Treatment Planning for Panic Disorder

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 life^4,5 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

Pharmacotherapy

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.

DURATION OF PHARMACOTHERAPY

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-epines^45-47 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

Treatment for NONRESPONDERS

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 (clinicaltrials.gov: 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.

Conclusion

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.

References:

References

1.

Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of

DSM-IV

disorders in the National Comorbidity Survey Replication.

Arch Gen Psychiatry.

2005;62:593-602.

2.

Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month

DSM-IV

disorders in the National Comorbidity Survey Replication.

Arch Gen Psychiatry.

2005;62:617-627.

3.

Kessler RC, Chiu WT, Jin R, et al. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication.

Arch Gen Psychiatry.

2006;63:415-424.

4.

Candilis PJ, McLean RY, Otto MW, et al. Quality of life in patients with panic disorder.

J Nerv Ment Dis.

1999;187:429-434.

5.

Markowitz JS, Weissman MM, Ouellette R, et al. Quality of life in panic disorder.

Arch Gen Psychiatry.

1989;46:984-992.

6.

Gomez-Caminero A, Blumentals WA, Russo LJ, et al. Does panic disorder increase the risk of coronary heart disease? A cohort study of a national managed care database.

Psychosom Med.

2005;67:688-691.

7.

Zane RD, McAfee AT, Sherburne S, et al. Panic disorder and emergency services utilization.

Acad Emerg Med.

2003;10:1065-1069.

8.

Roy-Byrne PP, Stein MB, Russo J, et al. Panic disorder in the primary care setting: comorbidity, disability, service utilization, and treatment.

J Clin Psychiatry.

1999;60:492-499.

9.

Clark DM. A cognitive approach to panic.

Behav Res Ther.

1986;24:461-470.

10.

Craske MG, Barlow DH, Clark D, et al. Specific (simple) phobia. In: Widiger TA, Frances A, Pincus H, et al, eds.

DSM-IV Sourcebook.

Vol 2. Washington, DC: American Psychiatric Association; 1996:473-506.

11.

Guy W.

ECDEU Assessment Manual for Psychopharmacology

. Bethesda, Md: National Institute of Mental Health; 1976.

12.

Shear MK, Clark D, Feske U. The road to recovery in panic disorder: response, remission, and relapse.

J Clin Psychiatry.

1998;59(suppl 8):4-10.

13.

Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety.

J Clin Psychiatry.

1998;59(suppl 8):47-54.

14.

Mavissakalian M. Clinically significant improvement in agoraphobia research.

Behav Res Ther.

1986; 42:369-370.

15.

Jacobson N, Follette W, Revenstorf D. Psychotherapy outcome research: methods for reporting variability and evaluating clinical significance.

Behav Ther.

1984;15:336-352.

16.

Barlow DH, Craske MG, Cerny JA, Klosko JS. Behavioral treatment of panic disorder.

Behav Ther.

1989;20:261-282.

17.

Beck AT, Sokol L, Clark DA, et al. A crossover study of focused cognitive therapy for panic disorder.

Am J Psychiatry.

1992;149:778-783.

18.

White KS, Barlow DH. Panic disorder and agoraphobia. In: Barlow DH, ed.

Anxiety and Its Disorders: The Nature and Treatment of Anxiety and Panic

. 2nd ed. New York: The Guilford Press; 2002:328-379.

19.

Clark DM, Salkovskis PM, Hackmann A, et al. Brief cognitive therapy for panic disorder: a randomized controlled trial.

J Consult Clin Psychol.

1999;67:583-589.

20.

Klosko JS, Barlow DH, Tassinari R, Cerny JA. A comparison of alprazolam and behavior therapy in treatment of panic disorder.

J Consult Clin Psychol.

1990;58:77-84.

21.

Dannon PN, Gon-Usishkin M, Gelbert A, et al. Cognitive behavioral group therapy in panic disorder patients: the efficacy of CBGT versus drug treatment.

