Treatment Planning for Panic Disorder

Psychiatric TimesPsychiatric Times Vol 25 No 2
Volume 25
Issue 2

Panic disorder with or without agoraphobia is a chronic, debilitating psychiatric illness that affects about 4.7% of the general US population.

Panic disorder with or without agoraphobia is a chronic, debilitating psychiatric illness that affects about 4.7% of the general US population.1 Kessler and colleagues2 report that close to one third of the general population has met criteria for panic disorder within the past year.2 The mean age at onset is in one's 20s, and women are twice as likely as men to present with panic disorder.3

Panic disorder is associated with poor quality of life4,5 and with substantial and moderately severe functional impairment in 45% and 30% of persons, respectively.2 Many patients have at least one other psychiatric diagnosis, most commonly substance use disorder, mood disorder, or another anxiety disorder.3 Panic disorder is associated with a 2-fold increased risk of coronary heart disease6 and frequent use of emergency and medical services.7,8

Despite its chronic nature and severity of illness, many patients do not receive therapy that meets standard treatment guidelines.3 In the primary care setting, only 22% of patients with panic disorder receive adequate medication and only12% receive adequate psychotherapy.8 The purpose of this brief report is to increase the awareness of evidence-based treatments for panic disorder.

Evaluation and differential diagnosis

Patients should be thoroughly evaluated to eliminate any conditions that may mimic symptoms of panic disorder, including medical illnesses (eg, cardiac, respiratory, or thyroid diseases) and substance use (eg, marijuana, cocaine, methamphetamines). One of the core symptoms of panic disorder is recurrent, unexpected panic attacks. A full-symptom panic attack requires the abrupt onset of at least 4 physical symptoms (eg, palpitations or dizziness) or cognitive symptoms (eg, fear of going crazy or losing control) that reach a peak within 10 minutes. Another core feature is anticipatory anxiety about future panic attacks or the implications of these attacks. This often leads to agoraphobia in which the person avoids situations where escape or help is not readily available if a panic attack occurs. Thus, expected, or cued, panic attacks can be triggered by the anticipation or presence of a phobic situation.

Panic attacks and phobic avoidance are also present in other anxiety disorders, and examining the focus of the patient's fear helps in the differential diagnosis. According to the cognitive model of panic disorder, panic attacks are the result of catastrophic misappraisals of bodily sensations.9 The focus of fear is the perceived harmful consequence of panicking (eg, losing control, going crazy, and so forth) and the associated physical sensations (eg, having a heart attack or stroke). In other anxiety disorders, the fear is not of the panic attacks themselves. In generalized anxiety disorder, for example, panic attacks are the exacerbation of persistent worries and anxiety about daily life events and the anticipation of future bad events. Panic attacks in social anxiety disorder are limited to the anticipation or presence of social or performance situations caused by fear of embarrassment or humiliation. Panic attacks in posttraumatic stress disorder are triggered by reminders of the traumatic event. In specific phobia, the focus of fear is often the perceived danger of the object or situation.10

Acute treatment

Cognitive-behavioral therapy (CBT) and pharmacotherapy are among the empirically supported treatments for panic disorder.

Defining treatment response and remission

Treatment response is usually defined by a "panic-free" status that is the absence of full-symptom panic attacks. Other measures include clinician's ratings of overall improvement and severity on the Clinical Global Impression (CGI) scale11 and changes in panic symptoms in the Panic Disorder Severity Scale (PDSS).12 Remission has been defined in one of several ways. The international consensus group considers remission as the complete resolution of symptoms for at least 3 months.13 However, most pharmacotherapy studies have defined remission by using a combination of panic-free status and improved CGI and/or PDSS scores. CBT trials have focused on rates of "clinically significant improvement," such as achieving high end-state functioning14 or meeting the criteria developed by Jacobson and colleagues.15

Cognitive-behavioral therapy

Treatment components of CBT include education, breathing retraining, cognitive restructuring, interoceptive exposure, and in vivoexposure.16,17 Education helps establish treatment alliance and teach key concepts, including the course of panic disorder, the nature of panic attacks, behaviors that maintain the panic cycle, the cognitive model, and the treatment rationale. Breathing retraining was initially thought to reduce physical symptoms of panic, but it was later conceptualized as a way to demonstrate how hyperventilation can exacerbate physical symptoms.18

The goal of cognitive restructuring is to identify and challenge anxious thoughts regarding a panic attack. In interoceptive exposure, patients perform various exercises (eg, hyperventilation, spinning in a chair) in a controlled setting in order to repeatedly confront anxiety-provoking physical symptoms. With exposure, patients learn that symptoms are not as dangerous as originally perceived. In vivo exposure traditionally has been used in the treatment of agoraphobia. During in vivo exposure, patients confront the actual phobic situation, such as traveling alone or being in an airplane or elevator. These treatment components are based on 2 CBT approaches to panic disorder: panic control treatment (PCT) developed by Barlow and colleagues,16 which introduced interoceptive exposure as a key element; and the cognitive therapy (CT) program developed by Clark,9 which emphasized cognitive restructuring.

