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Practice Guideline for the Treatment of Patients With Panic Disorder, Second Edition

DOI: 10.1176/appi.books.9780890423905.154688
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Work Group on Panic Disorder

Murray B. Stein, M.D., M.P.H., Chair

Marcia K. Goin, M.D., Ph.D.

Mark H. Pollack, M.D.

Peter Roy-Byrne, M.D.

Jitender Sareen, M.D.

Naomi M. Simon, M.D., M.Sc.

Laura Campbell-Sills, Ph.D., consultant

This practice guideline was approved in July 2008 and published in January 2009.

A guideline watch, summarizing significant developments in the scientific literature since publication of this guideline, may be available.

For the period from September 2005 to June 2008, Dr. Stein reports receiving research grants from the National Institute of Mental Health, the Department of Veterans Affairs, the Department of Defense, Eli Lilly and Company, Forest Pharmaceuticals, Inc., Hoffmann-La Roche, Inc., Novartis, Pfizer, GlaxoSmithKline, Solvay, UCB, and Wyeth. He reports receiving consultant fees from Allergan, Inc., ALZA Corporation, Alexza Molecular Delivery Corp., AstraZeneca, Avera Pharmaceuticals, BrainCells Inc., Bristol-Myers Squibb, Cephalon, Comprehensive NeuroScience, Eli Lilly and Company, EPI-Q Inc., Forest Pharmaceuticals, Inc., GlaxoSmithKline, Hoffmann-La Roche, Inc., Integral Health Decisions Inc., Janssen Research Foundation, Jazz Pharmaceuticals, Inc., Johnson & Johnson, Mindsite, Pfizer, sanofi-aventis, Solvay, Transcept Pharmaceuticals, Inc., UCB, and Wyeth. He reports receiving honoraria from Eli Lilly and Company, GlaxoSmithKline, Solvay, and Wyeth.

For the period from October 2005 to June 2008, Dr. Goin reports no competing interests.

For the period from September 2005 to June 2008, Dr. Pollack reports serving on advisory boards and doing consultation for AstraZeneca, BrainCells Inc., Bristol-Myers Squibb, Cephalon, Dov Pharmaceutical Inc., Forest Pharmaceuticals, Inc., GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Inc., Eli Lilly and Company, MedAvante, Neurocrine Biosciences, Neurogen Corp., Novartis, Otsuka Pharmaceutical, Pfizer, Predix Pharmaceuticals, Roche, sanofi-aventis, Sepracor Inc., Solvay, Tikvah Therapeutics, Inc., Transcept Pharmaceuticals, Inc., UCB, and Wyeth. He reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Forest Pharmaceuticals, Inc., GlaxoSmithKline, Janssen, Eli Lilly and Company, National Alliance for Research on Schizophrenia and Depression, the National Institute on Drug Abuse, the National Institute of Mental Health, Pfizer, Roche, Sepracor Inc., UCB, and Wyeth. He reports receiving speaker fees from Bristol-Myers Squibb, Forest Pharmaceuticals, Inc., GlaxoSmithKline, Janssen, Eli Lilly and Company, Pfizer, Solvay, and Wyeth. He reports equity holdings in MedAvante and Mensante Corporation. He reports receiving copyright royalties for the Structured Interview Guide to the Hamilton-A (SIGH-A) and SAFER.

For the period from August 2004 to June 2008, Dr. Roy-Byrne reports receiving consultant or advisory fees from Jazz Pharmaceuticals, Inc., and Solvay. He reports receiving speaker honoraria (via a continuing medical education company) from Forest Pharmaceuticals, Inc., Pfizer, and Wyeth.

For the period from August 2005 to June 2008, Dr. Sareen reports receiving honoraria from Wyeth, AstraZeneca, Lundbeck, and GlaxoSmithKline.

For the period from September 2005 to June 2008, Dr. Simon reports receiving research support from Cephalon, Pfizer, AstraZeneca, Forest Pharmaceuticals, Inc., GlaxoSmithKline, UCB, Sepracor Inc., Janssen Research Foundation, Eli Lilly and Company, National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health. She reports receiving consultant fees or honoraria from Paramount BioSciences, Anxiety Disorders Association of America, American Psychiatric Association, American Foundation for Suicide Prevention, Forest Pharmaceuticals, Inc., Solvay, Sepracor Inc., UCB, and Pfizer.

For the period from November 2005 to June 2008, Dr. Campbell-Sills reports no competing interests.

The Executive Committee on Practice Guidelines has reviewed this guideline and found no evidence of influence from these relationships.

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Overview of Guideline Development Process

This practice guideline was developed under the auspices of the Steering Committee on Practice Guidelines. The development process is detailed in a document entitled "APA Guideline Development Process," which is available from the APA Department of Quality Improvement and Psychiatric Services or at Appendix: Practice Guideline Development Process. Key features of this process include the following:

  • A comprehensive literature review to identify all relevant randomized clinical trials as well as less rigorously designed clinical trials and case series when evidence from randomized trials was unavailable

  • Development of evidence tables that reviewed the key features of each identified study, including funding source, study design, sample sizes, subject characteristics, treatment characteristics, and treatment outcomes

  • Initial drafting of the guideline by a work group that included psychiatrists with clinical and research expertise in panic disorder

  • Production of multiple revised drafts with widespread review; 29 organizations and 80 individuals submitted significant comments

  • Approval by the APA Assembly and Board of Trustees

  • Planned revisions at regular intervals

Relevant updates to the literature were identified through a MEDLINE literature search for articles published since the initial guideline edition, published in 1997. Thus, relevant literature was identified through a computerized search of MEDLINE, using PubMed, for the period from 1994 to 2005. Using the key words "panic" OR "panic attack" OR "panic attacks" OR "panic disorder" OR "anxiety attack" OR "anxiety attacks" OR "agoraphobia" OR "agoraphobic," a total of 5,088 citations limited to articles on humans were found. Using PsycInfo (EBSCOHost), the same search strategy yielded 5,444 references. Using Psychoanalytic Electronic Publishing (http://www.p-e-p.org), a search of the terms "panic disorder" OR "agoraphobia" yielded 132 references. Additional, less formal, literature searches were conducted by APA staff and individual work group members, to include references through mid-2007. Practice guidelines for the treatment of patients with panic disorder that have been published by other organizations also were reviewed (1, 2). The Cochrane databases were also searched for relevant meta-analyses. Sources of funding were considered when the work group reviewed the literature but are not always identified in this document. When reading source articles referenced in this guideline, readers are advised to consider the sources of funding for the studies.

This document represents a synthesis of current scientific knowledge and rational clinical practice regarding the treatment of patients with panic disorder. It strives to be as free as possible of bias toward any theoretical approach to treatment. In order for the reader to appreciate the evidence base behind the guideline recommendations and the weight that should be given to each recommendation, the summary of treatment recommendations is keyed according to the level of confidence with which each recommendation is made. Each rating of clinical confidence considers the strength of the available evidence and is based on the best available data. When evidence is limited, the level of confidence also incorporates clinical consensus with regard to a particular clinical decision. In the listing of cited references, each reference is followed by a letter code in brackets that indicates the nature of the supporting evidence.

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Guide to Using This Practice Guideline

The Practice Guideline for the Treatment of Patients With Panic Disorder, Second Edition, consists of three parts (Parts A, B, and C) and many sections, not all of which will be equally useful for all readers. The following guide is designed to help readers find the sections that will be most useful to them.

Part A, "Treatment Recommendations," is published as a supplement to the American Journal of Psychiatry and contains general and specific treatment recommendations. Section I summarizes the key recommendations of the guideline and codes each recommendation according to the degree of clinical confidence with which the recommendation is made. Section II is a guide to the formulation and implementation of a treatment plan for the individual patient. Section III, "Specific Clinical Features Influencing the Treatment Plan," discusses a range of clinical considerations that could alter the general recommendations discussed in Section I.

Part B, "Background Information and Review of Available Evidence," and Part C, "Future Research Needs," are not included in the American Journal of Psychiatry supplement but are provided with Part A in the complete guideline, which is available in print format from American Psychiatric Publishing, Inc., and online through PsychiatryOnline (http://psychiatryonline.org/guidelines.aspx). Part B provides an overview of panic disorder, including general information on natural history, course, and epidemiology. It also provides a structured review and synthesis of the evidence that underlies the recommendations made in Part A. Part C draws from the previous sections and summarizes areas for which more research data are needed to guide clinical decisions.

To share feedback on this or other published APA practice guidelines, a form is available at http://mx.psych.org/survey/reviewform.cfm.

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Off-Label Use of Medications

Medications discussed in this practice guideline may not have an indication from the U.S. Food and Drug Administration for the disorder or condition for which they are recommended. Off-label use of medications by individual physicians is permitted and common. Decisions about off-label use can be guided by the evidence provided in the APA practice guideline, other scientific literature, and clinical experience.

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Part A: Treatment Recommendations

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I. Executive Summary

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A. Coding System

Each recommendation is identified as falling into one of three categories of endorsement, indicated by a bracketed Roman numeral following the statement. The three categories represent varying levels of clinical confidence:

[I] Recommended with substantial clinical confidence

[II] Recommended with moderate clinical confidence

[III] May be recommended on the basis of individual circumstances

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B. Psychiatric Management

Panic disorder is a common and often disabling mental disorder. Treatment is indicated when symptoms of the disorder interfere with functioning or cause significant distress [I]. Effective treatment for panic disorder should lead not only to reduction in frequency and intensity of panic attacks, but also reductions in anticipatory anxiety and agoraphobic avoidance, optimally with full remission of symptoms and return to a premorbid level of functioning [I]. Psychiatric management consists of a comprehensive array of activities and interventions that should be instituted for all patients with panic disorder, in combination with specific modalities that have demonstrated efficacy [I].

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1. Establishing a therapeutic alliance

Psychiatrists should work to establish and maintain a therapeutic alliance so that the patient's care is a collaborative endeavor [I]. Careful attention to the patient's preferences and concerns with regard to treatment is essential to fostering a strong alliance [I]. In addition, education about panic disorder and its treatment should be provided in language that is readily understandable to the patient [I]. Many patients with panic disorder are fearful of certain aspects of treatment (e.g., medication side effects, confronting agoraphobic situations). A strong therapeutic alliance is important in supporting the patient through phases of treatment that may be anxiety provoking [I].

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2. Performing the psychiatric assessment

Patients should receive a thorough diagnostic evaluation both to establish the diagnosis of panic disorder and to identify other psychiatric or general medical conditions [I]. This evaluation generally includes a history of the present illness and current symptoms; past psychiatric history; general medical history; history of substance use; personal history (e.g., major life events); social, occupational, and family history; review of the patient's medications; previous treatments; review of systems; mental status examination; physical examination; and appropriate diagnostic tests (to rule out possible medical causes of panic symptoms) as indicated [I]. Assessment of substance use should include illicit drugs, prescribed and over-the-counter medications, and other substances (e.g., caffeine) that may produce physiological effects that can trigger or exacerbate panic symptoms [I].