Ann Clin Psychiatry.

2004;16:41-46.

22.

Clark DM. Anxiety disorders: why they persist and how to treat them.

Behav Res Ther.

1999;37(suppl 1):S5-S37.

23.

Ost LG, Thulin U, Ramnero J. Cognitive behavior therapy vs exposure in vivo in the treatment of panic disorder with agoraphobia.

Behav Res Ther.

2004;42: 1105-1127.

24.

Schmidt NB, Woolaway-Bickel K, Trakowski J, et al. Dismantling cognitive-behavioral treatment for panic disorder: questioning the utility of breathing retraining.

J Consult Clin Psychol.

2000;68:417-424.

25.

Telch MJ, Lucas JA, Schmidt NB, et al. Group cognitive-behavioral treatment of panic disorder.

Behav Res Ther.

1993;31:279-287.

26.

Arntz A. Cognitive therapy versus interoceptive exposure as treatment of panic disorder without agoraphobia.

Behav Res Ther.

2002;40:325-341.

27.

Bouchard S, Gauthier J, Laberge B, et al. Exposure versus cognitive restructuring in the treatment of panic disorder with agoraphobia.

Behav Res Ther.

1996; 34:213-224.

28.

Craske MG, DeCola JP, Sachs AD, Pontillo DC. Panic control treatment for agoraphobia.

J Anxiety Disord.

2003;17:321-333.

29.

Otto MW, Tuby KS, Gould RA, et al. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder.

Am J Psychiatry.

2001;158:1989-1992.

30.

Bakker A, van Balkom AJ, Spinhoven P. SSRIs vs TCAs in the treatment of panic disorder: a meta-analysis.

Acta Psychiatr Scand.

2002;106:163-167.

31.

Wilkinson G, Balestrieri M, Ruggeri M, Bellantuono C. Meta-analysis of double-blind placebo-controlled trials of antidepressants and benzodiazepines for patients with panic disorders.

Psychol Med.

1991;21: 991-998.

32.

Mitte K. A meta-analysis of the efficacy of psycho- and pharmacotherapy in panic disorder with and without agoraphobia.

J Affect Disord.

2005;88:27-45.

33.

Gould R, Otto MW, Pollack MH. A meta-analysis of treatment outcome for panic disorder.

Clin Psych Rev.

1995;15:819-844.

34.

van Balkom AJ, Bakker A, Spinhoven P, et al. A meta-analysis of the treatment of panic disorder with or without agoraphobia: a comparison of psychopharmacological, cognitive-behavioral, and combination treatments.

J Nerv Ment Dis.

1997;185:510-516.

35.

Gorman J, Shear K, Cowley DS, et al. Practice guideline for the treatment of patients with panic disorder. In: McIntyre J, Charles S, eds.

American Psychiatric Association Practice Guidelines for the Treatment of Psychiatric Disorders: Compendium 2002

. Washington, DC: American Psychiatric Association; 1998:635-696.

36.

Mathew SJ, Coplan JD, Gorman JM. Management of treatment-refractory panic disorder.

Psychopharmacol Bull.

2001;35:97-110.

37.

Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial.

J Clin Psychiatry.

2003;64: 1322-1327.

38.

Bradwejn J, Ahokas A, Stein DJ, et al. Venlafaxine extended-release capsules in panic disorder: flexible-dose, double-blind, placebo-controlled study.

Br J Psychiatry.

2005;187:352-359.

39.

Pollack MH, Lepola U, Koponen H, et al. A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder.

Depress Anxiety.

2007;24:1-14.

40.

Goddard AW, Brouette T, Almai A, et al. Early coadministration of clonazepam with sertraline for panic disorder.

Arch Gen Psychiatry.

2001;58:681-686.

41.

Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine.

J Clin Psychiatry.

2004;65:1696-1707.

42.

Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial.

JAMA.

2000;283:2529-2536.

43.

