47 | PHARMACOTHERAPY OF ANXIETY DISORDERS
JAMES W. MURROUGH, DAN V. IOSIFESCU, AND DENNIS S. CHARNEY
INTRODUCTION
Anxiety disorders are among the most prevalent mental disorders in the United States and are associated with a high degree of morbidity and public health costs (Kessler et al., 2005a). Approximately one in four adults will suffer from an anxiety disorder at some point in their lives. Anxiety disorders often have an age of onset in young adulthood or before and are frequently comorbid with general medical disorders and other psychiatric disorders. General risk factors for the development of an anxiety disorder include a temperamental trait described as behavioral inhibition—increased physiological reactivity and anxious behaviors observed in some children in response to unfamiliar surroundings—female gender, family history, and exposure to certain types of environmental stress in childhood or adulthood. Chapter 40 of this volume provides a thorough discussion of the genetics of anxiety disorders.
There are seven primary anxiety disorders defined in the Diagnostic and Statistical Manual of Mental Disorder—Fourth Edition, Text Revision (DSM-IV-TR): panic disorder, specific phobia, social phobia, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, and generalized anxiety disorder (GAD) (American Psychiatric Association, Task Force on DSM-IV, 2000). The current chapter will focus on the pharmacotherapeutic treatment of panic disorder, PTSD, GAD, and social phobia. The treatment of OCD is discussed by Dr. H. Blair Simpson in Chapter 48 and will not be reviewed here. Acute stress disorder is characterized by symptoms similar to those of PTSD that occur immediately following a traumatic event and will not be discussed separately from PTSD. Finally, specific phobia will not be discussed since there is a minimal role for pharmacotherapy for this disorder.
Other anxiety disorders defined in the DSM-IV-TR are considered to be secondary to either the direct physiological result of another medical condition (anxiety disorder due to a general medical condition: e.g., hyperthyroidism) or the direct physiological consequence of a substance (substance-induced anxiety disorder: e.g., withdrawal from alcohol or a sedative/hypnotic medication). These important secondary causes of anxiety disorders will not be discussed in depth; however, it is critical that these disorders be considered in the diagnostic assessment of the patient who presents with anxiety. The residual category termed “anxiety disorder not otherwise specified” is included in the DSM to enable patients who present with prominent anxiety symptoms and functional impairment but who do not meet the criteria for a specific anxiety disorder to be diagnosed. Chapter 39 of this volume provides a complete discussion of the diagnosis of anxiety disorders.
A general approach to the evaluation and treatment of anxiety disorders is presented in Table 47.1. A complete diagnostic assessment—including medical and psychiatric history, vital signs, physical exam, and laboratory or other tests if indicated—should precede initiation of a treatment intervention. As mentioned earlier, particularly important to consider in the differential diagnosis of a patient who presents with anxiety symptoms are general medical disorders and substance use disorders. Other important principles relevant to the diagnosis and treatment of anxiety disorders include the establishment of a therapeutic alliance, provision of psychoeducation and counseling, and ongoing assessment of treatment adherence (Table 47.1). For most patients, first-line treatment will consist of an evidence-based trial of a medication, a psychotherapeutic modality (e.g., cognitive-behavioral therapy ([CBT]), or a combination of the two. If the treatment is effective, it should generally be continued for at least 6–12 months in the case of pharmacotherapy while some prescribed forms of CBT are considerably shorter. If the initial treatment modality is either partially effective or ineffective, then the treating clinician must determine the next best treatment step for the particular patient. Pharmacotherapeutic next-step options typically consist of augmentation—the addition of another agent to increase the effectiveness of the primary agent, or combination—the addition of a second antianxiety agent, or switching agents (Table 47.1).
An overview of U.S. Food and Drug Administration (FDA)-approved pharmacotherapeutic agents available to the clinician for the treatment of anxiety disorders is presented in Table 47.2. As will be reviewed in detail in the following text for specific anxiety disorders, serotonin-selective reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are usually considered first-line medication treatment. Older monoaminergic agents—including the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)—are often efficacious but are usually reserved for second-line treatment due to safety and tolerability issues. The benzodiazepines (BZDs) play an important role in the treatment of some anxiety disorders; however, these agents, too, are usually reserved for second-line or adjunctive use due to tolerability and abuse liability issues. Benzodiazepines act by binding to a specific site on the gamma-aminobutyric acid (GABA)-A receptor and increasing the inhibitory effect associated with GABA binding. Other pharmacological agents, including anticonvulsants and atypical antipsychotics, have been investigated in different anxiety disorders, and the evidence to date generally does not support their use as first-line treatments; however, they may represent appropriate options in refractory patients.
