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V. Review and Synthesis of Available Evidence

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A. Interpreting Results From Studies of Treatments for Panic Disorder

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1. Measurement of outcomes

In the following sections available data on the efficacy of treatments for panic disorder are reviewed. Short-term efficacy has usually been evaluated over the course of 6- to 12-week clinical trials by observing changes in the presence and severity of patient- and physician-rated panic and agoraphobic symptoms. Earlier studies have focused on the primary outcome of being free of DSM-defined panic attacks at the end of the study. However, patients labeled "panic free" are not necessarily free of all panic symptoms (i.e., symptom free). Some studies have shown that reductions in other dimensions (e.g., agoraphobic avoidance, functional impairment) are more important to overall improvement than reduction in panic frequency (74). Thus, the field has moved toward a broader definition of remission that includes substantial reductions in panic attacks, anticipatory anxiety, and agoraphobic avoidance, as well as a return to full function and good quality of life. One scale commonly used to examine this is the PDSS (51). Some definitions of remission have included a Clinical Global Impression (CGI) improvement rating of 1 or 2 (much or very much improved) and zero panic attacks (88, 557) or a CGI severity rating of 1 or 2 (borderline or not at all ill) and zero panic attacks at study endpoint (89, 558).

The long-term efficacy of treatments has been measured in terms of relapse rates among panic-free or symptom-free patients receiving treatment over the course of several years. A variety of definitions of relapse have been used, based on the emergence of a certain number of symptoms or based on the percentage of change in scores on symptom rating scales. In some studies, requests for or use of additional treatment have been considered indicative of relapse; whereas such outcome measures may reflect an intervention's effect on patient functioning as well as symptoms, they may also be affected by other clinical and nonclinical factors. Many studies report only short-term outcome. More studies that include longer follow-up periods of several years are needed in order to assess the potential of different treatments to produce sustained remission.

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2. Issues in study design and interpretation

When evaluating clinical trials of medications for panic disorder, it is important to consider the design of the study (e.g., whether a placebo-control group was used, the response rate in the placebo-control group) and the definitions of treatment response and remission (e.g., which outcome measures were selected). Response rates as high as 75% have been observed among patients receiving placebo in clinical trials of patients with panic disorder (106). Placebo response rates (often in the range of 40%–50%) could explain much of the observed treatment effect in uncontrolled trials or make significant treatment effects more difficult to detect in controlled trials. It is also important to consider the potential use of additional treatments that are not prescribed as part of the study protocol (e.g., psychotherapy, other medications that are not being directly studied) and whether these factors were rigorously assessed in the study.

Some randomized controlled studies of medications for panic disorder use an "active" comparator, which may be a medication or psychosocial intervention with prior evidence supporting its efficacy in panic disorder. Although these studies are useful for comparing the efficacies of interventions, the lack of a placebo group limits the ability to determine if either agent is more effective than placebo in particular study populations or with specific treatment characteristics (e.g., treatment length, clinical contacts). It is also important to consider the dose of medication(s) employed in pharmacological trials. Some studies are designed as "fixed-dose" studies, which require titration to a set dose regardless of patients' response or side effects. Such trials allow assessment of a specific dose but are theoretically more likely to result in study discontinuation for those who cannot tolerate the medication. "Flexible-dose" studies allow dose adjustment based on individual tolerability and response, as would be done in clinical practice, but do not permit comparison of the efficacy and tolerability of specific doses of medication.

When evaluating studies of psychosocial treatments, such as CBT, which consist of multiple components, it may be difficult to determine which components are responsible for producing beneficial outcomes. It is also important to consider the nature of the components that are used. For example, although the types of CBT used in some trials have been rigorously defined and have been similar, they have not been identical and have been usually derived from one of several related, but not identical, approaches (133, 136, 138). It is also important to note whether a specific treatment protocol has been used and whether efforts have been made to ensure that all study clinicians have demonstrated adherence to the protocol as well as competence in delivering the intervention. Finally, some trials of psychosocial treatments have employed waiting-list control groups, which only control for the passage of time and not for the "nonspecific" effects of treatment (e.g., the benefits of a therapeutic relationship, positive expectancies for change).

Another factor to consider is the use of medications that are not prescribed as part of the treatment protocol. For example, patients in studies of CBT may be using prescription medications that are not taken into consideration in the study design or statistical analysis. In addition, patients in medication studies may be taking additional doses of the tested medications or other antipanic medications (either explicitly, as doses taken as needed, or surreptitiously). Studies that monitor such occurrences have shown rates of surreptitious benzodiazepine use to be as high as 33% (278). Furthermore, there is growing interest in specifically examining the role of treatment for those who do not respond to initial treatments; these studies may add a second agent to an initial agent to which a patient has had minimal or partial response to examine the safety and potential additional benefit derived from the combination. These studies provide guidance only for the potential efficacy of the treatment as an adjunct to the specific prior type of treatment (e.g., as augmentation of CBT or SSRIs). There are few data examining "next step" interventions for individuals with panic disorder who do not respond or tolerate initial first-line treatment(s).

For all studies, it is important to understand the characteristics of the study participants. The demographic features of the sample and the inclusion/exclusion criteria are important to consider. No clinical trial adequately represents all patients with panic disorder, and some studies have specifically excluded patients with features (e.g., agoraphobia, depression, substance use disorders) that are frequently encountered in clinical practice.

Another issue important to understand when interpreting results of any study is the use of statistical testing. The traditional determination of statistical significance has been the p value, which is typically set at no higher than p <0.05 (i.e., an alpha of 0.05, representing a 5% probability that the rejection of the null hypothesis—that there was no difference between the treatments—was in error). It is important to note that as sample sizes become large, smaller absolute differences between the effects of agents on outcome measures are more likely to be statistically significant (i.e., achieve a p value 0.05); these differences may be statistically—but not necessarily clinically—significant. Similarly, small studies that fail to find a difference between two agents may not have had sufficient statistical power to detect such a difference. Under such circumstances, small randomized controlled trials with negative results cannot provide definitive conclusions. Further, findings from small studies are less reliable (i.e., if the same study is repeated with a different small sample of patients, the results are more likely to differ from those of the original study than if a very large study is repeated).