Ferguson JM, Khan A, Mangano R, et al. Relapse prevention of panic disorder in adult outpatient responders to treatment with venlafaxine extended release.

J Clin Psychiatry.

2007;68:58-68.

44.

Choy Y, Peselow ED, Case BG, et al. Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study.

Compr Psychiatry.

2007;48:419-425.

45.

Noyes R Jr, Garvey MJ, Cook B, Suelzer M. Controlled discontinuation of benzodiazepine treatment for patients with panic disorder.

Am J Psychiatry.

1991;148:517-523.

46.

Fyer AJ, Liebowitz MR, Gorman JM, et al. Discontinuation of alprazolam treatment in panic patients.

Am J Psychiatry.

1987;144:303-308.

47.

Roy-Byrne PP, Dager SR, Cowley DS, et al. Relapse and rebound following discontinuation of benzodiazepine treatment of panic attacks: alprazolam versus diazepam.

Am J Psychiatry.

1989;146:860-865.

48.

Rapaport MH, Wolkow R, Rubin A, et al. Sertraline treatment of panic disorder: results of a long-term study.

Acta Psychiatr Scand.

2001;104:289-298.

49.

Dannon PN, Iancu I, Cohen A, et al. Three year naturalistic outcome study of panic disorder patients treated with paroxetine.

BMC Psychiatry.

2004;4:16.

50.

Mavissakalian MR, Perel JM. Long-term maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia.

Arch Gen Psychiatry.

1999;56:821-827.

51.

Mavissakalian MR, Perel JM. 2nd year maintenance and discontinuation of imipramine in panic disorder with agoraphobia.

Ann Clin Psychiatry.

2001;13: 63-67.

52.

Mavissakalian MR, Perel JM. Duration of imipramine therapy and relapse in panic disorder with agoraphobia.

J Clin Psychopharmacol.

2002;22:294-299.

53.

Otto MW, Pollack MH, Sachs GS, et al. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder.

Am J Psychiatry.

1993;150:1485-1490.

54.

Spiegel DA, Bruce TJ, Gregg SF, Nuzzarello A. Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder?

Am J Psychiatry.

1994;151:876-881.

55.

Biondi M, Picardi A. Increased probability of remaining in remission from panic disorder with agoraphobia after drug treatment in patients who received concurrent cognitive-behavioural therapy: a follow-up study.

Psychother Psychosom.

2003;72:34-42.

56.

Wiborg IM, Dahl AA. Does brief dynamic psychotherapy reduce the relapse rate of panic disorder?

Arch Gen Psychiatry.

1996;53:689-694.

57.

Rickels K, DeMartinis N, Rynn M, Mandos L. Pharmacologic strategies for discontinuing benzodiazepine treatment.

J Clin Psychopharmacol.

1999;19 (6 suppl 2):12S-16S.

58.

Ballenger JC. Current treatments of the anxiety disorders in adults.

Biol Psychiatry.

1999;46:1579-1594.

59.

Kampman M, Keijsers GP, Hoogduin CA, Hendriks GJ. A randomized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone.

J Clin Psychiatry.

2002; 63:772-777.

60.

Fava GA, Savron G, Zielezny M, et al. Overcoming resistance to exposure in panic disorder with agoraphobia.

Acta Psychiatr Scand.

1997;95:306-312.

61.

Hoffart A, Due-Madsen J, Lande B, et al. Clomipramine in the treatment of agoraphobic inpatients resistant to behavioral therapy.

J Clin Psychiatry.

1993;54:481-487.

62.

Cowley DS, Ha EH, Roy-Byrne PP. Determinants of pharmacologic treatment failure in panic disorder.

J Clin Psychiatry.

1997;58:555-561.

63.

Pollack MH, Otto MW, Kaspi SP, et al. Cognitive behavior therapy for treatment-refractory panic disorder.

J Clin Psychiatry.

1994;55:200-205.

64.