TABLE 47.1. Approach to the treatment of anxiety disorders
| 1. Diagnostic Assessment |
Complete medical and psychiatric history. |
Assess for general medical or substance-related causes of anxiety symptoms. |
Obtain laboratory (e.g., TSH) or other diagnostic tests if indicated by history. |
Establish working diagnosis of a primary anxiety disorder after ruling out secondary causes. |
Establish presence or absence of comorbid psychiatric, medical, or substance use disorders. |
| 2. Develop therapeutic alliance with patient to facilitate adherence to treatment. |
| 3. Provide initial and ongoing psychoeducation to facilitate adherence to treatment. |
| 4. Initiate first-line pharmacotherapeutic or psychotherapeutic treatment. |
| 5. If initial treatment is effective, continue treatment for a minimum of 6 to 12 months, depending on clinical situation. |
| 6. If initial treatment is ineffective: |
Assess adherence to treatment, provide psychoeducation, address potential barriers to treatment adherence, optimize therapeutic alliance. |
Reassess primary diagnosis and presence of comorbid psychiatric, medical, or substance use disorders. |
Consider switch to alternative first-line treatment option or augment current treatment with another evidence-based treatment option. |
| 7. If first-line treatment options are ineffective: |
Identify potential specific psychosocial stressors that may respond to nonmedical intervention. |
Recommend evidence-based psychotherapy if not already tried. |
Consider second-line treatment options based on clinical circumstances and patient preference. |
Pursue ongoing diagnostic reevaluation and adherence monitoring |
While there has been an increasing recognition of the public health burden of anxiety disorders, historically there has been relatively little research focus on the development of new treatments. Most of the treatments for anxiety disorders are based on medications developed for the treatment of major depressive disorder (MDD). New research focusing on targets outside of the monoamine system—e.g., amino acid, neurohormonal, and neuropeptide systems—may yield novel and much needed treatment interventions for these common disorders.
PANIC DISORDER
OVERVIEW
Panic disorder (PD) is characterized by recurrent, unexpected panic attacks with attendant adverse behavioral effects between attacks (American Psychiatric Association, Task Force on DSM-IV, 2000). Panic attacks are periods of intense fear that peak within 10 minutes but can continue on for much longer. The intense fear is typically accompanied by physical symptoms such as heart palpitations, sweating, shortness of breath, chest pain or tightness, nausea, and dizziness. Sensations of choking or smothering and/or derealization during a panic attack are also common. By definition, the panic attacks are not due to the direct physiological effects of a substance or a general medical condition—both of which are important for the clinician to consider in the differential diagnosis of panic disorder. Ongoing worry about the implications of the panic attacks and/or anxiety about experiencing another unprovoked attack characterizes the disorder, and a duration of at least one month of persistent concern is required for the diagnosis. Individuals diagnosed with panic disorder may or may not also have agoraphobia—anxiety about and avoidance of situations where escape may be difficult.
Panic disorder affects between 1% and 3% of the U.S. population and is associated with significant morbidity and public health costs (Kessler et al., 2005b). Increased health care utilization is common in patients with panic disorder, and the presence of the illness places individuals at elevated risk for suicide (Perna et al., 2011). Overall there is good evidence for the efficacy of both pharmacotherapeutic and psychotherapeutic treatments for panic disorder, although there is still significant room for improvement to current treatment options. While evidence supports both approaches as first-line treatment, this chapter will focus on pharmacotherapeutic approaches.
FIRST-LINE PHARMACOTHERAPY
There is good evidence for the efficacy of SSRIs, SNRIs, TCAs, and BZDs in the treatment of panic disorder (American Psychiatric Association, 2009; McHugh et al., 2009). The 2009 American Psychiatric Association practice guideline on the treatment of panic disorder found that there was insufficient evidence to recommend one of these therapeutic options over the others (American Psychiatric Association, 2009). Given their relative tolerability, safety, and efficacy, a trial of an SSRI or SNRI for the patient with panic disorder is a pragmatic first treatment step. As always, factors specific to a particular case will guide treatment selection, including patient preference and the presence of comorbid medical or psychiatric conditions.