Some studies will also report an "effect size," which is another way to measure the magnitude of a difference between treatments in a trial with somewhat less dependence on sample size (559). Effect sizes can provide a common metric for comparing the magnitude of effects across studies. Psychiatrists should also look at the clinical significance of the level of improvement reported in a study (e.g., Were patients free of symptoms at the end of the study? Did they all improve significantly more with one treatment, but only by a very small amount that would not be clinically meaningful?).

Two final measures of effect that may be used in studies are the odds ratio and the "number needed to treat." The odds ratio provides a measure of the odds of one binary event occurring versus another (e.g., the ratio of the odds of achieving remission with treatment A, compared to the odds of achieving remission with treatment B). For example, an odds ratio of 2 in a study of the proportion of patients achieving remission with two different interventions would suggest that one intervention resulted in twice the odds of remission as the other. In general, an odds ratio of 1 implies the odds of the outcome are equal for the interventions, an odds ratio of less than 1 suggests the odds are less for the comparator treatment, and an odds ratio greater than 1 suggests the odds are higher for the comparator treatment. When interpreting odds ratios, it is also important to realize that this is not a measure of absolute difference. Thus, the odds may be represented as the proportion achieving remission divided by the proportion who do not (e.g., if 20% achieve remission with treatment A, the odds are 0.2/0.8 = 0.25, or 1 in 4 for treatment A; if treatment B has a 40% remission rate then the odds of achieving remission with treatment B are 0.4/0.6 = 0.67, or 2 in 3. The odds ratio for treatment B versus A would then be 0.67/0.25 = 2.7).

The number needed to treat is another measure of effect designed to give a sense of how many patients would need to be treated with the new intervention to achieve the desired outcome for one additional patient. For example, if 20% of the study population achieved remission with one intervention and 40% with the alternate intervention, the absolute difference would be 20%, or one of five additional patients achieving remission. Thus, from a public health point of view, to have one additional patient achieve remission with the novel intervention than would with the standard intervention, five patients would need to be treated. When using these measures to assess the benefit of a novel intervention clinically, the risks associated with the intervention (side effects, higher costs, etc.) should also be considered in a risk/benefit assessment. More information about odds ratios and number needed to treat can be found in standard epidemiological textbooks (for example, see reference 560).

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B. Specific Psychosocial Interventions

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1. Cognitive-behavioral therapy

There are numerous controlled trials demonstrating the efficacy of CBT for panic disorder (67, 111, 133–144), although specific CBT protocols used in clinical trials vary in their emphasis on different treatment components. Meta-analyses of clinical trials have concluded the effects of CBT for panic disorder are robust and durable (172, 561–564).

To date, the largest controlled efficacy trial of CBT for panic disorder included 312 panic disorder patients who were randomly assigned to five groups: imipramine, CBT, CBT and imipramine, CBT and placebo, and placebo (111). CBT consisted of 11 individual 50-minute sessions over 12 weeks. The imipramine treatment was slowly titrated up to a maximum of 300 mg/day. Response was defined as a 40% or greater reduction in symptoms on the PDSS (50). In this study, CBT (49% response) was superior to placebo (22%) at the end of the 12-week acute treatment phase. The response rate in the CBT group was statistically equivalent to that of the imipramine (46%), CBT plus placebo (57%), and CBT plus imipramine (60%) groups. At the end of the 6-month maintenance phase (in which responders were continued on their medication or on monthly CBT), CBT (40%) was again superior to placebo (13%) and equivalent to imipramine (38%). However, the combination of CBT and imipramine (57%) was significantly superior to all other treatment conditions, including CBT alone. Finally, at the end of the 6-month follow-up phase (during which patients were receiving no treatment), CBT (32%) and CBT plus placebo (41%) were the only two treatment conditions that were superior to placebo (9.1%). This study provided evidence for the short- and long-term efficacy of CBT. It further showed that CBT is largely equivalent in short-term efficacy to imipramine and combination treatments, and that it may produce more durable effects than imipramine or the combination of CBT and imipramine. See Section V.B.6 for further discussion of this study.

Several studies have examined the use of one component of CBT, situational exposure, specifically for patients with panic disorder who also have substantial agoraphobia (149, 184, 218, 565–568). These studies support the efficacy of exposure treatment in reducing panic and agoraphobic symptoms. Given the efficacy of exposure treatment, some investigators have questioned whether more elaborate protocols that include cognitive restructuring are necessary for treatment of panic disorder (especially when agoraphobic symptoms are the main problem). One comparative study showed similar rates of response for patients treated with exposure therapy alone and for those who received a CBT package that included both cognitive and exposure techniques (140).

Some CBT protocols teach breathing retraining as an anxiety management skill; however, the incremental benefit of this treatment component has been questioned in the literature (142, 175). In one study, 77 patients with panic disorder were randomly assigned to receive CBT with breathing retraining, CBT without breathing retraining, or a delayed-treatment control (175). Both forms of CBT were superior to the waiting-list condition on most outcome measures; however, CBT with breathing retraining was no better than the version of CBT without breathing retraining, despite the fact that patients learned an additional anxiety management skill. Moreover, at posttreatment the group that received CBT without breathing retraining was superior to the control group on 11 of 12 outcome measures, whereas the group that received CBT with breathing retraining was superior to the control group on only 8 of 12 outcome measures. Thus, breathing retraining did not contribute any incremental benefit over other CBT components, and there was some evidence that it was associated with poorer response (175).

Many patients who respond to short-term CBT (i.e., 10–15 sessions) experience long-lasting beneficial effects (111, 135, 569, 570). In the longest follow-up study to date, reported by Fava and colleagues (571), 200 consecutive patients with panic disorder were treated with 12 sessions of exposure therapy. Patients with co-occurring major depressive disorder, social phobia, and/or obsessive-compulsive disorder were excluded. Of the 200 patients, 165 were panic free after treatment, and 132 patients were available for follow-up between 2 and 14 years (median of 8 years). Twenty-three percent of the 132 patients had a relapse at some time during follow-up. These findings suggested that the majority of patients who responded acutely to exposure therapy experienced long-lasting maintenance of response. However, the conclusion may not be generalizable to patients with co-occurring conditions (e.g., depression), who were not represented in the study. Another limitation is that some patients (30%) were unable to fully taper benzodiazepines during the treatment period. Remission of symptoms therefore may not be completely attributable to the exposure therapy. However, use of benzodiazepines during exposure treatment predicted worse outcome in this sample, making it unlikely that medication effects explain the sustained remission in the majority of patients who responded well to exposure therapy.