Otto MW, Pollack MH, Penava SJ, Zucker BG. Group cognitive-behavior therapy for patients failing to respond to pharmacotherapy for panic disorder: a clinical case series.

Behav Res Ther.

1999;37:763-770.

65.

Heldt E, Gus Manfro G, Kipper L, et al. One-year follow-up of pharmacotherapy-resistant patients with panic disorder treated with cognitive-behavior therapy: outcome and predictors of remission.

Behav Res Ther.

2006;44:657-665.

66.

Milrod B, Leon AC, Busch F, et al. A randomized controlled clinical trial of psychoanalytic psychotherapy for panic disorder.

Am J Psychiatry.

2007;164: 265-272.

67.

Hirschmann S, Dannon PN, Iancu I, et al. Pindolol augmentation in patients with treatment-resistant panic disorder: a double-blind, placebo-controlled trial.

J Clin Psychopharmacol.

2000;20:556-559.

68.

Pollack MH, Otto MW, Worthington JJ, et al. Sertraline in the treatment of panic disorder: a flexible-dose multicenter trial.

Arch Gen Psychiatry.

1998;55: 1010-1016.

69.

Sheikh JI, Londborg P, Clary CM, Fayyad R. The efficacy of sertraline in panic disorder: combined results from two fixed-dose studies.

Int Clin Psychopharmacol.

2000;15:335-342.

70.

Pohl RB, Wolkow RM, Clary CM. Sertraline in the treatment of panic disorder: a double-blind multicenter trial.

Am J Psychiatry.

1998;155:1189-1195.

71.

Ballenger JC, Wheadon DE, Steiner M, et al. Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder.

Am J Psychiatry.

1998;155:36-42.

72.

Sheehan DV, Burnham DB, Iyengar MK, Perera P. Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder.

J Clin Psychiatry.

2005;66:34-40.

73.

Michelson D, Allgulander C, Dantendorfer K, et al. Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder: randomized, placebo-controlled trial.

Br J Psychiatry.

2001;179:514-518.

74.

Wade AG, Lepola U, Koponen HJ, et al. The effect of citalopram in panic disorder.

Br J Psychiatry.

1997; 170:549-553.

75.

Black DW, Wesner R, Bowers W, Gabel J. A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder.

Arch Gen Psychiatry.

1993;50:44-50.

76.

Asnis GM, Hameedi FA, Goddard AW, et al. Fluvoxamine in the treatment of panic disorder: a multi-center, double-blind, placebo-controlled study in outpatients.

Psychiatry Res.

2001;103:1-14.

77.

Mavissakalian MR, Perel JM. Imipramine treatment of panic disorder with agoraphobia: dose ranging and plasma level-response relationships.

Am J Psychiatry.

1995;152:673-682.

78.

Marcourakis T, Gorenstein C, Ramos RT, da Motta Singer J. Serum levels of clomipramine and desmeth-ylclomipramine and clinical improvement in panic disorder.

J Psychopharmacol.

1999;13:40-44.

79.

Lotufo-Neto F, Bernik M, Ramos RT, et al. A dose-finding and discontinuation study of clomipramine in panic disorder.

J Psychopharmacol.

2001;15:13-17.

80.

Lydiard RB, Lesser IM, Ballenger JC, et al. A fixed-dose study of alprazolam 2 mg, alprazolam 6 mg, and placebo in panic disorder.

J Clin Psychopharmacol.

1992;12:96-103.

81.

Schweizer E, Patterson W, Rickels K, Rosenthal M. Double-blind, placebo-controlled study of a once-a-day, sustained-release preparation of alprazolam for the treatment of panic disorder.

Am J Psychiatry.

1993;150:1210-1215.

82.

Rosenbaum JF, Moroz G, Bowden CL. Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose-response study of efficacy, safety, and discontinuance. Clonazepam Panic Disorder Dose-Response Study Group.

J Clin Psychopharmacol.

1997;17:390-400.