TABLE 47.2. Overview of pharmacotherapy for anxiety disorders
The SSRIs fluoxetine, paroxetine, and sertraline are FDA approved for the treatment of panic disorder, as is the SNRI venlafaxine. Three meta-analytic reviews of SSRIs in panic disorder support the efficacy of these interventions (Bakker et al., 2002; Mitte, 2005; Otto et al., 2001). In one example, an analysis of 12 placebo-controlled trials found a mean effect size for acute treatment outcome for SSRIs relative to placebo of 0.55 (Otto et al., 2001). A study including 664 patients with panic disorder randomized to venlafaxine extended-release (ER) 75 mg or 150 mg daily, paroxetine 40 mg daily, or placebo for up to 12 weeks found response rates of 77–80% for the venlafaxine and paroxetine groups compared with 56% for the placebo group (Pollack et al., 2007). Studies comparing different agents in the SSRI class to each other or to venlafaxine have generally not found support for the efficacy of one agent over another (see Freire et al., 2011 for review).
SSRIs and SNRIs are generally safe and well tolerated in this and other anxiety disorder populations. The most commonly reported side effects include sleep changes, nausea, headache, sleep problems, and sexual dysfunction (see Table 47.2). Importantly, patients with panic disorder may be particularly sensitive to transient increases in anxiety that are sometimes observed at the initiation of treatment or upon a dosage increase with an SSRI or SNRI agent. Psychoeducation represents an important component of the treatment in this regard. Adjunctive treatment with BZD at the outset of treatment with an SSRI or SNRI to mitigate this increase in anxiety may also be indicated, as discussed in more detail next.
SECOND-LINE/OTHER APPROACHES
The BZDs alprazolam and clonazepam are FDA approved for the treatment of panic disorder. BZDs are potent anxiolytic medications that can result in substantial symptom relief for patients with panic and other anxiety disorders when used appropriately (American Psychiatric Association, 2009; Ballenger et al., 1988). BZDs have the advantage of a more rapid onset of action compared with SSRIs or other monoamineric agents, although data supporting their longer term efficacy is more limited. Alprazolam has a short half-life and a rapid onset of action, particularly desirable when rapid relief from a developing panic attack is the treatment goal. Clonazepam has a longer half-life and is more suited to standing dosing as opposed to as-needed (e.g., “prn”) use. See Table 47.1 for a description of commonly prescribed BZD medications. Principal disadvantages associated with the use of BZDs in panic or other anxiety disorders include their well-known abuse liability and the predictable development of tolerance, the need for dose escalation, and prominent withdrawal effects. Somnolence and cognitive problems are additional adverse effects characteristic of this drug class.
As mentioned in the preceding section, patients may experience a temporary increase in anxiety following initiation of treatment with an SSRI or SNRI agent. Another limitation commonly observed with monoaminergic treatments is a delay in onset of therapeutic effect of several weeks. BZDs can, therefore, have an important therapeutic role as adjunctive treatment to a first-line agent. Goddard et al. showed that coadministration of low-dose clonazepam with sertraline in the treatment of panic disorder resulted in a significantly greater proportion of responders in the sertraline/clonazepam compared with the sertraline/placebo group at the end of one week (41% compared with 4%) (Goddard et al., 2001). Notably, the groups did not differ in response rate by the end of the study. These data support the common clinical practice of initiating a BZD agent concurrently with an SSRI or SNRI at the outset of the treatment and then tapering the BZD after three to four weeks and continuing the first-line agent.
The TCAs clomipramine and imipramine are FDA approved for the treatment of panic disorder, and several early studies have established the efficacy of these agents in reducing the frequency and intensity of panic attacks (Bakker et al., 2002; Perna et al., 2011). The TCAs are considered second-line agents for the treatment of panic disorder—as well as other anxiety disorders—primarily due to their side effect burden. For example, a meta-analysis including 2,367 patients compared SSRIs with TCAs and found that the proportion of patients free of panic attacks did not differ while the number of dropouts was significantly lower in the group of patients treated with SSRIs compared with TCAs (18% vs. 31%, respectively) (Bakker et al., 2002). Commonly observed adverse effects for this drug class are attributable to blockade of the muscarinic acetylcholine receptor (e.g., dry mouth, constipation, urinary retention) or the alpha-adrenergic or histamine receptors (e.g., somnolence, orthostasis, weight gain). Serious adverse reactions such as cardiac arrhythmia can occur and TCAs can be fatal in overdose. Despite the potential for side effects, a trial of a TCA is warranted in patients who fail to demonstrate an adequate response to first-line therapy.