Given the efficacy of 12 weekly sessions of CBT, there have been attempts to modify the treatment such that it can be delivered to a wider population of patients with panic disorder. Initial open-label and small randomized controlled trials have found that modified forms of CBT are efficacious. Studies have examined the impact of CBT delivered by telephone (184), assisted by a computer (186), using virtual reality (572), or given in a high-density format (i.e., several hours of therapy within a few days) (182, 183). There has been interest in reducing clinician time by having a computer assist in some of the routine components of CBT (139, 188, 189). Although some studies have reported similar efficacy between computer-assisted psychotherapy and therapist-conducted psychotherapy (186), other studies have not replicated these findings (139). Larger controlled trials are required.

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2. Psychodynamic psychotherapy

Support for psychodynamic psychotherapy targeting panic disorder includes observations of experts in psychodynamic therapy (145, 204, 205, 573), as well as uncontrolled studies and case reports (201, 204, 574–579) published over its long history of use. Published literature also discusses the theoretical rationale for applying psychodynamic principles in panic disorder treatment (205, 580–582).

More recently, manual-guided PFPP (145, 583, 584) has been shown to be efficacious in a randomized controlled trial (146). This controlled trial supported the efficacy of PFPP in reducing the severity of panic symptoms and improving psychosocial functioning and showed that these treatment gains were maintained at a 6-month follow-up. Forty-nine adult patients with panic disorder were randomly assigned to either PFPP (26 patients) or applied relaxation therapy (23 patients). Both groups received individual sessions twice weekly for 12 weeks. Panic-focused psychodynamic psychotherapy showed significantly superior reduction in panic symptoms measured by the PDSS (76% vs. 39%) and a greater reduction in functional impairment as measured by the Sheehan Disability Scale. These findings provide initial support for the use of PFPP as a treatment for panic disorder and suggest a need for further research in this area. It is unknown whether the positive results obtained with PFPP generalize to other forms of psychodynamic psychotherapy that are more commonly offered in the community (e.g., psychodynamic psychotherapy that has a broader focus).

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3. Eye movement desensitization and reprocessing

Originally developed as a treatment for posttraumatic stress disorder (206), EMDR involves reprocessing distressing memories while engaging in guided eye movement. It has been studied as a possible treatment for panic disorder in two trials. In the first study, 40 patients with panic disorder were randomly assigned to EMDR, a version of EMDR that excluded the definitive eye movement component (eye fixation exposure and reprocessing [EFER]), or a waiting-list control condition (207). At posttreatment, the EMDR group was superior to the waiting-list control group on all outcome measures but superior to EFER on only two of five outcome measures. By 3-month follow-up, with 28 patients remaining in the sample, EMDR and EFER were equivalent. Because subjects in the waiting-list control group were crossed over to an active form of treatment, no comparison with a waiting-list control condition was possible. Although EMDR was statistically superior to the control conditions at post-test, the researchers questioned the clinical significance of its effect because very few patients who received EMDR showed substantial functional recovery at follow-up (207). The second trial included 46 patients with panic disorder who were assigned to EMDR, a credible attention-placebo control, or a waiting-list control (208). In this study, EMDR was superior to the waiting-list control on only two of four outcome measures and was equivalent to the attention-placebo control. Investigators concluded that the results did not support the use of EMDR as a treatment for panic disorder.

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4. Group therapy

Reports in the literature of group therapy in the treatment of panic disorder have consisted primarily of cognitive-behavioral approaches. Evidence suggests that group CBT and individually administered CBT may be equally effective (137, 176–179). In one study, 67 patients with panic disorder were randomly assigned to group CBT or a delayed treatment control (137). At posttreatment, 64% of the group CBT participants met the criteria for remission (defined as attainment of normal functioning on measures of panic attacks, anxiety, and avoidance). Only 9% of the control group met the remission criteria at posttreatment. The remission rate reported in this study compares favorably to remission rates reported in trials of individually administered CBT and pharmacotherapy.

Mindfulness-based stress reduction, which includes training in meditation and relaxation strategies, is another group-based treatment that has a limited research base in relation to panic disorder. The effectiveness of this treatment was evaluated in one uncontrolled trial that included 22 patients with either panic disorder or generalized anxiety disorder (209). The 8-week program was associated with significant reductions in ratings of anxiety symptoms and panic attacks (209), and a 3-year follow-up study suggested that these benefits were maintained (210).

Other types of groups that are sometimes recommended to patients with panic disorder (e.g., medication support groups, consumer-run self-help groups) have not been evaluated empirically.

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5. Marital and family therapy

There are very few studies on the use of marital or family therapy alone for the treatment of panic disorder or agoraphobia. Findings from one very small comparative efficacy study that included 11 patients suggested that systems-oriented marital therapy was inferior to partner-assisted exposure therapy in reducing panic symptoms (211). In contrast, partner-assisted exposure therapy for panic disorder has been shown to reduce symptoms of panic disorder in several studies, at levels roughly comparable to individually administered exposure therapy (180). Some studies of group CBT have shown an advantage when partners were included in the treatment group, compared to when patients attended the group alone (177, 212, 213). Another study showed more benefits of adding couples-based communication training to exposure treatment compared to adding couples-based relaxation training to exposure treatment (214). Thus, some evidence exists that couples-based interventions can enhance response to exposure treatment and CBT (180). No empirical studies of the involvement of partners or family members in other types of treatment (e.g., pharmacotherapy) have been published.

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6. Combined treatments

Investigators have examined use of the combination of antidepressants and CBT for patients with panic disorder and agoraphobia. Some older studies that evaluated short-term efficacy showed that the combination of the TCA imipramine with one component of CBT, behavioral exposure, was superior to imipramine alone (152, 153) or exposure plus placebo (91, 150, 153). In studies using SSRIs, paroxetine plus CBT was statistically superior to CBT plus placebo on two of three outcome measures after acute treatment (69), and, in the short-term, fluvoxamine plus placebo was superior to exposure alone in the treatment of panic disorder with severe agoraphobia (68).