Delineating the specific features of panic disorder that characterize a given patient is an essential element of assessment and treatment planning [I]. It is crucial to determine if agoraphobia is present and to establish the extent of situational fear and avoidance [I]. The psychiatrist also should evaluate other psychiatric disorders, as co-occurring conditions may affect the course, treatment, and prognosis of panic disorder [I]. It must be determined that panic attacks do not occur solely as a result of a general medical condition or substance use and that they are not better conceptualized as a feature of another diagnosis [I]. The presence of medical disorders, substance use, and other psychiatric disorders does not preclude a concomitant diagnosis of panic disorder. If the symptoms of panic disorder are not deemed solely attributable to these factors, then diagnosing (and treating) both panic disorder and another condition may be warranted [I].

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3. Tailoring the treatment plan for the individual patient

Tailoring the treatment plan to match the needs of the particular patient requires a careful assessment of the frequency and nature of the patient's symptoms [I]. It may be helpful, in some circumstances, for patients to monitor their panic symptoms using techniques such as keeping a daily diary [I]. Such monitoring can aid in identification of triggers for panic symptoms, which may become a focus of subsequent intervention.

Continuing evaluation and management of co-occurring psychiatric and/or medical conditions is also essential to developing a treatment plan for an individual patient [I]. Co-occurring conditions may influence both selection and implementation of pharmacological and psychosocial treatments for panic disorder [I].

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4. Evaluating the safety of the patient

A careful assessment of suicide risk is necessary for all patients with panic disorder [I]. Panic disorder has been shown to be associated with an elevated risk of suicidal ideation and behavior, even in the absence of co-occurring conditions such as major depression. An assessment of suicidality includes identification of specific psychiatric symptoms known to be associated with suicide attempts or suicide; assessment of past suicidal behavior, family history of suicide and mental illness, current stressors, and potential protective factors such as positive reasons for living; and specific inquiry about suicidal thoughts, intent, plans, means, and behaviors [I].

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5. Evaluating types and severity of functional impairment

Panic disorder can impact numerous spheres of life including work, school, family, social relationships, and leisure activities. The psychiatrist should develop an understanding of how panic disorder affects the patient's functioning in these domains [I] with the aim of developing a treatment plan intended to minimize impairment [I].

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6. Establishing goals for treatment

All treatments for panic disorder aim to reduce the frequency and intensity of panic attacks, anticipatory anxiety, and agoraphobic avoidance, optimally with full remission of symptoms and return to a premorbid level of functioning [I]. Treatment of co-occurring psychiatric disorders when they are present is an additional goal [I]. The intermediate objectives that will help achieve these goals will depend on the chosen modality or modalities [I].

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7. Monitoring the patient's psychiatric status

The different elements of panic disorder may resolve at different points during the course of treatment (e.g., panic attacks may remit before agoraphobic avoidance is eliminated). The psychiatrist should continue to monitor the status of all symptoms originally presented by the patient [I]. Psychiatrists may consider using rating scales to help monitor the patient's status at each session [I]. Patients also can be asked to keep a daily diary of panic symptoms to aid in ongoing assessment [I].

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8. Providing education to the patient and, when appropriate, to the family

Education alone may relieve some of the symptoms of panic disorder by helping the patient realize that his or her symptoms are neither life-threatening nor uncommon. Thus, once a diagnosis of panic disorder is made, the patient should be informed of the diagnosis and educated about panic disorder and treatment options [I]. Regardless of the treatment modality selected, it is important to inform the patient that in almost all cases the physical sensations that characterize panic attacks are not acutely dangerous and will abate [I]. Educational tools such as books, pamphlets, and trusted web sites can augment the face-to-face education provided by the psychiatrist [I].

Providing the family with accurate information about panic disorder and its treatment is also important for many patients [I]. Education sometimes includes discussion of how changes in the patient's status affect the family system and of how responses of family members can help or hinder treatment of the patient's panic disorder [II].

Patient education also includes general promotion of healthy behaviors such as exercise, good sleep hygiene, and decreased use of caffeine, tobacco, alcohol, and other potentially deleterious substances [I].

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9. Coordinating the patient's care with other clinicians

Many patients with panic disorder will be evaluated by or receive treatment from other health care professionals in addition to the psychiatrist. Under such circumstances, the clinicians should communicate periodically to ensure that care is coordinated and that treatments are working in synchrony [I].

It is important to ensure that a general medical evaluation has been done (either by the psychiatrist or by another health care professional) to rule out medical causes of panic symptoms [I]. Extensive or specialized testing for medical causes of panic symptoms is usually not indicated but may be conducted based on individual characteristics of the patient [III].

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10. Enhancing treatment adherence

Problems with treatment adherence can result from a variety of factors (e.g., avoidance that is a manifestation of panic disorder, logistical barriers, cultural or language barriers, problems in the therapeutic relationship). Whenever possible, the psychiatrist should assess and acknowledge potential barriers to treatment adherence and should work collaboratively with the patient to minimize their influence [I].

Many standard pharmacological and psychosocial treatments for panic disorder can be associated with short-term intensification of anxiety (e.g., because of medication side effects or exposure to fear cues during therapy). These temporary increases in anxiety may contribute to decreased treatment adherence. The psychiatrist should adopt a stance that encourages patients to articulate their fears about treatment and should provide patients with a realistic notion of what they can expect at different points in treatment [I]. In particular, patients should be informed about when a positive response to treatment can be expected so that they do not prematurely abandon treatment due to misconceptions about the time frame for response [I]. Patients should also be encouraged to contact the psychiatrist (e.g., by telephone if between visits) if they have concerns or questions, as these can often be readily addressed and lead to enhanced treatment adherence [I].

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11. Working with the patient to address early signs of relapse

Although standard treatments effectively reduce the burden of panic disorder for the majority of patients, even some patients with a good treatment response may continue to have lingering symptoms (e.g., occasional panic attacks) or have a recurrence of symptoms after remission. Patients should be reassured that fluctuations in symptoms can occur during the course of treatment before an acceptable level of remission is reached [I]. Patients should also be informed that symptoms of panic disorder may recur even after remission and be provided with a plan for how to respond [I].

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C. Formulation and Implementation of a Treatment Plan

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1. Choosing a treatment setting

The treatment of panic disorder is generally conducted entirely on an outpatient basis, as the condition by itself rarely warrants hospitalization [I]. However, it may be necessary to hospitalize a patient with panic disorder because of symptoms of co-occurring disorders (e.g., when acute suicidality associated with a mood disorder is present or when inpatient detoxification is required for a substance use disorder) [I]. Under such circumstances, the treatment of panic disorder can be initiated in the hospital along with treatment of the disorder that prompted hospitalization [I]. Rarely, hospitalization or partial hospitalization is required in very severe cases of panic disorder with agoraphobia when administration of outpatient treatment has been ineffective or is impractical [I]. Home visits are another treatment option for patients with severe agoraphobia who are limited in their ability to travel or leave the house [II]. When accessibility to mental health care is limited (e.g., in remote or underserved areas), telephone- or Internet-based treatments may be considered [II].

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2. Choosing an initial treatment modality

A range of specific psychosocial and pharmacological interventions have proven benefits in treating panic disorder. The use of a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), benzodiazepine (appropriate as monotherapy only in the absence of a co-occurring mood disorder), or cognitive-behavioral therapy (CBT) as the initial treatment for panic disorder is strongly supported by demonstrated efficacy in numerous randomized controlled trials [I]. A particular form of psychodynamic psychotherapy, panic-focused psychodynamic psychotherapy (PFPP), was effective in one randomized controlled trial and could be offered as an initial treatment under certain circumstances [II].

There is insufficient evidence to recommend any of these pharmacological or psychosocial interventions as superior to the others, or to routinely recommend a combination of treatments over monotherapy [II]. Although combination treatment does not appear to be significantly superior to standard monotherapy as initial treatment for most individuals with panic disorder, psychiatrists and patients may choose this option based on individual circumstances (e.g., patient preference) [II].

Considerations that guide the choice of an initial treatment modality include patient preference, the risks and benefits for the particular patient, the patient's past treatment history, the presence of co-occurring general medical and other psychiatric conditions, cost, and treatment availability [I]. Psychosocial treatment (with the strongest evidence available for CBT) is recommended for patients who prefer nonmedication treatment and can invest the time and effort required to attend weekly sessions and complete between-session practices [I]. One caveat is that CBT and other specialized psychosocial treatments are not readily available in some geographic areas. Pharmacotherapy (usually with an SSRI or SNRI) is recommended for patients who prefer this modality or who do not have sufficient time or other resources to engage in psychosocial treatment [I]. Combined treatment should be considered for patients who have failed to respond to standard monotherapies and may also be used under certain clinical circumstances (e.g., using pharmacotherapy for temporary control of severe symptoms that are impeding the patient's ability to engage in psychosocial treatment) [II]. Adding psychosocial treatment to pharmacotherapy either from the start, or at some later point in treatment, may enhance long-term outcomes by reducing the likelihood of relapse when pharmacological treatment is stopped [II].

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3. Evaluating whether the treatment is working

After treatment is initiated, it is important to monitor change in key symptoms such as frequency and intensity of panic attacks, level of anticipatory anxiety, degree of agoraphobic avoidance, and severity of interference and distress related to panic disorder [I]. Effective treatment should produce a decrease in each of these domains, although some may change more quickly than others. The severity of co-occurring conditions also should be assessed at regular intervals, as treatment of panic disorder can influence co-occurring conditions (e.g., major depression; other anxiety disorders) [I]. Rating scales are a useful adjunct to ongoing clinical assessment for the purpose of evaluating treatment outcome [I].

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4. Determining if and when to change treatment

Some individuals do not respond, or respond incompletely, to first-line treatments for panic disorder. Whenever treatment response is unsatisfactory, the psychiatrist should first consider the possible contribution of fundamental clinical factors such as an underlying untreated medical illness that accounts for the symptoms, interference by co-occurring general medical or psychiatric conditions (including depression and substance use), inadequate treatment adherence, problems in the therapeutic alliance, the presence of psychosocial stressors, motivational factors, and inability to tolerate a particular treatment [I]. These potential impediments to successful treatment should be addressed as early as possible in treatment [I]. In addition, if panic-related concerns are leading the patient to minimize the impact of avoidance or accept functional limitations, the patient should be encouraged to think through the costs and benefits of accepting versus treating functional limitations [I]. Clinicians should be reluctant to accept partial improvement as a satisfactory outcome and should aim for remission whenever feasible [I].