The MAOI phenelzine is approved for the treatment of panic disorder and represents an important third- or fourth-line agent for refractory patients. MAOIs irreversibly inhibit the enzyme monoamine oxidase and result in a net increase in monoamine availability in the synapse. The use of MAOIs is restricted by the need to maintain a low-tyramine diet and the risk of (potentially fatal) hypertensive crisis and drug–drug interactions. Moclobemide—a reversible MAOI (RIMA [reversible inhibitors of monoamine oxidase A]) not currently available in the United States—has some efficacy data in panic disorder and does not have the same strict dietary restrictions and safety liability as the irreversible MAOIs.
There is currently no controlled evidence supporting the use of anticonvulsant medications in panic disorder. RCTs examining the efficacy of the anticonvulsants gabapentin and tiagabine in panic disorder have been conducted, and these studies did not find support for the use of these agents.
There is a paucity of evidence available to the clinician to help determine the next treatment step in the management of panic disorder in the event that first-line pharmacotherapy fails. Given the evidence supporting the efficacy of specific psychotherapeutic interventions for panic disorder, this option should be considered at the top of the treatment algorithm. If a partial response is gained with an SSRI or SNRI, upward dose titration and/or augmentation with psychotherapy or a BZD may represent a pragmatic therapeutic step. If no response is achieved with a first-line agent after appropriate treatment duration (at least four to six weeks) and dose escalation, then a switch to a second first-line agent is an appropriate step. TCAs, MAOIs, or other agents (e.g., anticonvulsants) may be reserved for more refractory cases.
POSTTRAUMATIC STRESS DISORDER
OVERVIEW
Posttraumatic stress disorder is a disabling condition that develops in a subset of individuals exposed to extreme psychological stress. The disorder is characterized by intrusive reexperiencing of traumatic memories along with symptoms of increased arousal and avoidance of stimuli associated with the trauma (American Psychiatric Association, Task Force on DSM-IV, 2000). By definition, the symptoms must be present for more than one month and be associated with significant distress and functional impairment. PTSD is increasingly being recognized as a major public health problem, and the alarming rates of PTSD and associated sequelae—including suicide attempts and completed suicide—observed in U.S. soldiers returning from combat portend the urgent need to identify effective treatments.
The estimated lifetime prevalence of PTSD in the United States is 7.8% according to the National Comorbidity Survey, with women being approximately twice as likely to suffer from PTSD compared with men (10.4% vs. 5.0%, respectively) (Kessler et al., 1995). The estimated lifetime prevalence of trauma exposure is 60.7% for men and 51.2% for women. Therefore, while trauma exposure is very common, development of PTSD is relatively less so. It is estimated that 79% of women and 88% of men with PTSD have also been diagnosed with at least one other psychiatric disorder—most frequently MDD, other anxiety disorders, and substance use disorders (Pratchett et al., 2011).
FIRST-LINE PHARMACOTHERAPY
Two SSRIs—sertraline and paroxetine—are approved by the FDA for the treatment of PTSD, and SSRIs are generally recommended by practice guidelines as first-line pharmacotherapy for the disorder (American Psychiatric Association, 2004). In an early positive, 12-week RCT (randomized controlled trial) comparing sertraline with placebo, the response rate was 53% for drug compared with 32% for placebo (Brady et al., 2000) and similar data are available for paroxetine (Marshall et al., 2001). Sertraline was found to be more effective than placebo at preventing relapse in a 28-week relapse prevention study (Davidson et al., 2001). In contrast, a more recent acute-phase RCT comparing sertraline to placebo conducted in a Veterans Affairs (VA) setting was negative (Friedman et al., 2007). Some data are also available in support of the SNRI venlafaxine in the treatment of PTSD. Importantly, a report from the Institute of Medicine (IOM) found that the existent evidence was inadequate to support the efficacy of SSRIs or other pharmacotherapy in PTSD (Institute of Medicine, 2008). A Cochrane Review of pharmacotherapy for PTSD including 35 RCTs and 4,597 participants did support the use of SSRIs as first-line medication treatment; however, it also acknowledged that there exist significant gaps in the evidence base (Stein et al., 2006). Responder status from 13 trials included in the Cochrane Review demonstrated overall superiority of medication compared with placebo: relative risk 1.49 (95% CI: 1.28, 1.73).
The data just reviewed paints a sobering picture of the current state of pharmacotherapy for PTSD, and new, more effective treatments are clearly needed for this disability disorder. Although not the focus of the current review, it is important to note that specific psychotherapeutic interventions—most notably, exposure therapy—have relatively strong evidence for efficacy in PTSD and may be considered a first-line treatment for PTSD. For example, in contrast to its conclusions regarding pharmacotherapy, the IOM report described earlier found sufficient evidence to conclude that exposure therapy is effective for PTSD (Institute of Medicine, 2008).