The largest randomized controlled trial to date that evaluated combination treatment included 312 panic disorder patients who were randomly assigned to five groups: imipramine, CBT, CBT and imipramine, CBT and placebo, and placebo (111) (also described in Section V.B.1). A 12-week acute-phase assessment demonstrated that the response rate for the combination of CBT and imipramine (60%) was superior to the response rate for placebo (22%) but statistically equivalent to the response rate for CBT alone (49%), imipramine alone (46%), and CBT plus placebo (57%). The combination of CBT and imipramine (57%) demonstrated a statistically significant advantage over CBT alone (40%), imipramine alone (38%), CBT plus placebo (47%), and placebo (13%) at the end of the 6-month maintenance phase. However, at the end of an additional 6-month follow-up phase (during which patients were receiving no treatment), the combination of CBT plus imipramine (25%) was equivalent to placebo (9%). Only CBT (32%) and CBT plus placebo (41%) were superior to placebo after treatment withdrawal. This study suggested a relatively modest benefit of combination treatment, which was apparent at the assessment point conducted after 6 months of maintenance treatment. This modest benefit must be considered alongside the evidence that simultaneously initiating medication and CBT may have negatively influenced the durability of the effects of CBT after all treatments were withdrawn. Of those who responded to acute treatment and were carried into the follow-up phase, CBT and CBT plus placebo were shown to have higher response rates than CBT plus imipramine (111).

Another randomized controlled trial, which included 154 patients, compared alprazolam plus exposure, alprazolam plus relaxation (psychosocial placebo), placebo plus exposure, and placebo plus relaxation (double placebo) (149). Among patients who received alprazolam, doses were titrated up to 5 mg/day. In the acute term, all four groups improved significantly on panic measures and were not statistically different. After treatment withdrawal, participants who received exposure plus alprazolam were less likely to maintain their response, compared to those who received exposure plus placebo (149).

A study of treatment for panic disorder in primary care that included 232 patients found that a collaborative-care intervention that included CBT plus pharmacotherapy was more effective than the usual care (i.e., pharmacotherapy alone) (157). Collaborative care included six sessions of CBT adapted for primary care (159) and algorithm-based pharmacotherapy. At 12-month follow-up, 68% of the patients in the collaborative-care group and 38% in the treatment-as-usual group met the criteria for response. The addition of CBT to medications led to statistically and clinically significant improvements, compared to medications alone (158).

A follow-up study looking at remission from panic disorder with agoraphobia after drug treatment in patients who received concurrent CBT appeared to show a long-term therapeutic advantage of integrated treatment over medication alone. Among 32 patients who received medication alone, 25 (65%) relapsed during the first year, whereas among 21 patients who received integrated treatment, only three (14.3%) relapsed (585).

The discontinuation of benzodiazepines, such as alprazolam or clonazepam, for patients with panic disorder is often accompanied by withdrawal symptoms and relapse into panic disorder. Several studies have shown that using adjunctive CBT in this clinical situation results in successful discontinuation of the benzodiazepine for significantly more patients (354–357).

There has been one study of the combination of psychodynamic psychotherapy with medication (156). Patients with panic disorder (with and without agoraphobia) were randomly assigned to receive clomipramine alone or clomipramine plus 15 sessions of psychodynamic psychotherapy. The combination treatment resulted in a significantly reduced relapse rate over 18 months, relative to the clomipramine monotherapy (156).

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C. Pharmacological Interventions

Medications have been known to be useful in the treatment of panic disorder for more than 40 years. Most studies have focused on their ability to stop or reduce the frequency of panic attacks, but many have also addressed the effect of medication on anticipatory anxiety, agoraphobic avoidance, limited symptom attacks, associated depression, and global function. Medications from several classes have been shown to be effective. When interpreting results from trials of pharmacological interventions, it is important to consider the study design and methods for measuring treatment outcome (see Section V.A) and the funding source of the study.

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1. Selective serotonin reuptake inhibitors
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a. Efficacy

Numerous clinical trials indicate that the SSRIs are effective for the acute and long-term treatment of panic disorder, although there is no clear evidence of differential efficacy among agents in this class. Whereas an early meta-analysis (586) suggested that the effect size for improvement with SSRIs in panic disorder was significantly greater than for alprazolam or imipramine, subsequent meta-analyses incorporating a larger number of SSRI studies demonstrated comparable efficacy for the SSRIs and TCAs, with mixed results regarding the question of whether dropout rates were lower in studies in which patients received SSRIs, compared to those for TCAs (587, 588).

Data from a number of large randomized controlled trials demonstrate the acute and long-term efficacy of fluoxetine for panic disorder (74, 80, 83). Results from one multicenter, double-blind, placebo-controlled study demonstrated that doses of both 10 mg/day and 20 mg/day were effective, although the 20 mg/day dose was more consistently effective across a variety of measures (74).

Results for a number of large randomized controlled trials demonstrate the efficacy of sertraline for the acute and long-term treatment of panic disorder (76–78, 82, 85). Results from a fixed-dose randomized controlled trial of 50 mg/day, 100 mg/day, or 200 mg/day of sertraline showed significantly greater reduction for the SSRI, compared to placebo, on measures of panic and anxiety, without evidence of a dose-response relationship (76).

Paroxetine, both in its immediate-release and controlled-release formulation, has demonstrated efficacy for the acute and long-term (immediate-release formulation) treatment of panic disorder in several large randomized controlled trials (69, 70, 72, 73, 79, 87). Ballenger and associates (73) compared placebo to three doses of paroxetine; the percentages of patients given paroxetine at daily doses of 40 mg, 20 mg, and 10 mg and patients given placebo who were subsequently panic free were 86%, 65%, 67%, and 50%, respectively. Only the difference between 40 mg/day of paroxetine and placebo was statistically significant.

Several randomized controlled trials of fluvoxamine for panic disorder have also been published, with most (66–68, 84), although not all (256, 589), demonstrating efficacy of this agent for panic disorder. In one study (66), a greater proportion of patients who had been given fluvoxamine became panic free, compared with those who received placebo (61% vs. 36%). Fluvoxamine has been shown to be effective in doses from 100 mg/day to 300 mg/day (84).