If response to treatment remains unsatisfactory, and if an adequate trial has been attempted, it is appropriate for the psychiatrist and the patient to consider a change [I]. Decisions about whether and how to make changes will depend on the level of response to the initial treatment (i.e., none versus partial), the palatability and feasibility of other treatment options for a given patient, and the level of symptoms and impairment that remain [I]. Persistent significant symptoms of panic disorder despite a lengthy course of a particular treatment should trigger a reassessment of the treatment plan, including possible consultation with another qualified professional [I].

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5. Approaches to try when a first-line treatment is unsuccessful

If fundamental clinical issues have been addressed and it is determined that a change is desirable, the psychiatrist and patient can either augment the current treatment by adding another agent (in the case of pharmacotherapy) or another modality (i.e., add CBT if the patient is already receiving pharmacotherapy, or add pharmacotherapy if the patient is already receiving CBT) [I], or they can decide to switch to a different medication or therapeutic modality [I]. Decisions about how to address treatment resistance are usually highly individualized and based on clinical judgment, since few studies have tested the effects of specific switching or augmentation strategies. However, augmentation is generally a reasonable approach if some significant benefits were observed with the original treatment [II]. On the other hand, if the original treatment failed to provide any significant alleviation of the patient's symptoms, a switch in treatment may be more useful [II].

If one first-line treatment (e.g., CBT, an SSRI, an SNRI) has failed, adding or switching to another first-line treatment is recommended [I]. Adding a benzodiazepine to an antidepressant is a common augmentation strategy to target residual symptoms [II]. If the treatment options with the most robust evidence have been unsuccessful, other options with some empirical support can be considered (e.g., a monoamine oxidase inhibitor [MAOI], PFPP) [II]. After first- and second-line treatments and augmentation strategies have been exhausted (either due to lack of efficacy or intolerance of the treatment by the patient), less well-supported treatment strategies may be considered [III]. These include monotherapy or augmentation with gabapentin or a second-generation antipsychotic or with a psychotherapeutic intervention other than CBT or PFPP [III]. Psychiatrists are encouraged to seek consultation from experienced colleagues when developing treatment plans for patients whose symptoms have been resistant to standard treatments for panic disorder [I].

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6. Specific psychosocial interventions

Psychosocial treatments for panic disorder should be conducted by professionals with an appropriate level of training and experience in the relevant approach [I]. Based on the current available evidence, CBT is the psychosocial treatment that would be indicated most often for patients presenting with panic disorder [I]. Cognitive-behavioral therapy is a time-limited treatment (generally 10–15 weekly sessions) with durable effects. It can be successfully administered individually or in a group format [I]. Self-directed forms of CBT may be useful for patients who do not have ready access to a trained CBT therapist [II]. Cognitive-behavioral therapy for panic disorder generally includes psychoeducation, self-monitoring, countering anxious beliefs, exposure to fear cues, modification of anxiety-maintaining behaviors, and relapse prevention [I]. Exposure therapy, which focuses almost exclusively on systematic exposure to fear cues, is also effective [I].

Panic-focused psychodynamic psychotherapy also has demonstrated efficacy for panic disorder, although its evidence base is more limited. Panic-focused psychodynamic psychotherapy may be indicated as an initial psychosocial treatment in some cases (e.g., patient preference) [II]. Panic-focused psychodynamic psychotherapy is a time-limited treatment (twice weekly for 12 weeks) that is administered on an individual basis. Panic-focused psychodynamic psychotherapy utilizes the general principles of psychodynamic psychotherapy, with special focus on the transference as the therapeutic agent promoting change, and encourages patients to confront the emotional significance of their panic symptoms with the aim of promoting greater autonomy, symptom relief, and improved functioning. Although psychodynamic psychotherapies (other than PFPP) that focus more broadly on emotional and interpersonal issues have not been formally tested for panic disorder, some case report data and clinical experience suggest this approach may be useful for some patients [III].

Other psychosocial treatments have not been formally tested for panic disorder or have proven ineffective (e.g., eye movement desensitization and reprocessing [EMDR]) or inferior to standard treatments such as CBT (e.g., supportive psychotherapy).

Group CBT is effective and can be recommended for treatment of panic disorder [I]. Other group therapies (including patient support groups) are not recommended as monotherapies for panic disorder, although they may be useful adjuncts to other effective treatments for some patients [III].

Couples or family therapy alone is not recommended as a treatment for panic disorder, although it may be helpful in addressing co-occurring relationship dysfunction [III]. It can be beneficial to include significant others in CBT (e.g., partner-assisted exposure therapy for agoraphobia), especially if they are educated in the cognitive-behavioral model of panic disorder and enlisted to help with between-session practices [II]. When pursuing other treatments for panic disorder (e.g., pharmacotherapy), education of significant others about the nature of the disorder and enlisting significant others to improve treatment adherence may also be helpful [III].

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7. Specific pharmacological interventions

Selective serotonin reuptake inhibitors, SNRIs, TCAs, and benzodiazepines have demonstrated efficacy in numerous controlled trials and are recommended for treatment of panic disorder [I]. Monoamine oxidase inhibitors appear effective for panic disorder but, because of their safety profile, they are generally reserved for patients who have failed to respond to several first-line treatments [II]. Other medications with less empirical support (e.g., mirtazapine, anticonvulsants such as gabapentin) may be considered as monotherapies or adjunctive treatments for panic disorder when patients have failed to respond to several standard treatments or based on other individual circumstances [III].

Because SSRIs, SNRIs, TCAs, and benzodiazepines appear roughly comparable in their efficacy for panic disorder, selecting a medication for a particular patient mainly involves considerations of side effects (including any applicable warnings from the U.S. Food and Drug Administration [FDA]), cost, pharmacological properties, potential drug interactions, prior treatment history, co-occurring general medical and psychiatric conditions, and the strength of the evidence base for the particular medication in treatment of panic disorder [I]. The relatively favorable safety and side effect profile of SSRIs and SNRIs makes them the best initial choice for many patients with panic disorder [I]. Although TCAs are effective, the side effects and greater toxicity in overdose associated with them often limit their acceptability to patients and their clinical utility. Selective serotonin reuptake inhibitors, SNRIs, and TCAs are all preferable to benzodiazepines as monotherapies for patients with co-occurring depression or substance use disorders [I]. Benzodiazepines may be especially useful adjunctively with antidepressants to treat residual anxiety symptoms [II]. Benzodiazepines may be preferred (as monotherapies or in combination with antidepressants) for patients with very distressing or impairing symptoms in whom rapid symptom control is critical [II]. The benefit of more rapid response to benzodiazepines must be balanced against the possibilities of troublesome side effects (e.g., sedation) and physiological dependence that may lead to difficulty discontinuing the medication [I].

Patients should be educated about the likely time course of treatment effects associated with a particular medication [I]. Because patients with panic disorder can be sensitive to medication side effects, low starting doses of SSRIs, SNRIs, and TCAs (approximately half of the starting doses given to depressed patients) are recommended [I]. The low dose is maintained for several days then gradually increased to a full therapeutic dose over subsequent days and as tolerated by the patient [I]. Underdosing of antidepressants (i.e., starting low and then not increasing gradually to full therapeutic dosages as needed) is common in treatment of panic disorder and is a frequent source of partial response or nonresponse [II]. A regular dosing schedule rather than a p.r.n. ("as needed") schedule is preferred for patients with panic disorder who are taking benzodiazepines [II], where the goal is to prevent panic attacks rather than reduce symptoms once an attack has already occurred.

Once an initial pharmacotherapy has been selected, patients are typically seen every 1–2 weeks when first starting a new medication, then every 2–4 weeks until the dose is stabilized [I]. After the dose is stabilized and symptoms have decreased, patients will most likely require less frequent visits [I].

When considering any specific medication, the psychiatrist must balance the risks associated with the medication against the clinical need for pharmacotherapy [I]. The FDA has warned of the possibility that antidepressants may increase the risk of suicidal ideation and behavior in patients age 25 years and younger; this is an important factor to consider before using an SSRI, an SNRI, or a TCA for panic disorder. Other important safety considerations for SSRIs include possible increased likelihood of upper gastrointestinal bleeding (particularly when taken in combination with nonsteroidal anti-inflammatory drugs [NSAIDs] or with aspirin) and increased risk of falls and osteoporotic fractures in patients age 50 years and older. With venlafaxine extended release (ER), a small proportion of patients may develop sustained hypertension. It is recommended that psychiatrists assess blood pressure during treatment, particularly when venlafaxine ER is titrated to higher doses [I].

Tricyclic antidepressants should not be prescribed for patients with panic disorder who also have acute narrow-angle glaucoma or clinically significant prostatic hypertrophy. Tricyclic antidepressants may increase the likelihood of falls, particularly among elderly patients. A baseline electrocardiogram should be considered before initiating a TCA, because patients with preexisting cardiac conduction abnormalities may experience significant or fatal arrhythmia with TCA treatment. Overdoses with TCAs can lead to significant cardiac toxicity and fatality, and therefore TCAs should be used judiciously in suicidal patients.

Benzodiazepines may produce sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness. Geriatric patients taking benzodiazepines may be at higher risk for falls and fractures. Because of an increased risk of motor vehicle accidents with benzodiazepine use, patients should be warned about driving or operating heavy machinery while taking benzodiazepines [I]. Patients should also be advised about the additive effects of benzodiazepines and alcohol [I]. Caution and careful monitoring is indicated when prescribing benzodiazepines to elderly patients, those with preexisting cognitive impairment, or those with a history of substance use disorder [I].

For women with panic disorder who are pregnant, nursing, or planning to become pregnant, psychosocial interventions should be considered in lieu of pharmacotherapy [II]. Pharmacotherapy may also be indicated [III] but requires weighing and discussion of the potential benefits and risks with the patient, her obstetrician, and, whenever possible, her partner [I]. Such discussions should also consider the potential risks to the patient and the child of untreated psychiatric illness, including panic disorder and any co-occurring psychiatric conditions [I].

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D. Maintaining or Discontinuing Treatment After Response

Pharmacotherapy should generally be continued for 1 year or more after acute response to promote further symptom reduction and decrease risk of recurrence [I]. Incorporating maintenance treatment (e.g., monthly "booster" sessions focused on relapse prevention) into psychosocial treatments for panic disorder also may help maintain positive response [II], although more systematic investigation of this issue is needed.

Before advising a taper of effective pharmacotherapy, the psychiatrist should consider several factors, including the duration of the patient's symptom stability, the presence of current or impending psychosocial stressors in the patient's life, and the extent to which the patient is motivated to discontinue the medication [II]. Discussion of medication taper should also include the possible outcomes of taper, which could include discontinuation symptoms and recurrence of panic symptoms [I]. If medication is tapered, it should be done in a collaborative manner with continual assessment of the effects of the taper and the patient's responses to any changes that emerge [I].