SECOND-LINE/OTHER APPROACHES
As noted preceding, exposure therapy or related CBT approaches should be considered for patients with PTSD early in the treatment algorithm, particularly if a patient does not respond adequately to a trial of an SSRI. Regarding second-line pharmacotherapeutic options, some evidence exists supporting the use of MAOIs, TCAs, BZDs, atypical antipsychotics, or anticonvulsants in the treatment of PTSD (see Baker et al., 2009 for review). The TCA amitriptyline has weak evidence for efficacy while desipramine was not found to be effective. One trial comparing the MAOI phenelzine with the TCA, imipramine, or placebo found support for both drugs, although another study investigating phenelzine in PTSD was negative.
BZDs can be used to target specific anxiety symptoms, hyperarousal, or insomnia associated with PTSD. Well-controlled data supporting the overall efficacy of BZD in the treatment of PTSD, however, is lacking, and tolerance and abuse potential issues limit the role of these medications. Studies investigating the use of BZDs immediately following trauma were not favorable. A small amount of research investigating alpha-adrenergic antagonists—prazosin, in particular—provides some support for their use in treating nightmares and sleep disturbance associated with PTSD (Raskind et al., 2003).
Atypical antipsychotic medication is frequently used as an adjunctive treatment in PTSD when first-line agents fail to yield a complete response. Risperidone has been the focus of the majority of research in PTSD with several smaller studies suggesting a beneficial effect of the addition of risperidone to an SSRI or SNRI. A recent, large, six-month RCT of adjunctive risperidone in PTSD conducted in a VA setting, however, did not find a significant advantage of risperidone over placebo (Krystal et al., 2011). In the same study, risperidone was associated with significantly greater adverse events compared with placebo, including weight gain, fatigue, and somnolence. The data reviewed in the preceding, along with consideration of potentially serious longer term adverse effects associated with atypical antipsychotic agents, including tardive dyskinesias and metabolic syndrome, must be weighed against potentially therapeutic gains when considering risperidone or other antipsychotic agents as a treatment option for refractory PTSD.
Several studies investigating the use of anticonvulsants in PTSD have been conducted with generally discouraging results. Topiramate, tiagabine, and valproate have failed to demonstrate clear efficacy in PTSD in controlled study designs. Several case series and open studies of anticonvulsants have yielded favorable results, suggesting that these agents may help in select cases.
In summary, the evidence base for effective treatments in PTSD is unfortunately limited, and new treatments for this disabling condition are urgently needed. SSRIs and exposure therapy have the best efficacy evidence, but a significant proportion of patients will remain symptomatic with currently available treatments. The evidence supporting the use of TCAs, MAOIs, BZDs, anticonvulsants, atypical antipsychotics, or other agents is quite limited.
GENERALIZED ANXIETY DISORDER
OVERVIEW
Generalized anxiety disorder (GAD) is characterized by excessive anxiety and worry occurring more days than not for at least six months (American Psychiatric Association, Task Force on DSM-IV, 2000). By definition, the worry is difficult to control, is out of proportion to real or perceived external factors, and is associated with three or more of the following six symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, or sleep disturbance. To meet criteria for the disorder, the symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning, and the disturbance must not be due to the direct physiological effects of a general medical condition or substance.
GAD is a common disorder, with a lifetime prevalence of 5–6% in the general population, and is more common in women than in men (approximately 2:1). Notably, GAD is one of the most common psychiatric disorders in primary care settings and is associated with increased utilization of health services. The disorder has a high rate of comorbidity with mood and other anxiety disorders, as well as with substance use and general medical conditions. It is estimated that nearly 50% of patients with GAD also meet criteria for MDD. The high rate of comorbidity between GAD and MDD and symptomatic overlap have led to the idea that these syndromes may be different manifestations of the same disorder, although there continues to be debate regarding this issue.
FIRST-LINE PHARMACOTHERAPY
More than a dozen RCTs of drugs in the SSRI class support the use of SSRIs as first-line pharmacotherapy for GAD (Baldwin et al., 2011; Kapczinski et al., 2003). Escitalopram and paroxetine have an FDA indication for the treatment of GAD and good controlled data also exist for sertraline. Response rates for SSRIs of between 60% and 75% are generally reported in RCTs, compared with response rates of between 40% and 60% for placebo (Baldwin et al., 2011). In a study by Rickels et al. where outpatients with GAD (N = 566) were randomized to eight weeks of paroxetine at 20 or 40 mg/day or placebo, response rates were 62%, 68%, and 46% for patients receiving 20 mg, 40 mg, or placebo, respectively (Rickels et al., 2003). Data also support the longer term efficacy of SSRIs in sustaining treatment effects over a period of six months (Stocchi et al., 2003).