Citalopram has also demonstrated acute and long-term efficacy for panic disorder in large randomized controlled trials (71, 75, 81, 86). In one double-blind trial in which 475 patients were randomly assigned to receive citalopram (10–15 mg/day, 20–30 mg/day, or 40–60 mg/day), clomipramine (60–90 mg/day), or placebo, citalopram at 20–30 mg/day or 40–60 mg/day was significantly superior to placebo; citalopram at 20–30 mg/day was more effective than 40–60 mg/day and comparable to clomipramine (71). In one 10-week, double-blind, randomized controlled trial of escitalopram and citalopram, administration of escitalopram led to a significantly greater reduction in panic frequency, compared to placebo, and had comparable overall efficacy to citalopram (86).

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b. Implementation issues
+ 1. Side effects

The concerns and debate regarding the relationship between antidepressants and increased suicidality have already been reviewed (see Section II.H).

There is accruing evidence for a discontinuation syndrome caused by the abrupt discontinuation of SSRIs (85, 258, 259). Although most evidence comes from studies of patients who are being treated with SSRIs for depression, Black and colleagues (67) studied the effect of abrupt withdrawal of fluvoxamine from patients with panic disorder after 8 months of treatment. A discontinuation syndrome characterized by dizziness, incoordination, headache, irritability, and nausea began within 24 hours, peaked at day 5 after withdrawal, and was generally resolved by day 14.

+ 2. Length of treatment

There are few data on the optimum length of treatment following response. Gergel and associates (342) selected patients who had responded to paroxetine in an acute-phase trial and randomly assigned them to receive placebo or 10 mg/day, 20 mg/day, or 40 mg/day of paroxetine for a 12-week maintenance period. After the maintenance phase, the rate of relapse was significantly higher among the responders who had crossed over to placebo than among those whose paroxetine treatment had been maintained (30% vs. 5%).

LeCrubier and associates (70) evaluated the efficacy of paroxetine, clomipramine, and placebo for patients who completed a 12-week double-blind trial and then chose to continue receiving the randomly assigned treatment for an additional 36 weeks. Compared with the placebo-treated patients, the patients who received paroxetine experienced significantly greater reductions in panic symptoms, and a larger proportion remained free of panic attacks throughout the long-term study. There were no significant differences in efficacy between paroxetine and clomipramine.

Rapaport and associates (85) examined the long-term efficacy of sertraline in the treatment of panic disorder. Patients received 52 weeks of open-label sertraline treatment followed by a 28-week, double-blind, placebo-controlled discontinuation trial. Compared to those blindly tapered and switched to placebo, patients who continued to receive sertraline were less likely to have an exacerbation of panic symptoms (13% vs. 33%) or discontinue the study because of insufficient clinical response (12% vs. 24%).

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2. Serotonin-norepinephrine reuptake inhibitors

Three large, international, randomized controlled trials have been performed that together provide support for the efficacy and safety of venlafaxine ER for panic disorder. In a multicenter study of 361 individuals with panic disorder without co-occurring depression, the intent-to-treat population consisted of 160 participants who were randomly assigned to receive a 10-week course of venlafaxine ER flexibly dosed from 75 mg/day to 225 mg/day (initiated at 37.5 mg/day for 4 days) and 168 participants who were randomly assigned to receive matched placebo (88). Although this study failed to find a statistically significant difference between venlafaxine ER and placebo on the a priori primary endpoints (CGI severity rating and proportion of participants free of panic attacks at study endpoint), there was a significantly greater reduction in panic attacks, with overall improvement as rated by the CGI improvement rating and remission at endpoint (defined as a CGI improvement rating of 1 or 2 and no panic attacks) for the venlafaxine ER group. In a second multicenter randomized controlled trial, which included 664 individuals with panic disorder without co-occurring depression, participants were randomly assigned to receive venlafaxine ER at fixed doses of 75 mg/day or 150 mg/day, paroxetine at 40 mg/day, or placebo for 12 weeks after a 2-week placebo lead-in period (89). All active treatments were found to be significantly more effective than placebo, with no significant difference between the venlafaxine ER doses or paroxetine and somewhat less sedation with the venlafaxine ER doses (3% and 4%) than with paroxetine (13%). In a third multicenter randomized controlled trial, which included 653 individuals with non-co-occurring panic disorder, participants were randomly assigned to receive 225 mg/day of venlafaxine ER, 75 mg/day of venlafaxine ER, 40 mg/day of paroxetine, or placebo for 12 weeks after a single-blind placebo lead-in (590). In this study, a significantly greater proportion of patients receiving the active medications were panic free and in remission (defined as a CGI severity score of 1 or 2 or zero panic attacks) at endpoint and had greater response from weeks 2 or 3 onward as measured by the CGI improvement rating. All active treatments were generally well tolerated.

An additional study examined the ability of venlafaxine ER to prevent relapse in individuals whose panic disorder symptoms had responded to a 12-week course of flexibly dosed (75–225 mg/day) venlafaxine ER (344). Of the 89 individuals who had been randomly assigned to receive venlafaxine ER, time to relapse was significantly longer than in the 80 individuals assigned to receive placebo. During the 26-week follow-up period, secondary measures of therapeutic efficacy, including quality of life and disability, also showed a significant benefit for venlafaxine ER treatment, relative to placebo.

There are currently no systematic data available on the use of duloxetine in panic disorder, although its similar mechanism of action to venlafaxine suggests it could be a potentially effective agent.

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3. Tricyclic antidepressants
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a. Efficacy

The first controlled study documenting the efficacy of the TCA imipramine in blocking panic attacks was conducted by Klein and published in 1964 (90). In this study, imipramine was superior to placebo for antipanic effect and for change in the CGI. Since then, numerous controlled trials have shown that imipramine is effective in reducing panic attacks (91, 92, 94–102, 104, 105, 107, 108, 111). After treatment with imipramine, 45%–70% of patients were found to be panic free, compared to 15%–50% of those receiving placebo. In addition, patients with panic disorder who were treated with imipramine had less agoraphobic avoidance and anticipatory anxiety than those receiving placebo.

A number of placebo-controlled randomized trials have documented the acute and long-term efficacy of clomipramine for panic disorder (70, 72, 79, 103, 109, 110). Clomipramine appears at least as effective as imipramine for panic disorder (93); in the one double-blind, placebo-controlled study addressing this issue, clomipramine (mean dose of 109 mg/day) was superior to both imipramine (mean dose of 124 mg/day) and placebo in panic reduction and decrease in score on the Hamilton anxiety scale (102). Most placebo-controlled studies comparing clomipramine to an SSRI demonstrate equivalent efficacy, although with a less favorable side effect profile for the TCA.