If a decision is made to discontinue successful treatment with an SSRI, an SNRI, or a TCA, the medication should be gradually tapered (e.g., one dosage step down every month or two), thereby providing the opportunity to watch for recurrence and, if desired, to reinitiate treatment at a previously effective dose [II]. However, under more urgent conditions (e.g., the patient is pregnant and the decision is made to discontinue medications immediately), these medications can be discontinued much more quickly [I].

The approach to benzodiazepine discontinuation also involves a slow and gradual tapering of dose [I]. Withdrawal symptoms and symptomatic rebound are commonly seen with benzodiazepine discontinuation, can occur throughout the taper, and may be especially severe toward the end of the taper. This argues for tapering benzodiazepines very slowly for patients with panic disorder, probably over 2–4 months and at rates no higher than 10% of the dose per week [I]. Cognitive-behavioral therapy may be added to facilitate withdrawal from benzodiazepines [I].

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II. Formulation and Implementation of a Treatment Plan

The formulation of a treatment plan considers the full range of predispositions, precipitants, and symptoms exhibited by patients with panic disorder. Effective treatment involves not only resolution of panic attacks but also satisfactory reductions in anticipatory anxiety and agoraphobic avoidance, optimally with full remission of symptoms and return to a premorbid level of functioning.

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A. Psychiatric Management

Psychiatric management consists of a comprehensive array of activities and interventions that should be instituted by psychiatrists for all patients with panic disorder, in combination with specific treatment modalities.

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1. Establishing a therapeutic alliance

As in all of medical practice, the physician first works to establish and then to maintain a therapeutic alliance so that the patient's care is a collaborative endeavor. By the very nature of the illness, many patients with panic disorder are anxious about treatment. Therefore, education and support are important components of the psychiatric management of panic disorder. As is true for most individuals who are first initiating treatment for psychiatric or general medical disorders, patients with panic disorder may require additional support and access to their health care professionals in the early phase of treatment, before symptoms resolve. Patients should be informed about courses of action they can pursue if they need help urgently, such as having the psychiatrist paged, going to the emergency department, or calling 911. This information should be provided in the context of education that panic symptoms themselves are rarely dangerous and that occurrence of panic symptoms does not usually require immediate medical attention.

Panic disorder can be a chronic condition for which adherence to a treatment plan is important. Hence, a strong treatment alliance is crucial. It is often the case that the treatment of panic disorder involves asking the patient to do things that may be frightening and uncomfortable, such as confronting agoraphobic situations. Here again, a strong treatment alliance is necessary to support the patient in doing these things.

Therapeutic communications explaining panic disorder should be made in language that is culturally sensitive and worded in a way that the patient can understand. Careful attention to the patient's fears and wishes with regard to his or her treatment is essential in establishing and maintaining the therapeutic alliance. Management of the therapeutic alliance may involve an awareness of the patient's beliefs about medication and psychotherapy, cultural differences, transference, countertransference, and other factors that may influence the psychiatrist-patient relationship.

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2. Performing the psychiatric assessment

Patients with panic symptoms should receive a thorough diagnostic evaluation both to determine whether a diagnosis of panic disorder is warranted and to identify the presence of other psychiatric or general medical conditions. This evaluation will generally include a history of the present illness and current symptoms; past psychiatric history; general medical history and history of substance use; personal history (e.g., major life events); social, occupational (including military), and family history; review of the patient's medications; review of previous treatments; review of systems; mental status examination; physical examination; and diagnostic tests (to rule out possible general medical causes of panic symptoms) as indicated. Family history of anxiety disorders and childhood traumatic events are reported more often by patients with panic disorder than by many comparison groups (3–5), and longitudinal data suggest that childhood physical and sexual abuse are risk factors for panic disorder (6). Patients with panic disorder also report more stressful events in the month preceding panic onset, compared with control participants (7). Therefore, the psychiatric assessment should include careful inquiry about the patient's developmental history, life events, family history, and the events that preceded onset of the panic symptoms. Additional details about the general principles and components of a complete psychiatric evaluation have been outlined in APA's Practice Guideline for the Psychiatric Evaluation of Adults, Second Edition (8).

Delineating the features of panic disorder that are present in a given patient is also important in establishing a diagnosis of panic disorder and developing a plan of treatment. The essential features of panic disorder are recurrent panic attacks and persistent concern about these attacks (or change in behavior as a result of the attacks). Panic attacks are discrete periods of intense fear or discomfort that have abrupt onset and usually reach a peak within 10 minutes. These attacks are characterized by distressing physical and psychological symptoms and often by a sense of imminent danger and an urge to escape. Persistent concern about panic attacks can manifest in several ways: worry about having additional attacks, worry about the implications or consequences of the attacks, or changes in behavior that are intended to prevent attacks or cope with an attack should one occur. Fear and avoidance of situations and places such as driving, restaurants, shopping malls, and elevators commonly occur in individuals with panic disorder; this avoidance is referred to as agoraphobia. Patients with concurrent agoraphobia fear and/or avoid situations in which escaping or obtaining help may be difficult or embarrassing if they have panic symptoms. In any evaluation of panic disorder, it is crucial to determine if agoraphobia is present and to establish the extent of situational fear and avoidance. Tables 1, 2, 3, and 4 provide the DSM-IV-TR criteria for the diagnoses of panic attack, agoraphobia, panic disorder without agoraphobia, and panic disorder with agoraphobia. More detailed discussion of the diagnostic features of panic disorder can be found in DSM-IV-TR and in Section IV.A of this guideline.

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Table Reference Number
Table 1. Diagnostic Criteria for 300.01 Panic Disorder Without Agoraphobia
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Table Reference Number
Table 2. Diagnostic Criteria for 300.21 Panic Disorder With Agoraphobia
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Table Reference Number
Table 3. DSM-IV-TR Diagnostic Criteria for Panic Attack
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Table Reference Number
Table 4. DSM-IV-TR Criteria for Agoraphobia

In addition to a full assessment of the features of panic disorder and agoraphobia, a comprehensive psychiatric assessment is essential to identify other anxiety disorders, mood disorders, substance use disorders, personality disorders, and other disorders that often co-occur with panic disorder (9–33). Co-occurring psychiatric disorders require particular attention as some of them affect the course, treatment response, and prognosis of panic disorder (34).

Establishing the context in which panic attacks occur is important for accurate diagnosis. Panic attacks frequently occur in other disorders, and in only a subset of individuals is panic disorder an appropriate diagnosis. First, it must be determined that panic attacks do not occur solely as a result of a general medical condition. Some examples of medical conditions that can be associated with panic symptoms include hyperthyroidism, hypothyroidism, hypercalcemia, hypoglycemia, pheochromocytoma, vestibular dysfunction (e.g., Ménière's disease), seizure disorders, and cardiac conditions such as arrhythmias and supraventricular tachycardia (35). With most of these conditions, definitive causal relationships between the general medical condition and panic disorder have not been established. Although there appears to be an increased co-occurrence of mitral valve prolapse and panic disorder (36–39), mitral valve prolapse is typically an incidental finding in a patient with panic disorder and does not usually change the treatment plan (i.e., the panic disorder remains the primary target of treatment). Section III.B provides further discussion of the impact of co-occurring medical conditions on treatment planning for panic disorder.

Panic attacks are often associated with intoxication with (e.g., cannabis, stimulant) or withdrawal from (e.g., sedative-hypnotic, alcohol, benzodiazepine) drugs of abuse. Prescription or over-the-counter medications, including decongestants (pseudoephedrine, phenylpropanolamine), stimulants, dopaminergic agents, and agents to treat asthma (beta-adrenergic agonist inhalers, theophylline, steroids) may also induce or worsen panic attacks. Finally, caffeine and related compounds in beverages (e.g., coffee, colas, tea, "energy drinks") and other ingested products (e.g., "energy bars") can induce panic attacks in anyone at excessive doses (typically more than 800–1,000 mg/day), but can do so even at lower doses in individuals susceptible to panic disorder. Reduction or elimination of intake of such medications and substances may lead to a marked decrease or cessation of panic episodes.

Psychiatrists also should consider other psychiatric disorders for which panic attacks can be an associated feature. A diagnosis of panic disorder requires the presence of at least some unexpected attacks during the course of illness that are not triggered by a specific stimulus. Psychiatrists should consider other disorders when panic attacks appear to be exclusively associated with the following:

  • Exposure to a specific feared situation or stimulus (specific phobia)

  • Exposure to situations in which the patient fears negative evaluation (social phobia)

  • Exposure to the focus of an obsession or a situation in which the patient was prevented from performing a compulsive behavior (obsessive-compulsive disorder)

  • Exposure to a reminder of a traumatic experience or to a situation in which the patient feels that safety is threatened (posttraumatic stress disorder)

  • Intense bouts of worrying (generalized anxiety disorder)

  • Exposure to separation from home or an attachment figure in children or adolescents (separation anxiety disorder)

  • Hallucinations or delusional thinking (psychotic disorders)

  • Use or withdrawal from use of a substance (substance use disorders; especially, intoxication with central nervous system stimulants or cannabis and withdrawal from central nervous system depressants)

In addition to establishing that panic attacks are not exclusively associated with the circumstances listed above, it must be determined that the patient has experienced 1 month or more of worry about having more attacks, worry about the implications of the attacks, or panic-related behavioral changes. If a patient reports panic attacks without associated worry or behavioral change, the psychiatrist should consider whether panic attacks are an associated feature of another disorder or represent a subthreshold panic disorder (i.e., the patient demonstrates many features of panic disorder but does not meet full criteria). Although subthreshold panic disorder is associated with a lesser degree of symptoms, comorbidity, and functional impairment than full panic disorder (40), subthreshold panic disorder is often distressing for the patient, can interfere with functioning, and may progress to full panic disorder in some individuals (41). Standard treatments for panic disorder are generally indicated for patients presenting with subthreshold symptoms, although education or a briefer course of treatment may be sufficient as a first treatment step if symptoms are mild.

Panic attacks that occur in the absence of worry about the attacks or behavior change in response to the attacks also may be conceptualized as associated features of other disorders. For instance, it is fairly common for patients with mood disorders to report occasional unexpected panic attacks; however, if persistent concerns about the attacks and behavioral changes in response to the attacks are both absent, then the panic attacks should be conceptualized as an associated feature of the mood disorder. In other cases, patients may present with panic attacks that are part of a reaction to a specific stressful situation; in this circumstance, a diagnosis of adjustment disorder may be indicated. Finally, patients may report panic symptoms that, upon further examination, appear to be normal reactions to truly threatening situations (e.g., deployment to a war zone, diagnosis of a serious illness).