In addition to that of SSRIs, good controlled data also support the use of SNRIs as a first-line treatment option in GAD. The SNRIs venlafaxine ER and duloxetine both carry FDA indications for the treatment of GAD and observed response rates and drug–placebo differences in RCTs generally similar to what is observed in trials of SSRIs (Baldwin et al., 2011). In one study, patients with GAD (n = 377) were randomized to venlafaxine ER 75, 150, or 225 mg/day or placebo for eight weeks, and resulting analysis indicated that patients had significant reductions in illness severity under venlafaxine ER compared with placebo conditions (Rickels et al., 2000). A second RCT including 251 patients with GAD assessed longer term efficacy of venlafaxine ER over six months and found response rates of 69% or higher in the active drug group compared with 42–46% in the placebo group (Gelenberg et al., 2000). Duloxetine has demonstrated efficacy comparable to venlafaxine for GAD (Hartford et al., 2007), although longer term maintenance studies of duloxetine in GAD have not been conducted to date.
As reviewed in previous sections, SSRI and SNRI medications have favorable tolerability profiles. Alerting patients to the common, usually transient, adverse effects of these medication classes—including nausea, headache, changes in sleep, and nervousness—is an important component of psychoeducation and will facilitate treatment adherence. Transient nervousness, jitteriness, or worsening of anxiety at the onset of treatment with an SSRI or SNRI may be a particular concern for this patient population. In addition to psychoeducation, short-term treatment with low-dose BZD at the outset of treatment, as described next, may be a fruitful pharmacotherapeutic strategy.
Considering the safety, efficacy, and tolerability of SSRIs and SNRIs, these drugs represent first-line treatment for GAD.
SECOND-LINE/OTHER APPROACHES
There is limited data available to guide clinicians regarding next best steps for treatment in patients with GAD who manifest an inadequate response to first-line therapy. There is fair evidence for BZDs, the azapirone buspirone, TCAs, and the anticonvulsant agent pregabalin in the treatment of GAD. Weak evidence also exists for other anticonvulsants (e.g., valproic acid), antihistamines (e.g., hydroxyzine), and atypical antipsychotics (e.g., quetiapine). CBT is an important therapeutic consideration for patients with GAD, especially if they have not responded to a prior first-line medication trial.
The rapid and robust anxiolytic effects of BZDs make this class of drugs an important component of the treatment armamentarium for GAD. A key early RCT comparing diazepam with trazodone and imipramine found that diazepam was associated with the most improvement in anxiety during the first two weeks of treatment (Rickels et al., 1993). In contrast, during weeks three through eight, imipramine was superior to diazepam in the proportion of patients achieving moderate or marked symptom improvement (73% vs. 66%). Given the limitation of BZD therapy discussed in the preceding sections, including sedation, cognitive disturbance, and abuse or dependence liability, these agents should be used judiciously in the treatment of GAD. Specific circumstances that may be particularly suited to the use of BZDs include short-term use as an adjunct to antidepressant medication or in patients who are refractory to first-line treatments after consideration of the risk:benefit ratio for the individual patient. Patients with a history of substance use disorder may be particularly vulnerable to the abuse or dependence liability of BZDs, and additional caution should be used in this patient population.
The azapirone buspirone is a unique partial agonist at the 5-HT1A receptor and is FDA approved for the treatment of GAD. Buspirone and other azapirones have demonstrated superiority to placebo in the treatment of GAD in a number of large RCTs (Chessick et al., 2006). Despite reasonable controlled evidence for its efficacy, buspirone is not generally considered a first-line treatment for GAD, in part due to its relatively slow onset of action, tolerability issues at higher doses, and some data suggesting inferiority to antidepressant or BZD treatment options (Davidson et al., 1999).
As referenced earlier, there is some data for the effectiveness of TCAs, imipramine in particular, in the treatment of GAD (Rickels et al., 1993). Potential advantages of TCAs over BZDs include their ability to treat symptoms of both anxiety and depression and the absence of potential for abuse and physiological dependence. As a class, TCAs are generally reserved for patients who have failed other treatment strategies, owing to safety and tolerability issues related to this class of medications. As discussed in previous sections, pharmacological blockade of muscarinic, histamine, and alpha-adrenergic receptors limit their use. The utility of TCAs is also limited by their cardiotoxic potential and lethality in overdose.