In the first controlled trial of PCT (N = 56), 3 active treatments-PCT, muscle relaxation, and PCT plus muscle relaxation-were compared with wait-list controls.16 PCT outperformed the other treatment conditions. Approximately 87% of patients in the PCT groups, 60% of patients who received muscle relaxation, and 36% of controls were panic-free at the end of their respective treatments. There was a greater distinction when patients who had dropped out were included in the analysis: 74% to 79% of PCT patients, 40% of patients who received muscle relaxation, and 33% of controls were panic-free. However, only 46% of patients who were treated with PCT achieved high-end functioning, despite the high panic-free status associated with this group. This suggests that many patients were still symptomatic at the end of treatment.

A controlled study of 2 versions of CT (N = 42) showed favorable results. A full 12-session and a brief 5-session course of CT were compared with wait-list controls.19 A greater proportion of patients who received CT had panic-free status relative to controls; 79% in the 12-session CT group, 71% in the 5-session CT group, and 8% in the control group had panic-free status. Thus, the investigators concluded that brief intervention was as effective as full 12-session treatment.

Other randomized controlled studies have confirmed the efficacy of CBT for panic disorder, with findings of panic-free status achieved in approximately 70% to 90% of patients.17,20-22 Rates of clinically significant improvement were found to be 38% to 79%, depending on the criteria used.23-25

Dismantling studies have attempted to determine which treatment component is the "active" ingredient or the most effective intervention. With the exception of breathing retraining, which was not shown to be helpful and may possibly increase the risk of relapse,24 the other 3 main interventions-cognitive restructuring, interoceptive exposure, and in vivoexposure-have been shown to be equally effective.23,26-28


Several classes of psychotropics have been shown to be effective and have comparable efficacy in the treatment of panic disorder, including tricyclic antidepressants (TCAs), benzodiazepines, and SSRIs.29-34 SSRIs are now considered first-line pharmacotherapy because of a more favorable adverse-effect profile than with TCAs30 and less concern for withdrawal and dependence than with benzodiazepines.35 Based on clinical practice, SSRIs are generally started at one half to one third of the typical starting dose for depression to limit the adverse effects of jitteriness and anxiety.36 Benzodiazepines are better tolerated than antidepressants and may help with adverse effects.33Table 1 presents common adverse effects and suggested dosages.

On average, 55% to 60% of patients treated with pharmacotherapy achieve panic-free status.30,33 Efficacy data are most extensive for imipramine, fluvoxamine, paroxetine, and alprazolam. There is relatively less controlled data for monoamine oxidase inhibitors, the newer SSRI escitalopram, and the serotonin-norepinephrine reuptake inhibitor venlafaxine. Studies have shown either minimal or modest efficacy for the newer drugs.37,38

A recent placebo-controlled trial compared the efficacy of venlafaxine extended release (ER) with that of paroxetine.39 Venlafaxine ER and paroxetine achieved a greater panic-free status compared with placebo (70%, 58%, and 48%, respectively). Venlafaxine ER also resulted in greater improvement than paroxetine in the PDSS scale. Based on CGI-improvement responders, active treatments resulted in a response rate of 80% to 85%, compared with a placebo response of 60%.

In addition to monotherapy, there is some evidence that combining an antidepressant with a benzodiazepine may facilitate early treatment response. For example, one study randomized patients (N = 50) to clonazepam or placebo during the initial 4 weeks of treatment with sertraline.40 Compared with sertraline alone, combination treatment resulted in a greater reduction of panic symptoms. Treatment gains were maintained even after clonazepam was discontinued.

Remission rates in pharmacotherapy trials are infrequently reported. A retrospective analysis of paroxetine studies found a rate of 24.6% to 35.5%, depending on the definition of remission.41 Remission was achieved in 50% of patients treated with venlafaxine ER based on CGI severity score.39 These rates are probably an overestimation of true remission, because the more stringent definition proposed by the international consensus group was not used.

CBT, medication, or combination?

A large (N = 312) randomized, placebo-controlled, head-to-head comparison trial examined the efficacy of monotherapy (CBT alone or imipramine alone) with combination treatment (CBT and imipramine).42 All active treatments were superior to placebo during the acute treatment phase, but imipramine produced a higher quality of response than CBT. During maintenance, combination treatment fared better than monotherapy. However, imipramine appeared to decrease the long-term efficacy of CBT.