Some patients endorse worry about panic-like symptoms and/or avoidance of situations because of fears of developing panic-like symptoms; however, the episodes of fearfulness they describe do not meet DSM-IV-TR criteria for a panic attack. In these cases, a diagnosis of agoraphobia without history of panic disorder should be considered. Patients with this diagnosis often fear and avoid situations that are commonly avoided by patients with panic disorder (e.g., crowded places, driving long distances). In contrast to patients with panic disorder, such patients report only limited symptom attacks (i.e., subthreshold panic attacks) or perhaps one discrete symptom (e.g., stomach distress). Standard treatments for panic disorder (especially cognitive-behavioral approaches) are indicated for most patients with agoraphobia without history of panic disorder, although they should be tailored to address the patient's particular concerns and symptoms.

Some atypical presentations of panic disorder may be misinterpreted as other disorders. For instance, some patients experience choking sensations as a prominent symptom of panic and avoid eating many foods due to fears of choking. Their restricted eating may cause them to initially appear to have a primary eating disorder. However, upon further questioning these patients reveal that they avoid eating certain foods because they fear choking and that the symptoms they experience while eating are consistent with the definition of a panic attack. If the patient also reports some unexpected panic attacks, the diagnosis of panic disorder may be appropriate. If unexpected attacks are absent, then a specific phobia of choking may be a more accurate diagnosis. Regardless, determining the concern (fear of gaining weight versus fear of panicking and choking) that motivates the problematic behavior (restricted eating) is essential to differential diagnosis.

Finally, it is important to note that the presence of general medical conditions, substance use, and other psychiatric disorders does not preclude a concomitant diagnosis of panic disorder. If the symptoms of panic disorder are not deemed to be solely attributable to these factors, then diagnosing both panic disorder and another condition (medical, psychiatric, or substance related) may be warranted.

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3. Tailoring the treatment plan for the individual patient

Although patients with panic disorder share common features of the illness, there may be important individual differences. The frequency of panic attacks varies widely among patients, and the symptoms associated with panic attacks can be highly individualized. For example, some patients report attacks that primarily involve somatic symptoms (e.g., palpitations, chest pain), whereas others are more focused on psychological symptoms (e.g., depersonalization, fear of "going crazy"). The amount of anticipatory anxiety and the degree of agoraphobic avoidance also vary from patient to patient. Many patients with panic disorder exhibit only mild levels of avoidance; at the opposite extreme are patients who will not leave the house without a trusted companion. Patients also present with significant variation in their profiles of panic-related apprehension, which seem to fall into one or more of several major foci of concern (i.e., physical, social, or mental catastrophe) (42). Sensitivity to these individual differences in the elements of panic disorder is essential for two reasons. First, it is important for the patient to feel that the psychiatrist understands his or her individual experience of panic symptoms. Second, treatment selection, delivery, and response may be influenced by the particular constellation of symptoms of a given patient.

Tailoring the treatment to match the needs of the particular patient requires a careful assessment of the frequency and nature of the patient's symptoms. It may be helpful for patients to monitor their panic symptoms using techniques such as keeping a daily diary, in order to gather information regarding the relationship of panic symptoms to internal stimuli (e.g., emotions) and external stimuli (e.g., substances, particular situations or settings). Such monitoring can reveal triggers of panic symptoms that may be the focus of subsequent intervention.

In addition, it is extremely important when formulating the treatment plan to address the presence of any of the many psychiatric and medical conditions that frequently co-occur with panic disorder. Continuing evaluation and management of co-occurring conditions are a crucial part of the treatment plan. In some individuals, treatment of co-occurring conditions may be required before interventions for panic disorder can become successful. For example, patients with serious substance use disorders may need detoxification before it is possible to institute treatment for panic disorder. However, total abstinence should not usually be a condition of initiating panic disorder treatment, especially if the substance use appears to be triggered by panic disorder symptoms. Symptoms of co-occurring personality disorders (e.g., borderline personality disorder) may also be so prominent that they interfere with symptom-based treatment of panic disorder. In these circumstances, the personality disorder may require appropriate intervention before or concomitant with the panic treatment (see APA's Practice Guideline for the Treatment of Patients With Borderline Personality Disorder [43]).

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4. Evaluating the safety of the patient

A careful assessment of suicide risk is an essential element of the evaluation of all patients with panic disorder. Panic disorder has been shown to be associated with an elevated risk of suicidal ideation and behavior, even after controlling for the effects of co-occurring conditions (44). The assessment should include 1) identification of specific psychiatric symptoms known to be associated with suicide attempts or suicide, which include aggression, violence toward others, impulsiveness, hopelessness, agitation, psychosis, mood disorders, and substance use disorders; 2) assessment of past suicidal behavior, including the intent and lethality of self-injurious acts; 3) family history of suicide and mental illness; 4) current stressors such as recent losses, poor social support, family dysfunction, physical illnesses, chronic pain, or financial, legal, occupational, or relationship problems; 5) potential protective factors such as positive reasons for living (e.g., children, other family members, pets, positive therapeutic relationships, sense of responsibility to others), spirituality/religious beliefs, or good reality testing, frustration tolerance, or coping skills; and 6) specific inquiry about suicidal thoughts, intent, plans, means, and behaviors. For more information about assessing and managing suicidality, readers may consult APA's Practice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors (45). Issues relating to the potential for emergence of suicidality with antidepressant treatment are reviewed in Section II.H.

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5. Evaluating types and severity of functional impairment

The degree of functional impairment varies considerably among patients with panic disorder. While panic attack frequency and severity contribute to functional impairment, so do the extent of anticipatory anxiety and agoraphobic avoidance. In particular, agoraphobic avoidance can lead to considerable dysfunction in both work and social domains. Levels of agoraphobic avoidance and apprehension have been shown to be stronger predictors of functional impairment and quality of life than frequency of panic attacks (46). Even after panic attacks have subsided, the patient may continue to have significant functional limitations that should be addressed in treatment.

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6. Establishing goals for treatment

The ultimate goals of first-line treatments for panic disorder are reducing the frequency and intensity of panic attacks, anticipatory anxiety, and agoraphobic avoidance, optimally with full remission of symptoms and attainment of a premorbid level of functioning. Treatment of co-occurring psychiatric disorders when they are present is an additional goal. The intermediate objectives that will help achieve these goals will depend on the chosen modality or modalities (see Section II.C). For example, in the case of pharmacotherapy the initial objectives include educating the patient about panic disorder and medication treatment (including medication side effects), selecting an appropriate starting dose of medication, titrating up to a therapeutic dose, promoting adherence to the medication regimen, and recommending and reinforcing positive behavioral changes. When any psychosocial treatment is pursued, a coherent explanation of how that treatment is thought to influence panic disorder should be provided to the patient. The conceptual model of panic pertinent to the type of therapy or therapies being deployed, principles of treatment, and expected outcomes should be made explicit to the patient.

Treatment of panic disorder should also include substantial effort to alleviate or minimize functional impairment that may be associated with panic attacks, associated anxiety, and agoraphobic avoidance. In addressing such functional impairment, it is critical to determine how patients define satisfactory outcomes and desirable levels of functioning for themselves, but also to assist patients who may not believe certain goals are attainable to become aware of the possibility of functional gains.

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7. Monitoring the patient's psychiatric status

The different elements of panic disorder often resolve at different points during the course of treatment. Usually, panic attacks are controlled first, but subthreshold panic attacks, anticipatory anxiety, and agoraphobic avoidance often continue and require further treatment (47). The psychiatrist should continue to monitor the status of all of the symptoms with which the patient originally presented and should monitor the effectiveness of the treatment plan on an ongoing basis. Many illnesses, including depression and substance use disorders, co-occur with panic disorder at higher rates than are seen in the general population (33). Therefore, the psychiatrist should monitor the patient's mood (and symptoms of any other co-occurring disorder) on an ongoing basis.

Psychiatrists may consider using rating scales to help monitor the patient's status at each session. Other resources provide detailed information about rating scales that may help with ongoing measurement of the severity of panic disorder symptoms and symptoms of co-occurring conditions (48, 49). Rating scales such as the Panic Disorder Severity Scale (PDSS) (50) may complement the psychiatrist's interview by offering a quantitative measure of severity that can be tracked over time. The PDSS can be administered and rated by the psychiatrist (50, 51), or a self-report version can be used (52). Rating scales that measure symptoms of anxiety more broadly also may aid in monitoring the patient's status. The Overall Anxiety Severity and Impairment Scale (OASIS) (53) is an example of a rating scale that measures symptoms of anxiety more broadly (i.e., includes both panic and other anxiety disorder symptoms), which may also be a useful way to measure outcome for some patients. Many other rating scales for anxiety, panic symptoms, and agoraphobia are available. Psychiatrists may refer to clinical handbooks to find other appropriate measures of panic symptoms as well as measures of common co-occurring illnesses (e.g., depression). These handbooks offer descriptions of various rating scales along with information about reliability and validity, administration and scoring, and instructions about how to obtain each scale (48, 49).

Psychiatrists also can evaluate the frequency and severity of a patient's panic symptoms by asking the patient to keep a daily diary that includes information such as the time, location, nature, and intensity of panic symptoms. Before instructing patients to monitor panic symptoms, the psychiatrist should discuss the potential costs (e.g., temporary increase in anxiety because of increased focus on symptoms) and benefits (e.g., more accurate assessment of symptoms than by using retrospective report) of this assessment strategy (54).

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8. Providing education to the patient and, when appropriate, to the family

Once the diagnosis of panic disorder is made, the patient should be informed of the diagnosis and educated about panic disorder, its clinical course, and its complications. The psychiatrist should convey hope and reasonable expectations for how treatment will influence the course of the disorder. Regardless of the treatment modality selected, it is important to inform the patient that in almost all cases the physical sensations that characterize panic attacks are not acutely dangerous and will abate. In a few rare circumstances (e.g., possible elevated risk of hypoperfusion or placental abruption in pregnant women with panic attacks), panic attacks may in fact be associated with harmful effects; this information should be disseminated as needed for individual patients who present with co-occurring conditions that put them at risk for possible complications of panic attacks.

Many patients with panic disorder believe they are suffering from a disorder of an organ system other than the central nervous system. They may fervently believe, for example, that they have heart or lung disease. Partners and involved family members of patients with panic disorder may share these beliefs, may be frustrated by the patient's disability, or may insist that absolutely nothing is wrong with the patient. Educating both the family and the patient and emphasizing that panic disorder is a real illness requiring support and treatment can be crucial. Regardless of the method of treatment selected, successful therapies of panic disorder usually begin by explaining to the patient that the attacks themselves are not life-threatening. By helping the patient realize that these symptoms are neither life-threatening nor uncommon, education alone may relieve some of the symptoms of panic disorder. This information also may enhance motivation for treatment. The family may be helped to understand that panic attacks are terrifying to the patient, that avoidant behavior can perpetuate panic symptoms, and that the disorder, unless treated, can interfere significantly with the patient's life. In addition to receiving education provided by the treating psychiatrist, patients and their families may benefit from access to organizations and to materials that promote understanding of anxiety disorders and other mental health problems (see Appendix). As with other therapeutic communication, cultural and language differences may need to be considered and accommodated in imparting information about panic disorder to patients and their families.

