatry 158:275–281, 2001

Van Ameringen M, Mancini C, Oakman J, et al: Nefazodone in the treatment of generalized social

phobia: a randomized, placebo-controlled trial. J Clin Psychiatry 68:288–295, 2007

van der Kolk BA, Dreyfuss D, Michaels M, et al: Fluoxetine in posttraumatic stress disorder [see

comment]. J Clin Psychiatry 55:517–522, 1994

van Vliet IM, den Boer JA, Westenberg HG: Psychopharmacological treatment of social phobia:

clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor. Eur

Neuropsychopharmacol 2:21–29, 1992

van Vliet IM, den Boer JA, Westenberg HG: Psychopharmacological treatment of social phobia: a

double blind placebo controlled study with fluvoxamine. Psychopharmacology (Berl) 115:128–134,

1994

van Vliet IM, den Boer JA, Westenberg HG, et al: Clinical effects of buspirone in social phobia: a

double-blind placebo-controlled study. J Clin Psychiatry 58:164–168, 1997

Versiani M, Nardi AE, Mundim FD, et al: Pharmacotherapy of social phobia. A controlled study with

moclobemide and phenelzine. Br J Psychiatry 161:353–360, 1992 [PubMed]

Versiani M, Nardi AE, Figueria J: Double-blind placebo-controlled trial with bromazepam in social

phobia. J Bras Psiquitr 46:167–171, 1997

Versiani M, Cassano G, Perugi G, et al: Reboxetine, a selective norepinephrine reuptake inhibitor, is

an effective and well-tolerated treatment for panic disorder. J Clin Psychiatry 63:31–37, 2002

[PubMed]

Wade AG, Lepola U, Koponen HJ, et al: The effect of citalopram in panic disorder. Br J Psychiatry

170:549–553, 1997 [PubMed]

Wagner KD, Berard R, Stein MB, et al: A multicenter, randomized, double-blind, placebo-controlled

trial of paroxetine in children and adolescents with social anxiety disorder. Arch Gen Psychiatry

61:1153–1162, 2004 [PubMed]

Walker JR, Van Ameringen MA, Swinson R, et al: Prevention of relapse in generalized social phobia:

results of a 24-week study in responders to 20 weeks of sertraline treatment. J Clin

Psychopharmacol 20:636–644, 2000 [PubMed]

Weathers FW, Keane TM, Davidson JRT: Clinician-administered PTSD scale: a review of the first tenPrint: Chapter 56. Treatment of Anxiety Disorders http://www.psychiatryonline.com/popup.aspx?aID=424279&print=yes…

40 of 40

10/05/2009 16:36

years of research. Depress Anxiety 13:132–156, 2001 [PubMed]

Westenberg HG, Stein DJ, Yang H, et al: A double-blind placebo-controlled study of controlled

release fluvoxamine for the treatment of generalized social anxiety disorder. J Clin

Psychopharmacol 24:49–55, 2004 [PubMed]

Westenberg HG, Fineberg N, Denys D: Neurobiology of obsessive-compulsive disorder: serotonin

and beyond. CNS Spectr 12 (suppl 3):14–27, 2007

Williams JE, Nieto FJ, Sanford CP, et al: Effects of an angry temperament on coronary heart disease

risk: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 154:230–235, 2001 [PubMed]

Wittchen HU, Hoyer J: Generalized anxiety disorder: nature and course. J Clin Psychiatry 62 (suppl

11):15–19, 2001

Wittchen HU, Zhao S, Kessler RC, et al: DSM-III-R generalized anxiety disorder in the National

Comorbidity Survey. Arch Gen Psychiatry 51:355–364, 1994 [PubMed]

Wurthmann C, Klieser E, Lehmann E: [Differential pharmacologic therapy of generalized anxiety

disorders—results of a study with 30 individual case experiments]. Fortschritte der

Neurologie-Psychiatrie 63:303–309, 1995 [PubMed]

Zigmond AS, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand

67:361–370, 1983 [PubMed]

Zimmerman M, Mattia JI: Principal and additional DSM-IV disorders for which outpatients seek

treatment. Psychiatr Serv 51:1299–1304, 2000 [Full Text] [PubMed]

Zitrin CM, Klein DF, Woerner MG, et al: Treatment of phobias, I: comparison of imipramine

hydrochloride and placebo. Arch Gen Psychiatry 40:125–138, 1983 [PubMed]

Zohar J, Amital D, Miodownik C, et al: Double-blind placebo-controlled pilot study of sertraline in

military veterans with posttraumatic stress disorder. J Clin Psychopharmacol 22:190–195, 2002

[PubMed]

Zwanzger P, Baghai TC, Schule C, et al: Tiagabine improves panic and agoraphobia in panic disorder

patients. J Clin Psychiatry 62:656–657, 2001 [PubMed]

Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.