Once treatment was discontinued, patients treated with medication (alone or with CBT) were more vulnerable to relapse than those treated with CBT alone. One possible reason may be that medication was discontinued too rapidly (over 1 to 2 weeks). Based on this study, all 3 treatment modalities are effective for acute stabilization. Medication is helpful if a more potent response is desired, but the long-term effects of medication are limited. Discontinuation of medication over a longer period may reduce the chance of relapse. CBT alone is better tolerated and has a more lasting effect.

In addition to treatment efficacy, other factors should be considered when recommending treatment, including patient preference, treatment history, severity of illness, and presence of comorbid disorders. Table 2 summarizes the advantages and disadvantages of the different treatment modalities.

TABLE 2 Advantages and disadvantages ofdifferent treatments for panic disorder
Treatment modality
Antidepressants (SSRIs)
 Low cost (generic  form); treatment of comorbid depression  and anxiety disorders;  single daily dosing  available
 Delayed onset of action; medication adverse  effects
 Rapid onset of action;  well-tolerated; low cost
 Medication adverse  effects; withdrawaland  dependence; may  interfere withexposure;  multiple daily dosing
Cognitive-behavioral therapy (CBT)
 Long-term benefits,  prevention of relapse;  safein pregnancy;  safe in those with  history of bipolar disorder and substance  use
 High cost; time  commitment;limited  access to expert  therapists
Combination medication and CBT
 Rapid onset of action;  treatment ofcomorbid  disorders
 Highest cost; time  commitment; limited  access to expert  therapists; medication  adverse effects; no  additional long-term  benefits


Acute treatment with medication should be at least 8 to 12 weeks' duration to ensure optimal response. CBT treatment can range from 8 to 12 weekly sessions. Most maintenance studies lasting 6 months to 1 year have largely found that gains achieved during acute treatment with CBT or pharmacotherapy are either sustained or improved during the maintenance phase.19,23,24,26,27,42,43 However, one naturalistic long-term, follow-up study reported that survival probability decreased over time even with continued treatment, from 87% at 1 year to 64% at 4 years following a 3-year maintenance period.44

Relapse is common on medication discontinuation, with the highest rates (up to 88%) reported for benzodiaz-epines45-47 and the lowest rates (15% to 30%) for SSRIs.48,49 The American Psychiatric Association guidelines recommend that treatment be maintained for at least 1 year,35 and the international consensus group recommends 1 to 2 years.13 Subsequent to these guidelines, a series of controlled discontinuation studies suggest that the length of maintenance treatment is not predictive of relapse. For example, the relapse rate (37%) within 1 year of medication discontinuation was the same after 6 months or 18 months of maintenance with imipramine.50-52 In an SSRI discontinuation study, relapse rates within 1 year of discontinuation did not differ between those who received treatment over 1 or 2 years with paroxetine (18% vs 15%).49 Similarly, another study found a high relapse rate (46% within 1 year of discontinuation) even after 3 years of maintenance treatment in a select group of moderately healthy patients.44

Given that a longer length of maintenance treatment does not seem to protect against relapse, medication discontinuation can be considered 6 months after full and sustained remission is obtained. Discontinuation should be conducted slowly over 2 to 6 months.13 Clinicians should prepare patients for what to expect following discontinuation so that treatment can be reinstituted promptly should relapse occur. Patients should also be advised to consider adjunctive CBT to optimize their chance of maintaining improvement after medication discontinuation. There is extensive evidence that CBT reduces the chance of relapse after medication discontinuation.53-55 One study also showed that brief psychodynamic psychotherapy reduces the incidence of relapse.56 Treatment should be continued in patients with significant residual anxiety or depressive symptoms, because premature medication discontinuation in these patients is less successful.57 Treatment should also be continued in patients with a history of relapse after discontinuation, in those with significant comorbidities, and in those with current severe life stressors.13


A substantial number of patients do not completely recover from panic disorder with either CBT or pharmaco-therapy; in fact, only 25% to 45% of treated patients are considered to be in remission.58

The reasons for failure to respond to CBT have not been adequately studied.59 In a group of patients who received in vivo exposure, those who were treatment resistant (n = 21) were younger, more likely to be male and unmarried, and had a longer duration of illness, greater baseline depression, and poorer adherence to exposure homework than those who were successfully treated (n = 81).60

A limited number of studies suggest that the addition of medication or prolonged treatment with CBT may help patients who do not respond to CBT. An early, small study (N = 18) found that augmentation with clomipramine resulted in significant but modest improvement in patients who failed exposure therapy.61In a later study with SSRIs, patients who did not adequately respond to CBT (n = 43) were given additional CBT with or without paroxetine.59 Adjunctive paroxetine improved 3 of 7 outcome measures, including agoraphobic symptoms and anxiety discomfort. A greater proportion of patients in the CBT plus paroxetine group were panic-free compared with the CBT alone group (74% vs 47%), but this finding was not statistically significant. On the other hand, one study of 21 patients who were treatment-resistant suggested that prolonged (at least an additional 8 weeks) exposure to treatment alone can achieve a greater chance of panic-free status than augmentation with either imipramine or cognitive therapy.60 However, imipramine was not given a fair trial since many of the patients (6 of the 14) could not tolerate imipramine, and the medication had to be discontinued prematurely.