The few studies that have evaluated other TCAs for panic disorder support the efficacy of desipramine (106) and nortriptyline (112). However, randomized trials comparing desipramine with clomipramine (591) and maprotiline with fluvoxamine (272) both found the more noradrenergic TCA to be less effective than the serotonergic comparator.

+
b. Implementation issues
+ 1. Side effects

Several research studies have shown that some patients with panic disorder are sensitive to both the beneficial and adverse effects of TCAs (91, 106). For example, Zitrin and associates (91) found that 20% of the patients in their study could not tolerate doses of imipramine higher than 10 mg/day but still experienced panic blockade. Higher doses of TCAs are associated with a higher dropout rate in research studies. For example, Mavissakalian and Perel (108) reported that among subjects treated with an average of 35 mg/day, 99 mg/day, and 200 mg/day of imipramine, the dropout rates because of drug side effects were 6%, 15%, and 36%, respectively.

+ 2. Dose

Few studies have rigorously addressed the optimum dose of TCAs for panic disorder. In most research studies, the mean final dose is approximately 150 mg/day of imipramine and the maximum final dose is up to 300 mg/day. Mavissakalian and Perel (108) randomly assigned patients with panic disorder to low-dose (mean, 35 mg/day), medium-dose (mean, 99 mg/day), and high-dose (mean, 200 mg/day) imipramine. They found that both the medium and high doses were superior to placebo in reducing panic and not significantly different from each other; the low dose was no more effective than placebo.

There is a suggestion in the literature that clomipramine may be effective in somewhat lower doses than imipramine. Clomipramine can generally be used effectively with doses less than 150 mg/day. Given the results of the studies by Modigh and associates (102) and Cassano and colleagues (93), it may be reasonable to administer clomipramine in a dose range of 25–150 mg/day.

+ 3. Length of treatment

Most controlled trials of TCAs for the treatment of panic disorder were for a minimum of 8 weeks, and time to patients' response has not always been reported. There are few long-term studies of TCA treatment for panic disorder in the literature. Cassano and colleagues (99) continued to treat patients with imipramine or placebo for 6 months after an acute-phase 8-week study and found that imipramine remained superior to placebo for panic reduction. Curtis and associates (104) also maintained patients on a regimen of placebo or imipramine for up to 8 months after acute 8-week treatment and found that the placebo-treated patients had more panic attacks and agoraphobic avoidance and were more likely to drop out of treatment during the maintenance phase. The limited available data are mixed about whether patients who remit during treatment benefit more from over a year of subsequent treatment, compared with 6 months of continued pharmacotherapy prior to discontinuation (343, 592, 593). In one study that examined the impact of longer-term treatment with imipramine on relapse, relapse rates for a combined group of patients who were randomly assigned to receive placebo discontinuation or open discontinuation after 12–30 months of remission were compared with relapse rates for patients randomly assigned to placebo discontinuation after 6 months of remission (592). The rates of reported relapse were nearly identical for the two groups (37%) during the follow-up period after discontinuation, suggesting that the achievement of remission prior to treatment discontinuation may be a more critical determinant in preventing relapse than the subsequent duration of maintenance therapy.

+
4. Benzodiazepines
+
a. Efficacy

Alprazolam has been studied more extensively than any other benzodiazepine for the treatment of panic disorder and is approved by the FDA for the treatment of panic disorder. Eleven trials of alprazolam IR for treatment of panic disorder have been published, including the Cross-National Collaborative Panic Study, which involved more than 1,000 patients randomly assigned to receive imipramine, alprazolam, or placebo (594). Nine of the trials were double-blind, and seven were placebo-controlled. Two meta-analyses of studies on alprazolam treatment for panic disorder are also available (402, 586).

In six of the seven double-blind, placebo-controlled trials, alprazolam was found to be superior to placebo in the treatment of panic attacks (104, 116, 118, 122, 123, 126), although the remaining trial did not assess panic attacks as an outcome measure (276). The percentage ranges of patients who were panic free (generally assessed over a 1-week period) at endpoint were 55%–75% for alprazolam (at doses of 5–6 mg/day) and 15%–50% for placebo. These percentages represent the intent-to-treat proportions (i.e., the panic-free proportion of patients who were originally assigned to receive active treatment or placebo at the start of the trial); the differences between the completers were less striking or nonsignificant because of higher dropout rates for the nonresponders in the placebo groups. Alprazolam was superior to placebo in reducing agoraphobic avoidance in five of the six studies in which it was assessed, disability in five of five studies, anticipatory anxiety in three of three studies, and Hamilton anxiety scale scores in six of seven studies. In most of the studies, patients with primary current major depression were excluded and the level of agoraphobic avoidance was moderate.

Four of the 11 trials compared alprazolam to imipramine (104, 126, 221, 594). Three of these trials were double-blind. Alprazolam and imipramine were comparable in efficacy as measured by reduction of panic attacks and phobias, Hamilton anxiety scores, disability ratings, and CGI ratings. More dropouts occurred in the imipramine group in three of the four studies.

These data support the efficacy of alprazolam (especially in the 5–6 mg/day range) in treating multiple dimensions of illness in patients with panic disorder who do not have primary current major depression. A sustained-release form of alprazolam is FDA-approved for once-daily dosing based on two placebo-controlled studies (125, 129).

Fourteen studies regarding other benzodiazepines have also been published (113–117, 119–122, 124, 127, 128, 130–132). These studies support the short-term efficacy of other benzodiazepines for panic disorder. The agents studied include clonazepam (effective in the three double-blind, placebo-controlled trials and the only other FDA-approved benzodiazepine besides alprazolam), diazepam (effective in two of two trials, both double-blind and one placebo-controlled), and lorazepam (equivalent to alprazolam in three of three double-blind trials). One study showed superiority of imipramine over chlordiazepoxide.

Three controlled trials have established that the short-term (4–6 week) addition of benzodiazepines (alprazolam and clonazepam) to antidepressants produces a more rapid therapeutic response (100, 222, 223). Whereas no discontinuation problems were reported in the two studies using the longer half-life clonazepam added to an SSRI and a 3-week taper (222, 223), 10 of 17 patients in the alprazolam study were unable to taper from 1.5 mg/day to discontinuation in 2 weeks after 4–6 weeks of treatment added to imipramine (100).