There are rare situations in which agoraphobic avoidance becomes such a routine part of the patient's life that the family is actually reluctant to see it remit. A patient who is homebound because of panic disorder, for example, may have assumed all of the household chores for the family. Remission of this kind of agoraphobic avoidance might lead the patient to engage in more activities outside of the home and create a potential for conflict in the family system. Without recognizing this, family members might tacitly undermine a potentially successful treatment to avoid disrupting their ingrained patterns. It is also possible (although not necessarily common) that successful resolution of agoraphobia may place strain on significant relationships as others adjust to the changes in the patient's ability to pursue independent activities (55). Therefore, education sometimes includes discussion of how changes in the patient's status might affect the family system and how responses of family members can help or hinder treatment of the patient's panic disorder.

Patient education also includes general promotion of healthy behaviors such as exercise, good sleep hygiene, and decreased use of caffeine, tobacco, alcohol, and other potentially deleterious substances. Preliminary evidence suggests that aerobic exercise may benefit individuals with panic symptoms (56–59). Given the myriad health benefits of exercise, even if benefits for panic disorder are largely unproven, psychiatrists should consider recommending aerobic exercise (e.g., walking for 60 minutes or running for 20–30 minutes at least 4 days per week) to patients who are physically able. However, in doing so the psychiatrist should consider that fears of physical exertion are common in patients with panic disorder and that exercise may actually trigger panic attacks in some patients (although most patients can tolerate exercise without difficulty) (60). In these individuals, the psychiatrist may wish to incorporate exercise into the treatment regimen more gradually, as the patient experiences symptom relief and develops coping skills for panic symptoms. For patients receiving CBT, aerobic exercise can be incorporated into the interoceptive exposure component of treatment.

When co-occurring tobacco use is present, smoking cessation interventions may be useful adjuncts to standard treatments for panic disorder. Epidemiologic data suggest that daily smoking increases risk for panic attacks and panic disorder. Thus, smoking may be a causal or exacerbating factor in some individuals with panic disorder. The effects of other substance use disorders on panic disorder symptoms and treatment are reviewed in Section III.A.2.

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9. Coordinating the patient's care with other clinicians

Many patients with panic disorder will be evaluated by or will receive treatment from other health care professionals in addition to the psychiatrist. Under such circumstances, the clinicians should communicate periodically to ensure that care is coordinated and that any treatments are working in synchrony. Psychiatric management may also involve educating nonpsychiatric health care professionals about panic disorder, including the ability of panic attacks to masquerade as other general medical conditions and strategies for assisting patients who are convinced that panic attacks represent serious abnormalities of other organ systems.

It is important to ensure that a general medical evaluation has been done (either by the psychiatrist or by another physician) to rule out medical causes of panic symptoms. By the time a psychiatrist is consulted, many patients with panic disorder may already have undergone medical testing, which the psychiatrist should review. Generally, physicians should test thyroid-stimulating hormone levels to rule out thyroid disease and obtain a substance use history (including caffeine, nicotine, alcohol, and other potentially deleterious substances) to rule out overuse, abuse, or dependence that could be causing or exacerbating symptoms of panic disorder. If cardiac symptoms are prominent, an electrocardiogram may be warranted, and if seizures are suspected the physician should refer the patient to a neurologist for evaluation. Extensive or specialized testing for medical causes is usually not indicated during the initial assessment but may be conducted based on the patient's specific presentation (e.g., frequent palpitations may be cause to conduct a Holter monitoring examination or other specific cardiac tests). In fact, attempting to diagnose and treat a variety of nonspecific somatic symptoms may delay initiation of treatment for the panic disorder itself. However, with some patients it may be therapeutic and enhance the therapeutic alliance to undertake assessment that will disconfirm other causative sources for the panic attacks. Therefore, the extent of assessment for medical causes of panic attacks will vary according to the individual patient.

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10. Enhancing treatment adherence

The treatment of panic disorder involves confronting many things that the patient fears. Patients are often afraid of medically adverse events; hence, they fear taking medications and can be very sensitive to somatic sensations induced by them (e.g., initial tremulousness or nervousness caused by antidepressants). As described in Section II.G.1, patients receiving CBT may be required to confront both interoceptive fear cues (i.e., feared bodily sensations) and external fear cues (i.e., agoraphobic situations) and to keep careful records of anxiety symptoms. These activities may temporarily increase the patient's anxiety level.

The short-term intensification of anxiety in association with standard treatments for panic disorder may decrease adherence. For example, some patients may miss or arrive late for treatment sessions, may abruptly stop medication, or may not complete required assignments during CBT. Recognition of these possibilities guides the psychiatrist to adopt a stance that encourages the patient to articulate his or her fears. It is also helpful to inform the patient that response is not likely to be immediate and that there may even be an initial increase in anxiety as treatment begins. Patients should be educated that relapses may occur during the course of recovery but that these events do not typically indicate that treatment will be ineffective over time. The psychiatrist should indicate how the patient could obtain help in the event of a severe relapse.

Problems with treatment adherence can result from a variety of factors. An empathic and nonjudgmental stance can facilitate discussion of adherence issues such as missed sessions, lapses in medication use, or failure to complete CBT homework assignments. In addition, incomplete adherence may simply be a manifestation of the disorder. For example, the patient might be afraid of somatic sensations that accompany medication use or be afraid to complete an exposure to a feared situation. Agoraphobic avoidance might also cause patients to miss sessions because of fears of leaving the house or traveling. Psychiatrists should acknowledge the possibility that anxiety might sometimes interfere with adherence to treatment and should help patients plan ahead to minimize this possibility. For example, for a patient who fears driving, initially arrangements could be made for a family member to drive the patient to sessions. Family members or other trusted individuals also may play other helpful roles in improving treatment adherence, such as reminding the patient to take medication at scheduled times or giving the patient positive reinforcement for confronting situations previously avoided.

Adherence may be limited not only by the disorder but also by practical issues such as scheduling conflicts, lack of transportation or child care, or insufficient financial resources. With regard to scheduling, transportation, and child care issues, it is useful to identify these potential obstacles at an early juncture and help the patient generate possible solutions. Pharmaceutical companies may provide free medications for patients with severe financial limitations, with the exact criteria differing from company to company. Information on patient assistance programs is available from the web site of the Partnership for Prescription Assistance (http://www.helpingpatients.org) and from Rx Assist (http://www.rxassist.org).

Finally, incomplete adherence may reflect issues in the psychiatrist-patient relationship. If adherence is not improved by measures such as discussing fears, providing reassurance and nonpunitive acceptance, providing education, and mobilizing family support, it may indicate more complex resistance that is not within the patient's awareness and that may need to become the main focus of treatment.

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11. Working with the patient to address early signs of relapse

Studies have shown that panic disorder is often a chronic illness, especially for patients with agoraphobia (61, 62). Symptom exacerbation can occur even while the patient is undergoing treatment and may indicate the need for reevaluation of the treatment plan. Because such exacerbations can be disconcerting, the patient and, when appropriate, the family should be reassured that fluctuations in symptom levels can occur during treatment before an acceptable level of remission is reached. Although treatment works for most patients to reduce the burden of panic disorder, patients may continue to have lingering symptoms, including occasional panic attacks and residual avoidance. Other problems, such as a depressive episode, could also develop and require specific attention.

Relapse following treatment cessation is also possible. Patients should be instructed that panic disorder may recur and that, if it does, it is important to initiate treatment quickly to reduce the likelihood of complications such as agoraphobic avoidance (63). The patient should be assured that he or she is welcome to contact the psychiatrist and that resuming treatment almost always results in improvement.

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B. Choosing a Treatment Setting

The treatment of panic disorder is generally conducted entirely on an outpatient basis, and the condition by itself rarely warrants hospitalization. Occasionally, the first contact between patient and psychiatrist occurs in the emergency department or the hospital when the patient has been admitted in the midst of an acute panic episode. The patient may even be admitted by emergency department staff to rule out myocardial infarction or other serious general medical events. In such individuals, the psychiatrist may be able to make the diagnosis of panic disorder and initiate treatment once other general medical conditions have been ruled out. Because panic disorder frequently co-occurs with mood disorders and may elevate the risk of suicide attempts, it may also be necessary to hospitalize the patient with panic disorder when suicidal ideation is of clinical concern. Similarly, patients with panic disorder frequently have co-occurring substance use disorders, which can occasionally require inpatient detoxification. Under such circumstances, the treatment of panic disorder can be initiated in the hospital along with treatment of the disorder that prompted hospitalization. Rarely, hospitalization or partial hospitalization is required in very severe cases of panic disorder with agoraphobia when administration of outpatient treatment has been ineffective or is impractical. For example, a housebound patient may require more intensive and closely supervised treatment in the initial phase of therapy than that provided by outpatient care (64, 65). Home visits are another option for severely agoraphobic patients who are limited in their ability to travel or leave the house.

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C. Choosing an Initial Treatment Modality

A range of specific psychosocial and pharmacological interventions have proven benefits in treating panic disorder. The use of an SSRI (66–87), SNRI (88, 89), TCA (70, 72, 79, 90–112), benzodiazepine (appropriate as a monotherapy only in the absence of a co-occurring mood disorder) (104, 113–132), or CBT (67, 111, 133–144) as the initial treatment for panic disorder is strongly supported by demonstrated efficacy in numerous controlled trials. A particular form of psychodynamic psychotherapy called panic-focused psychodynamic psychotherapy (145) has also been shown to be effective in a randomized controlled trial (146), suggesting that under certain circumstances (e.g., patient preference for a dynamically oriented therapy), PFPP could be offered as an initial treatment. Other psychosocial treatments for patients with panic disorder have either been found equivalent to placebo conditions (e.g., EMDR), have proven inferior to standard treatments (e.g., supportive psychotherapy [147]), or have not been formally tested in controlled studies (e.g., certain forms of psychodynamic psychotherapy).