One of the most common reasons for drug treatment failures is inadequate dose and/or duration of treatment. True treatment resistance is found in only 24% of adequate medication trials.62 Thus, it is important to first optimize treatment by ensuring an adequate trial of medication. This may require improving tolerability by initiating treatment at low doses and aggressively managing adverse effects. For treatment-refractory situations, one strategy is to augment treatment with psychotherapy.

Three small open trials have shown that CBT can reduce panic symptoms in patients who are not responding. In the first study, patients (N = 15) who had an incomplete response to pharmacotherapy were given 12 weeks of group CBT treatment.63 These patients reported a decrease in panic frequency and improved global functioning. There also appeared to be a greater response to CBT in those who received an inadequate trial of medication compared with those who were treatment refractory.

A later study (N = 24) by the same group of researchers confirmed that CBT was an effective strategy in patients who were not responding to medication, but there was no significant difference in response between those who received an adequate trial and those who received an inadequate trial of medication.64 However, there was a greater effect size for those who were adequately treated relative to those who were in the inadequately treated sample. Approximately 60% of the adequately treated sample responded to treatment and had lower PDSS scores compared with 43% of the inadequately treated sample.

In addition, researchers in Brazil found CBT reduced panic symptoms in patients (N = 71) who were resistant to an adequate trial of SSRI, with gains maintained at 1-year follow-up. A little over 80% of patients were panic-free after CBT, and medication use decreased over time. In addition, the presence of baseline comorbid dysthymia, social anxiety disorder, and generalized anxiety disorder predicted worse outcomes.65

Most recently, a short-term, panic-focused psychodynamic psychotherapy has been shown to be effective in the treatment of panic disorder.66 Psychodynamic psychotherapy reduced the severity of panic symptoms compared with applied relaxation. The response rate was 73% for psychodynamic therapy versus 39% for applied relaxation in the intent-to-treat group. However, this difference was no longer significant when comparing only the patients who completed treatment. Although there are no augmentation studies with psychodynamic psychotherapy, it may be a good alternative for those who cannot tolerate medication or who do not respond to CBT.

Another strategy for patients who do not respond to pharmacotherapy is to switch to another medication that has proved effective for panic disorder, be it an SSRI, venlafaxine ER, a TCA, a benzodiazepine, or a combination of antidepressant and benzodiazepine. However, these strategies are largely based on clinical practice.13,36 The efficacy of switching from one antidepressant to another has not been examined in any controlled studies. There are also limited studies on combination pharmacotherapy for patients who are treatment refractory. Although b-blockers are not generally used in panic disorder, one controlled study (N = 25) looked at augmentation with pindolol versus augmentation with placebo in patients who did not respond to fluoxetine.67 Compared with placebo, the addition of pindolol decreased overall anxiety, but the panic-free rates were not reported. Treatment with fluoxetine was also not optimized in this study because 20 mg was the maximum dose. A clinical trial is under way at Massachusetts General Hospital in Boston to determine whether the addition of clonazepam or CBT would benefit patients who did not respond to sertraline ( NCT00118417).

In patients who do not respond even after switching to a different medication or the addition of adjunctive treatment, clinicians should consider the presence of comorbid conditions, such as personality disorder, mood disorder, substance abuse, or another anxiety disorder that may complicate the treatment of panic disorder. The Figure presents a suggested treatment algorithm.


Panic disorder is a chronic, debilitating psychiatric illness that should be recognized and adequately treated with CBT, SSRIs, or a combination of both. Combination treatment is effective in the short term but may not confer any additional benefits compared with CBT alone in the long term. Most recently, psychodynamic psychotherapy and venlafaxine ER have also been shown to be effective. During acute treatment, both dosage and duration of medication should be optimized to maximize the chance of recovery. Patients should be given medication for at least 6 months after they have achieved full sustained remission. Relapse is common after medication discontinuation, and measures to decrease the chance of relapse include slow discontinuation of medication and the addition of CBT. Switching medications or adjunctive CBT or SSRI may help with patients who do not respond to monotherapy.




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