+
b. Implementation issues
+ 1. Side effects

The adverse effects of benzodiazepines in patients with panic disorder appear similar to those reported when benzodiazepines are used for other indications. They include primarily sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness. Some sedation or drowsiness occurred in 38%–75% of alprazolam-treated subjects and 11%–21% of those taking placebo. In addition, an increased risk of motor vehicle accidents in association with benzodiazepine use has been reported (288). In geriatric patients, the risk of falls and fractures appears to be greater in individuals taking a benzodiazepine, regardless of the medication half-life or duration of use (283–287, 295, 458, 595, 596).

Memory problems were reported by up to 15% of patients taking alprazolam and 8.5% of patients taking placebo in the Cross-National Collaborative Panic Study (101). However, patients may not recognize their own cognitive impairment, which limits spontaneous reporting of this side effect and has prompted several controlled studies to more systematically investigate the cognitive effects of these agents in people with panic disorder. Two placebo-controlled studies have examined the effects of alprazolam on short-term memory at baseline and in the acute (8–12 week) treatment phase in small samples of patients with panic disorder (about 20 patients per group). In one study using alprazolam IR at a mean dose of 5.5 mg/day, some evidence of memory impairment was found (292), whereas no evidence of memory impairment was found in another study using alprazolam extended release at a mean dose of 4 mg/day (293). A follow-up of the positive study found that, 3.5 years after discontinuation, there were no long-term memory deficits, suggesting that there is no carryover effect after medication has been discontinued (597). Two other reports, one meta-analysis (598) and one review (296), do not provide convincing evidence of long-term cognitive effects of benzodiazepines in mixed groups of patients because of the spotty nature of the findings and because many studies have serious methodologic flaws.

Major concerns about benzodiazepine tolerance and withdrawal have been raised. However, according to the report of the APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse, "There are no data to suggest that long-term therapeutic use of benzodiazepines by patients commonly leads to dose escalation or to recreational abuse" (294). The studies of long-term alprazolam treatment for panic disorder show that the doses patients use at 32 weeks of treatment are similar to those used at 8 weeks, indicating that, as a group, patients with panic disorder do not escalate alprazolam doses or display tolerance to alprazolam's therapeutic effects, at least in the first 8 months of treatment. Furthermore, data in the more severely ill Medicaid population with a mix of mostly mood and anxiety disorder diagnoses show that long-term use of benzodiazepines (at least 2 years) does not typically result in dose escalation, with the incidence of escalation to a high dose being 1.6% (346). Nevertheless, studies of dose escalation following longer periods of benzodiazepine use, especially in specific cohorts of patients with panic disorder, are lacking, making it difficult to draw definitive conclusions about the potential for benzodiazepine tolerance in the clinical treatment of panic disorder.

In terms of the occurrence of benzodiazepine withdrawal symptoms, studies of alprazolam discontinuation in patients with panic disorder demonstrated that significant numbers (ranging from 33% to 100%) are unable to complete a taper of the medication after 6 weeks to 22 months of treatment. Another study showed that, compared with imipramine, alprazolam causes significantly more withdrawal symptoms, recurrent panic attacks, and inability to discontinue the medication (351). An additional study suggested that patients with panic disorder have more difficulty during tapering of alprazolam than do those with generalized anxiety disorder, even when the patients in both groups are treated with similar doses (599). Difficulties during alprazolam tapering seem most severe during the last half of the taper period and the first week after the medication is discontinued. In many instances, it is difficult to determine the extent to which symptoms are occurring because of withdrawal, rebound, or relapse.

The one study comparing diazepam to alprazolam for panic disorder indicated that both are no different from placebo during gradual tapering of the first half of the dose (600). With abrupt discontinuation of the remaining dose, however, alprazolam caused significantly more anxiety, relapse, and rebound. This finding is consistent with reports of the APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse (294), which suggest that there are more difficulties with short half-life, high-potency compounds. However, apart from this one study, the issue of discontinuation of benzodiazepines with short versus long half-lives or high versus low potency has not been adequately addressed in relation to panic disorder. In addition, studies by Schweizer, Rickels, and associates (126, 351) of benzodiazepine-treated patients with other psychiatric disorders show no significant effect of half-life on the results of a gradual taper, but greater withdrawal severity after abrupt discontinuation with compounds that have shorter half-lives and with higher daily doses. Taken together, these studies suggest that half-life is less of a factor, or in fact may not be important, given a gradual taper schedule.

Other data suggest that certain personality traits may increase the likelihood of discontinuation effects in panic disorder patients. In one study of 123 patients with panic disorder, after accounting for the effects of dose and duration of alprazolam use, as well as pretreatment anxiety and panic frequency, measures of anxiety symptom sensitivity and avoidance predicted difficulty discontinuing alprazolam during a tapered, gradual withdrawal process (353).

+ 2. Dose

Very few studies have empirically evaluated dosing of benzodiazepines for panic disorder. Two studies compared alprazolam doses of 6 mg/day and 2 mg/day (95, 278). One of the studies showed a significant advantage for the higher dose in reducing frequency of panic attacks (95). The other study showed very little difference between the higher and lower doses; absence of panic attacks at study end was found for 65% of patients taking the higher dose, 50% of those taking the lower dose, but only 15% of those taking placebo (278). However, the rates of surreptitious benzodiazepine use for the lower-dose (23%) and placebo (35%) patients were considerably greater than the rate for the patients taking the higher alprazolam dose (4%) (278), perhaps suggesting that the patients did not find the lower dose or placebo clinically effective. In addition, adverse side effects were more pronounced at the higher dose than at the lower dose of alprazolam in that study.

In one multicenter dose-ranging trial, patients with panic disorder were randomly assigned to placebo or one of five fixed doses (0.5 mg/day, 1 mg/day, 2 mg/day, 3 mg/day, or 4 mg/day) of clonazepam (601). During 6 weeks of treatment, the minimum effective dose was 1 mg/day, and daily doses of 1 mg/day and higher were equally effective in reducing the number of panic attacks.

The dosing of other benzodiazepines in the treatment of panic disorder is less well established. In controlled studies, lorazepam has been given at doses of about 7 mg/day, usually two or three times daily (119, 128). Diazepam doses ranged from 5 mg/day to 40 mg/day in two published trials (115, 116).