There is insufficient evidence to recommend any proven efficacious psychosocial or pharmacological intervention over another or to recommend a combination of treatments over monotherapy. Considerations that guide the choice of an initial treatment modality include patient preference, the risks and benefits of the two modalities for the particular patient, the patient's past treatment history, the presence of co-occurring general medical and other psychiatric conditions, cost, and treatment availability. Advantages of pharmacotherapy include ready availability and the need for less effort by the patient for treatment to take effect. Disadvantages include risks of adverse effects, with roughly 10%–20% of patients in clinical trials of common medications for panic disorder specifically citing medication side effects as a reason for dropping out of the trial. Discontinuation symptoms can be an additional disadvantage, necessitating that patients taper medication slowly if a decision is made to stop medication. Costs of medications vary and are affected by the choice and dose of the agent, the availability of generic preparations, the duration of treatment, requirements for additional pharmacotherapy or psychosocial treatment, and the cost of treating medication-related side effects. From the standpoint of patient preference, many patients do not wish to take medications (148), and they may perceive a psychosocial treatment as a more favorable option. For example, studies of CBT have shown that patients may prefer it to pharmacotherapy (111, 149). On the other hand, psychotherapy requires considerable time and discipline on the part of the patient to confront feared situations or perform the "homework" associated with treatment. With CBT, approximately 10%–30% of patients have been found unwilling or unable to do this (133–135, 137). Patients who are reluctant to invest time, effort, and short-term increases in anxiety in exchange for possible longer-term resolution of symptoms may not desire, and are less likely to benefit from, psychosocial treatment. In terms of psychosocial treatment costs, contributory factors include the duration and frequency of treatment, its administration in an individual or group setting, and any requirements for additional psychosocial or pharmacological treatment. An additional disadvantage of specialized psychotherapies is that they may not be readily available to patients in some areas.

Combining psychotherapy and pharmacotherapy is intuitively attractive and common in clinical practice. Several specific combination treatments have been studied and shown to be effective for panic disorder, including CBT (or exposure therapy) plus imipramine (91, 111, 150–155), CBT plus paroxetine (69), exposure therapy plus fluvoxamine (68), psychodynamic psychotherapy plus clomipramine (156), and algorithm-based pharmacotherapy plus a collaborative care intervention that included CBT (157–159).

With regard to the comparative efficacy of combined treatment versus monotherapy, the most recent meta-analysis of randomized controlled trials of treatments for panic disorder suggested a small but significant advantage for the combination of antidepressants plus psychotherapy over monotherapies in the acute phase of treatment (160). However, combined treatment was no better than psychotherapy alone in longer-term follow-up, although it was superior to pharmacotherapy alone (160). In addition, some studies have raised concerns about the possibility that simultaneously initiating benzodiazepines (149, 161) or antidepressant medications (111) with CBT may diminish the durability of response to CBT after all treatments are withdrawn. These results, which are by no means definitive, should be considered in treatment of patients who plan to pursue CBT and are also contemplating starting medication.

Although combination treatment does not appear to be significantly superior to standard monotherapies for most individuals with panic disorder, psychiatrists and patients may choose this option for a variety of individual circumstances. For example, many clinicians combine pharmacotherapy to provide more immediate control of distressing symptoms with psychosocial treatments intended to address symptoms over the long term and reduce future need for medications.

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D. Evaluating Whether the Treatment Is Working

After treatment is initiated, it is important to monitor change in the patient's key symptom domains, such as frequency and intensity of panic attacks, level of anticipatory anxiety, degree of agoraphobic avoidance, and severity of interference and distress related to panic disorder. Effective treatment should produce a decrease in each of these domains, although some may change more quickly than others (e.g., the frequency of panic attacks may decrease before agoraphobic avoidance decreases). The pattern of symptom resolution varies depending on the individual patient; for example, some experience "sudden gains" in which they manifest a significant decrement in symptoms in a brief period of time, whereas others experience steady and gradual improvement over a period of many weeks. As described earlier in Section II.A.7, rating scales can be a useful adjunct to ongoing clinical assessment in evaluating treatment outcome. The severity of co-occurring conditions also should be assessed at regular intervals, as effective treatment of panic disorder can influence co-occurring conditions.

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E. Determining If and When to Change Treatment

Clinical trials suggest that many individuals do not respond, or respond incompletely, to first-line treatments for panic disorder. Whenever treatment response is unsatisfactory (e.g., inadequate reduction of panic attacks, continued agoraphobic avoidance), the psychiatrist should first consider the possible contribution of the following factors: an underlying untreated medical illness, interference by co-occurring general medical or psychiatric conditions (including substance use), inadequate adherence to treatment recommendations, problems in the therapeutic alliance, the presence of psychosocial stressors, motivational factors (e.g., secondary gain that results from the patient's panic disorder symptoms), and inability to tolerate a particular treatment. These potential impediments to successful treatment should be addressed as early as possible. With pharmacotherapy, the dose of medication may also be an important consideration. Clinical experience suggests that patients who do not respond after several weeks at the lower therapeutic dose range may do better with a further dose increase (i.e., to the highest tolerable level within accepted dosage ranges), although this strategy has not been systematically studied.

It is important for the psychiatrist to remember that patients with panic disorder may have become accustomed to avoiding anxiety- and panic-provoking situations and may resist treatments that focus on eliminating this avoidance (e.g., CBT, exposure instructions assigned as an adjunct to pharmacotherapy). Thus, the psychiatrist should explore whether fearfulness is leading the patient to minimize reporting the impact of avoidance or to accept functional limitations resulting from avoidance. If such fears are an issue, the patient can be encouraged to think through the costs and benefits of accepting versus treating functional limitations.

Another important consideration is that many patients with panic disorder have co-occurring depression. If the patient is in a dysphoric state he or she may be hopeless about the possibility of change. It is important to mitigate the effects of depression on the patient's level of optimism about treatment options (e.g., point out that depression may be affecting the patient's perceptions and recommend trying something new even if the patient is doubtful that it will work).

If response to treatment remains unsatisfactory, and if an adequate trial has been attempted, it is appropriate for the psychiatrist and the patient to consider a change. Although there is a lack of evidence for what constitutes an adequate trial, it is important to consider the usual time course of response to specific therapies. For example, with CBT, the literature shows that improvement may not plateau until 12 sessions of treatment have been completed. With benzodiazepines, psychiatrists and patients often note some reduction in panic within the first week of treatment, although full blockade of panic attacks can take several weeks, particularly as the dose is being titrated for the individual. With SSRIs, SNRIs, and TCAs, reduction in panic attack frequency, anticipatory anxiety, and avoidance may start within the first 3–4 weeks of treatment. However, there is evidence that therapeutic response continues to accrue with continued pharmacotherapy. For some patients and particularly for those with a significant level of agoraphobic avoidance, full remission of symptoms, including the complete cessation of panic attacks, full resolution of anticipatory anxiety and agoraphobia, and full return to functioning, may take up to 6 months or longer (72) (including 4–6 weeks at the highest comfortably tolerated dose). Thus, many experts recommend waiting at least 6 weeks from initiation of antidepressant treatment, with at least 2 of those weeks at full dose, before deciding whether more intensive, additional, or alternative treatments are warranted. When a patient's symptoms are severe, however, it is often not feasible to wait that long. Consequently, the approach and timing of treatment changes must be individualized to the patient's symptoms and circumstances.

Decisions about whether to make changes will also depend on the following factors: level of partial response (e.g., if virtually no benefits are apparent, a change should almost certainly be undertaken; if slow but steady progress is apparent, the psychiatrist and patient may decide to continue the current trial for a brief period then reassess); the palatability and feasibility of other treatment options (e.g., a patient who does not respond to psychosocial treatment might benefit from pharmacotherapy, but some patients are unwilling to take medication; a patient who does not respond to medication might benefit from psychosocial treatment, but psychosocial treatment may not be feasible because the patient cannot commit the time for weekly sessions and homework with CBT); and the level of symptoms and impairment the patient is willing to accept (e.g., the patient may still avoid some situations but may not be motivated to overcome those fears at present; the patient may still experience occasional panic attacks but may view this as tolerable and not wish to pursue further treatment to eliminate remaining symptoms). However, persistent significant symptoms of panic disorder despite a lengthy course of a particular treatment should trigger a reassessment of the treatment plan, including possible consultation.

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F. Approaches to Try When a First-Line Treatment Is Unsuccessful

If the fundamental clinical issues described in the previous section have been addressed and it is determined that a change in treatment approach is desirable, the psychiatrist and patient have two basic options. The first option is to augment the current treatment by adding another agent (in the case of pharmacotherapy) or another modality. Alternatively, the psychiatrist and patient may decide to switch to a different medication or therapeutic modality.

Decisions about how to address treatment resistance are likely to be highly individualized and based on clinical judgment, since few studies have tested the effects of specific augmentation and switching strategies. Decisions, however, can be informed by the extent of the patient's response and by the evidence that supports specific treatments as initial monotherapies. In general, if one first-line treatment has failed, adding or switching to another first-line treatment is recommended. Augmentation is also a reasonable approach if some significant benefits were observed with the original treatment. For instance, for a patient who had partial response to an SSRI or SNRI, the psychiatrist may consider adding a benzodiazepine or a course of CBT. On the other hand, if the original treatment did not provide any alleviation of the patient's symptoms, a switch in treatment may be more useful. For example, patients who do not respond to standard pharmacotherapies may respond to CBT (162–164), whereas those who do not respond to CBT or exposure therapy may benefit from pharmacotherapy (165, 166). If a patient's first unsuccessful treatment is with an SSRI or an SNRI, a recommended approach is to switch to a different SSRI or SNRI. If the patient's symptoms do not respond to two different SSRIs or SNRIs, switching to or adding other classes of medication that have demonstrated efficacy for panic disorder (e.g., TCAs, benzodiazepines) may be considered. When switching between antidepressants, psychiatrists will often cross-titrate (e.g., decreasing the dose of the original medication over 1–2 weeks while gradually increasing the dose of the new medication). Adding or switching to CBT may also be considered at any point when a patient shows incomplete or nonresponse to standard pharmacotherapy.

If the above treatment options, which have the highest levels of empirical support, have been unsuccessful, other options with some empirical support can be considered. Monoamine oxidase inhibitors are widely regarded as effective for panic disorder. Although the safety profile of MAOIs limits their use, they have demonstrated efficacy in older studies that included patients with probable panic disorder. Thus, MAOIs may be considered if the psychiatrist is experienced in managing these agents and if the patient is willing to adhere to a low-tyramine diet and to restrictions on the use of certain other medications. In addition, before switching to an MAOI, the psychiatrist should discontinue other antidepressant medications and allow a sufficient washout period (usually at least 2 weeks for most antidepressants and longer for those with very long half-lives such as fluoxetine) before treatment with the MAOI is initiated. The effectiveness of PFPP is supported by positive findings of a randomized controlled trial (146), making it another reasonable choice to consider for patients who prefer nonmedication treatments or for those who have not responded to other treatments. Other forms of psychodynamic psychotherapy have not been formally tested but are supported by case report evidence and clinical experience; these forms of treatment also may be considered as options for patients who have not responded to other treatments for panic disorder.