Pregabalin, a voltage-dependent calcium channel modulator approved for the adjunctive treatment of seizure disorder, has fair efficacy data for the treatment of GAD from several RCTs (Montgomery et al., 2006; Rickels et al., 2005). In one study, patients were randomized to four weeks of treatment with pregabalin, 300 mg, 450 mg, or 600 mg per day, alprazolam, 1.5 mg per day, or placebo, and results indicated that both pregabalin and alprazolam produced significant reductions in anxiety compared with placebo (Rickels et al., 2005). A second study randomized patients with GAD (n = 421) to six weeks of double-blind treatment with pregabalin 400 mg or 600 mg per day, venlafaxine 75 mg per day, or placebo and found both pregabalin and venlafaxine to be more effective than placebo in decreasing anxiety symptoms (Montgomery et al., 2006).
A recent effect size analysis of treatments for GAD—including SSRIs, SNRIs, BZDs, buspirone, hydroxyzine, and pregabalin—yielded an overall effect size of 0.39 for all drugs versus placebo (Hidalgo et al., 2007). Drug-specific effect sizes, listed from largest to smallest effect, were as follows: pregabalin: 0.50, hydroxyzine: 0.45, SNRI: 0.42, BZD: 0.38, SSRI: 0.36, buspirone: 0.17. While this analysis provides some interesting insights and suggests that overall our current treatments for GAD vary from modestly to poorly effective, methodological limitations inherent in effect size analysis limit specific conclusions that can be drawn.
In summary, first-line pharmacotherapy for GAD—including SSRIs and SNRIs—provides substantial symptomatic relief in many but not all patients with GAD. Second-line treatment options include BZDs, buspirone, TCAs, pregabalin, and hydroxyzine, among other agents. Future research is required to establish the optimal treatment approach for patients who do not respond to a first-line treatment trial.
SOCIAL PHOBIA
OVERVIEW
Social phobia—also known as social anxiety disorder—is a common and potentially disabling anxiety disorder with a lifetime estimated prevalence of approximately 12% (Kessler et al., 2005b). The disorder is characterized by marked anxiety in reaction to social or performance situations, often leading to avoidance behavior (American Psychiatric Association, Task Force on DSM-IV, 2000). By definition, exposure to the feared social situation nearly always provokes anxiety, and the resulting avoidance, anxious anticipation, or distress interferes significantly with the person’s social or occupational functioning. Comorbidity is common, and social phobia often precedes the onset of other disorders, in particular MDD and substance use disorders. (Stein and Stein, 2008). The disorder often begins in childhood or early adolescence and has been associated with the heritable temperament trait behavior inhibition.
FIRST-LINE PHARMACOTHERAPY
More than two dozen RCTs of SSRIs or SNRIs support the use of these medications as first-line pharmacotherapy in social phobia (de Menezes et al., 2011; Stein et al., 2004; Stein and Stein, 2008). Fluvoxamine, paroxetine, sertraline, and venlafaxine have FDA approval for the treatment of social phobia. In the case of paroxetine trials, reported response rates for active drug vary from 55% to 72% compared with response rates for placebo between 8% and 50% (Stein and Stein, 2008a). Reported response rates are similar for other SSRIs and venlafaxine. A Cochrane Review including 36 RCTs and 4,268 patients with social phobia demonstrated short-term superiority of medication over placebo with a relative risk of nonresponse of 0.63 (95% CI: 0.55, 0.72) (Stein et al., 2004). For SSRIs in particular, the relative risk of nonresponse was 0.67 (95% CI: 0.59, 0.76). A recent quantitative meta-analysis including 27 RCTs aimed to compare efficacy between members of the SSRI, SNRI, and atypical antidepressant classes and found paroxetine, sertraline, fluvoxamine, escitalopram, and venlafaxine to be consistently more effective than placebo (de Menezes et al., 2011). The superiority of drug over placebo was less convincing for other agents, including citalopram, mirtazapine, and nefazodone.
Fewer data exist concerning the effectiveness of longer-term treatment in social phobia. The Cochrane Review just described included three maintenance studies and five relapse prevention studies and found some support for longer term treatment (relative risk of nonresponse was 0.58 [95% CI: 0.39, 0.85] and 0.33 [95% CI: 0.22, 0.49], respectively). Considering the safety, efficacy, and tolerability of SSRIs, these drugs—along with the SNRI venlafaxine—represent first-line treatment for social phobia.