+ 3. Length of treatment

Very few data indicate the optimum length of maintenance therapy for responders to benzodiazepines. Two published trials have compared maintenance imipramine, alprazolam, and placebo treatment, and both suggested that imipramine may be superior. In the study by Cassano and colleagues (99), patients who received imipramine and those who received alprazolam fared equally well in terms of panic reduction during a 6-month maintenance phase, but the imipramine-treated patients had less agoraphobic avoidance. There were more dropouts in the alprazolam group during the maintenance phase than during the 8-week acute treatment phase, whereas the number of dropouts in the imipramine group did not differ between the two phases. Curtis and associates (104) found that from month 4 through the end of an 8-month maintenance phase patients taking imipramine had virtually no panic attacks, whereas alprazolam-treated patients continued to experience infrequent panic attacks. On all other measures, however, the two medications performed equally well. In a third investigation by Lepola and colleagues (602), 27 patients who had been treated with alprazolam and 28 patients who had been treated with imipramine in a 9-week trial were then followed for 3 years in a naturalistic study. Significantly more alprazolam users than imipramine users were found to still be using their original medication after 3 years (74% vs. 32%). The authors pointed out that it is difficult to know whether this difference is attributable to a better long-term response among the imipramine users than among the alprazolam users, a greater degree of intolerable side effects for the imipramine users, or greater difficulty in discontinuing treatment among the alprazolam users because of physiologic dependence.

+
5. Other antidepressants
+
a. Monoamine oxidase inhibitors

No studies of the nonselective MAOIs phenelzine and tranylcypromine have been performed since the diagnosis of panic disorder was introduced in DSM-III. The most modern and rigorous study (603) involved the use of phenelzine for the treatment of "phobic neurosis" (604). This study included patients with what would now be called panic disorder and found phenelzine to be effective (297).

Four studies have examined the effectiveness of moclobemide, a reversible inhibitor of monoamine oxidase A, in panic disorder, and the results are only modestly encouraging. Although two studies with active comparators, but no placebo, showed comparable efficacy to both fluoxetine (298) and clomipramine (299), respectively, the only two published placebo-controlled studies of this medication failed to show an effect greater than placebo (300, 301). Although the MAO-B inhibitor selegiline is available in the United States, there are no data to support its efficacy for the treatment of panic disorder.

+
b. Trazodone

There is minimal support for the use of trazodone in panic disorder. Although a single-blind study of 11 patients with panic disorder treated with trazodone found significant improvement in panic symptoms compared to a baseline period of placebo treatment (307), a double-blind study in which 74 patients with panic disorder were assigned to trazodone, imipramine, or alprazolam showed trazodone to be less effective than either imipramine or alprazolam (221). Further, a study of trazodone flexibly dosed from 50 mg/day to 300 mg/day (mean, 178 mg/day) alone and as augmentation to CBT failed to show greater efficacy with trazodone or combination therapy than with CBT alone, and patients who took trazodone had greater rates of side effects and study discontinuation (308).

+
c. Bupropion and bupropion sustained release

Bupropion has been found to be effective in the treatment of depression, but there is little systematic study of its efficacy in panic disorder, and the available data are contradictory. Two small uncontrolled trials have been published, one positive and one negative. In the positive trial, which included 20 patients, bupropion sustained release flexibly dosed at 200 mg b.i.d. was effective and well tolerated (313). In the negative trial, which included 12 patients, bupropion immediate release at high doses of 300–700 mg/day was associated with significant side effects, including myoclonus and one seizure (314).

+
d. Nefazodone

Although there are a few small, positive open-label reports examining nefazodone in panic disorder, large randomized controlled trials are lacking (605), and there are concerns about liver toxicity (309–311).

+
e. Mirtazapine

Although there are a few open short-term studies supporting the potential efficacy of mirtazapine for panic disorder (315–319) and a very small randomized controlled trial (involving 27 patients) of mirtazapine compared with paroxetine suggesting similar efficacy (320), substantial side effects have been noted, and no data from large randomized controlled trials are available.

+
f. Reboxetine

Reboxetine, a norepinephrine reuptake inhibitor, is currently not available for use in the United States or Canada. Reboxetine has been studied with preliminary support for its efficacy and safety in a small randomized controlled trial involving 42 patients in Europe and Brazil (606) and an open-label trial for resistant patients (607), with mixed support in single-blind comparison with SSRIs (608, 609).

+
6. Other agents
+
a. Anticonvulsants

There are limited data concerning the use of anticonvulsant medications in the treatment of panic disorder. One randomized controlled trial of gabapentin in 103 patients with panic disorder provided partial support for its efficacy and safety (321). The only other randomized study, a small placebo-controlled trial, suggested that carbamazepine was not effective for panic disorder (328). Data from small open-label studies support the efficacy of valproic acid (322–324) and levetiracetam (326), and very preliminary case report data support the efficacy of tiagabine (327) and vigabatrin (327), but more rigorous studies of these medications are needed.

+
b. Antipsychotic agents

There is minimal evidence that first-generation antipsychotic medications are effective for panic disorder. In small open-label trials, significant reductions in symptoms were observed in patients with treatment-resistant panic disorder treated with olanzapine (329) and adjunctive risperidone (330). Double-blind, randomized controlled trials are needed.

+
c. Antihypertensives

A limited number of trials of antihypertensive medications have been conducted in panic disorder. Results with beta-adrenergic blocking agents are mixed but suggest that propranolol offers peripheral blockade but is ineffective and/or less effective than benzodiazepines (115, 332, 333). A single small, 4-week, randomized controlled trial that included 25 patients supported the potential efficacy of pindolol, dosed 2.5 mg t.i.d., as augmentation for patients with panic disorder resistant to 8 weeks of treatment with an SSRI (334). Data are even more limited for calcium channel blockers (335) and clonidine (336, 337) and suggest only mild and/or transient effects, if any, for panic disorder.

+
d. Inositol

Although inositol is rarely used clinically for panic disorder, two small studies have supported its potential efficacy in treatment of panic disorder (216, 217).

+
e. Buspirone

Minimal data are available on the use of buspirone in panic disorder, and no systematic controlled trials support its efficacy. Two reports suggest that buspirone monotherapy is not effective for panic disorder (338, 339), and a randomized controlled trial examining augmentation of CBT does not suggest additional efficacy with buspirone (340).

References

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