SECOND-LINE/OTHER APPROACHES
A series of early studies established the efficacy of the MAOI phenelzine in the treatment of social phobia (Blanco et al., 2002). For example, an RCT including 85 patients with social phobia found a 64% response rate in the phenelzine group compared with 23% in the placebo group (Liebowitz et al., 1992). Despite safety and tolerability issues related to irreversible MAOIs, a trial of phenelzine or other MAOI should be considered in cases where patients fail to achieve response to first-line treatment. The RIMA moclobemide has some efficacy evidence from RCTs in social phobia conducted in Europe. To date there have been no RCTs published of TCAs in social phobia.
There is limited data to support the use of BZDs in the treatment of social phobia. An early 10-week RCT found support for clonazepam (mean dose 2.4 mg/day) with a 78% response rate in the active arm compared with a 20% response rate in the placebo arm while evidence for the efficacy of alprazolam or other BZDs was less favorable (Blanco et al., 2002). Given the predictable disadvantages of chronic BZD therapy, this class of medication should be used judiciously and reserved for treatment-refractory cases.
Several studies have investigated the role of anticonvulsants in social phobia and have yielded generally negative results. RCTs of levetiracetam, gabapentin, and pregabilin have failed to demonstrate superiority of these agents over placebo. A small amount of evidence exists for the atypical antipsychotic quetiapine in social phobia.
As with other anxiety disorders, CBT has been shown to be effective for patients with social phobia and should be considered as part of the treatment plan, particularly if first-line pharmacotherapy has been ineffective. An interesting and potentially important line of research focuses on using glutamate-based pharmacotherapy to enhance the effectiveness of CBT. An initial RCT conducted in 27 patients with social phobia investigated the efficacy of combining the glutamatergic N-methyl-d-aspartate (NMDA) receptor agonist d-cycloserine with exposure therapy and found that patients receiving d-cycloserine in addition to exposure therapy reported significantly less social anxiety compared with patients receiving exposure therapy plus placebo (Hofmann et al., 2006). While these results are preliminary and await replication, the strategy of leveraging pharmacotherapy to enhance learning-based treatments represents a novel and potentially powerful treatment approach to anxiety disorders in the future.
CONCLUSIONS AND FUTURE DIRECTIONS
Substantial progress has been made over the past several decades in the treatment of anxiety disorders. Large RCTs support the efficacy of SSRIs and in some cases SNRIs in the treatment of many of the anxiety disorders, including panic disorder, GAD, and social phobia. Second-, third-, or fourth-line agents for the different anxiety disorders include TCAs, MAOIs, BZDs, buspirone, anticonvulsants, or atypical antipsychotics wherein the evidence base is less than optimal. Despite their superiority compared with placebo, the effect sizes for first-line agents in most anxiety disorders are only modest, and a substantial number of patients suffering from anxiety disorders do not gain full relief from their symptoms with currently available treatments. In the case of PTSD, the situation is particularly concerning, and there is current uncertainty regarding the effectiveness of any medication in the treatment of this potentially disabling disorder. Taken together, improved treatments for anxiety disorders represent a critical unmet public health need.
Significant progress in neuroscience is illuminating potential new avenues of treatment discovery and novel targets from rational drug development. The rapidly developing neuroscience related to fear and anxiety is described in several chapters in the current volume, including Chapters 41, 42, 43, 44, 45, 48 and 49. Compounds with novel mechanisms of action currently in development for anxiety disorders include corticotropic releasing factor antagonists, neurokinin receptor antagonists, a variety of glutamate modulators, and glucocorticoid modulators. The endocannabinoid system has recently emerged as an interesting target in PTSD and other anxiety disorders. Continued progress in basic and translational neuroscience is expected to meet the need for new, more effective treatments for patients suffering from these disorders.
DISCLOSURES
Dr. Iosifescu has consulted for CNS Response, Inc. and has received grant/research support through Mount Sinai School of Medicine from Brainsway, Euthymics Bioscience Inc., Neosync, and Shire.
Dr. Murrough is supported by a Career Development Award from the National Institute of Mental Health (K23MH094707) and by the Brain and Behavior Research Foundation (NARSAD Young Investigator Award) and the American Foundation for Suicide Prevention.
Dr. Charney has been named as an inventor on a pending use-patent of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially.
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