Other treatments with even more limited evidence also may be considered as monotherapies or augmentation agents under some circumstances (e.g., several other treatments have been unsuccessful; the patient cannot tolerate other treatments). Mirtazapine and gabapentin have modest evidence bases that support their use in some individuals with panic disorder. Although beta-blockers have generally been found ineffective as monotherapy for panic disorder, there is some preliminary support for the use of pindolol as an augmentation agent to enhance antidepressant response. Antipsychotics are not recommended because of limited evidence for their efficacy and concerns about side effects. However, there is very preliminary evidence for the efficacy of second-generation antipsychotics such as olanzapine and adjunctive risperidone, so these agents could be considered for patients with very severe, treatment-resistant panic disorder. Some clinical experience suggests that patient support groups may be helpful, adjunctive to other treatment. With the exception of group CBT, which has demonstrated efficacy in controlled trials, other forms of group therapy are unstudied and have unclear efficacy. Eye movement desensitization and reprocessing and couples and family therapy have been shown to be ineffective in the treatment of panic disorder.

Sections II.G and II.H provide additional information on the second- and third-line psychotherapeutic and pharmacological treatments described above, as well as for other unproven treatments. Psychiatrists are encouraged to seek consultation from experienced colleagues when developing treatment plans for patients whose symptoms have been resistant to first-line treatments for panic disorder.

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G. Specific Psychosocial Interventions

The following sections review psychosocial interventions that have been formally evaluated for treatment of panic disorder, as well as some treatments that have not been tested but are occasionally utilized by patients with panic disorder. Psychosocial treatments for panic disorder should be conducted by professionals with an appropriate level of training and experience in the relevant approach.

Based on the current available evidence, CBT is the psychosocial treatment that would be indicated most often for patients presenting with panic disorder. The efficacy of CBT (including exposure therapy alone) for panic disorder has been documented in numerous controlled trials. CBT is effective when delivered individually or in a group format. Individually administered PFPP also has demonstrated efficacy for panic disorder, although research on this treatment is in earlier stages and its evidence base is more limited. Panic-focused psychodynamic psychotherapy may be indicated as an initial psychosocial treatment for panic disorder in some circumstances (e.g., with a patient who is motivated for and able to engage in this approach). Other psychosocial treatments either have not been formally tested for panic disorder (e.g., certain forms of psychodynamic psychotherapy) or have proven ineffective or inferior to standard treatments (e.g., EMDR, emotion-focused therapy).

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1. Cognitive-behavioral therapy

The use of CBT for panic disorder is based on the assumption that maladaptive patterns of cognition and behavior maintain panic disorder. Cognitive-behavioral therapy generally targets these maintaining factors and places less emphasis on determining the origins of panic disorder for a particular patient. Cognitions hypothesized to maintain panic disorder include catastrophic misinterpretations of physical symptoms (e.g., the belief that palpitations signal an impending heart attack) (for example, see references 167 and 168). Therefore, many versions of CBT seek to identify and change mistaken beliefs about physical symptoms and their consequences. The symptoms of panic disorder and agoraphobia also have been conceptualized as resulting from conditioning processes (for example, see references 169–171). Consequently, many versions of CBT include techniques aimed at 1) weakening or extinguishing learned associations between stimuli (both internal and external) and panic and 2) creating opportunities for learning and strengthening nonanxious responses. All forms of CBT conceptualize avoidance behavior as a maintaining factor in panic disorder, either because it prevents patients from disconfirming their anxious beliefs or because it prevents habituation of fear responses. Thus, confronting feared stimuli and situations is an essential part of CBT for panic disorder.

Most forms of panic-focused CBT employ the following treatment components: psychoeducation, self-monitoring, cognitive restructuring, exposure to fear cues, modification of anxiety-maintaining behaviors, and relapse prevention. In providing CBT, the clinician may opt to focus more on certain treatment components than on others, depending on the patient's symptom profile and response to different CBT techniques.

Panic-focused CBT is generally administered in 10–15 weekly sessions (172). Therapy usually begins with one or more psychoeducation sessions that serve to identify the patient's symptoms and areas of impairment, provide accurate information about the nature and purpose of anxiety and fear, conceptualize the patient's experiences in terms of the CBT model, and outline a rationale and plan for treatment. Information gathering and education are done in an interactive manner, with a continual focus on applying the CBT model to a patient's particular symptoms and situations. The CBT therapist adopts a collaborative stance, and the educational material sets the stage for the therapist and patient to develop a shared understanding of the patient's problems. A major goal of psychoeducation for panic disorder is conveying that panic symptoms result from the body's natural fear response and are not dangerous. Reading material that reinforces the concepts introduced in the psychoeducation sessions is usually assigned for homework (see the Appendix for titles of patient workbooks that include these materials).

Self-monitoring is another core component of CBT. Patients monitor their panic attacks using techniques such as keeping a daily diary. They are asked to record the date, time, location, and any perceived triggers of the panic attack. They also may be asked to record the physical symptoms, anxious thoughts, and behavioral responses that occurred during the attack. Patients are informed that this will help to assess the frequency and nature of their panic attacks and to provide data regarding the relationship of panic symptoms to potential triggers.

Another component of CBT is exposure to fear cues. Patients with panic disorder can experience panic attacks in response to internal and external cues (169). The most common internal fear cues are bodily sensations (e.g., heart racing, dizziness, shortness of breath). Common external fear cues include situations in which having a panic attack would be embarrassing or in which escape would be difficult (e.g., public places, enclosed spaces).

For most patients, exposure to both internal and external fear cues is necessary for remission of panic symptoms to occur. Exposure proves to be the most challenging and often the most potent component of CBT. Additional effort on the part of the clinician is often required to motivate the patient to initiate and persevere with increasingly difficult exposure practices. Internal fear cues are addressed through interoceptive exposure. Interoceptive exposure involves exposing the patient to feared bodily sensations in a systematic way, until he or she no longer responds fearfully to those sensations. Feared bodily sensations are provoked using a series of exercises such as running in place (to induce heart pounding), spinning in a chair or while standing up (to induce dizziness), and hyperventilation or breathing through a straw (to induce light-headedness or shortness of breath). The CBT therapist first assesses which of these exercises produce symptoms that are anxiety provoking for the patient, and then instructs the patient to perform those exercises repeatedly until the patient is no longer afraid of the exercises or the symptoms that result. External fear cues are targeted through situational exposure, which involves confronting situations or activities that commonly provoke fear. Situational exposure can include a wide variety of exercises such as driving on a highway, riding in an elevator, or visiting a grocery store or shopping mall.

The process of conducting exposures to internal and external fear cues is systematic. The therapist first works with the patient to identify a hierarchy of fear-evoking situations. The degree of anxiety elicited in each of these situations is graded on a 0–10 scale, and several situations that evoke anxiety at each level are documented. The patient is then asked to confront the symptom or situation, usually beginning at the low end of the hierarchy on a regular (usually daily) basis until the fear has attenuated. The symptom or situation that arouses the next level of anxiety is then targeted. Interoceptive exposures are usually conducted in the therapist's office and at home in naturalistic situations. Situational exposures are best carried out in the actual situation(s). Patients typically conduct situational exposures on their own for homework; however, some CBT therapists will accompany patients to locations for situational exposures. Whereas the usual practice is to start with the least anxiety-provoking exercises and move up in intensity, patients who are motivated to treat their panic disorder more aggressively can begin exposure treatment with exercises that are more challenging (i.e., those near the top of their hierarchy) with the notion that this approach may help them achieve their treatment goals more quickly (54). Patients also are encouraged to combine interoceptive and situational exposure as they progress through treatment (e.g., deliberately hyperventilating while driving) in order to learn that they can enter feared situations and cope with them even while experiencing intense physical sensations.

Most CBT practitioners include cognitive restructuring techniques as one element of treatment, although some CBT therapists and some studies (for example, see reference 140) have questioned whether cognitive restructuring provides benefits beyond those obtained with exposure. When used as a CBT component, cognitive restructuring focuses on identifying and countering erroneous beliefs that contribute to panic disorder. Patients with panic disorder commonly interpret panic symptoms in a catastrophic manner (e.g., as signs of an impending heart attack or fainting spell). They also typically underestimate their ability to cope with panic attacks (42). In CBT, the therapist encourages the patient to recognize the thoughts that occur during panic attacks and to consider the evidence for and against these thoughts. When erroneous or exaggerated beliefs are identified, the CBT therapist and patient work together to review the evidence and generate a more realistic appraisal of the situation. The skill of countering anxious thoughts and generating more evidence-based thoughts is reinforced throughout treatment with in-session practice and homework assignments. Many CBT therapists integrate cognitive and exposure procedures. This integration focuses on using the exposure to fear cues as a vehicle for helping the patient acquire corrective threat-disconfirming information (e.g., "even though I felt anxious and dizzy while at the grocery store, I did not faint").

Modification of anxiety-maintaining "safety behaviors" is another common goal of CBT. Common safety behaviors include carrying medication bottles, establishing exit routes, and checking the locations of hospitals (173). Safety behaviors often provide the patient with an immediate feeling of security; however, within CBT they are conceptualized as maintaining anxiety in the longer term. Safety behaviors may reinforce the notion that everyday situations are inherently dangerous, prevent patients from disconfirming their threat-laden beliefs, and interfere with deriving maximum benefit from exposure practices (174). Fading and eventual elimination of safety behaviors is therefore a goal of most CBT protocols.

Some CBT protocols also teach slow, diaphragmatic breathing as a skill that patients can use to decrease anxiety and interrupt the cycle of panic (for example, see reference 111). Although the evidence suggests that breathing retraining is likely not a necessary component of treatment (175), it is still often included in CBT for panic disorder and may be a useful anxiety-reduction tool for some patients.

Cognitive-behavioral therapy for panic disorder is often provided individually, but there is evidence that group treatments may be equally effective (137, 142, 176–179). Exposure treatments for patients with agoraphobia also are efficacious when conducted in a group format (178). The inclusion of the spouse or significant other in treatment can be helpful, especially if the significant other is educated about the CBT model of panic disorder and can provide support and encouragement when the patient confronts feared situations (180, 181).

Because CBT is not widely available in some communities, some patients may have to travel a great distance to see a clinician who is proficient in CBT, or they may not have access to CBT at all. Some evidence suggests that high-density therapy (i.e., several hours of therapy within a few days) can be effective (182, 183), and this approach may be useful for patients who cannot attend a standard course of weekly sessions. One small waiting-list-controlled study showed that telephone-based CBT was effective for patients with severe agoraphobia who lived in rural areas (184). Self-directed forms of CBT and exposure therapy that are guided by a computer (often with minimal therapist contact via email or phone) also have been shown to be effective in several controlled studies (185, 186). Studies that directly compare live CBT to largely computer-guided formats have generally shown both to be effective, but in some studies live CBT produced larger effects and was associated with lower dropout rates (139, 186–189). When available, computer-guided CBT may be a useful option for patients with panic disorder who do not have ready access to a specialist.

The available data suggest that the benefits of a short-term course of CBT are long-lasting (for example, see reference 160). However, once patients have achieved a satisfactory reduction in symptoms and impairment, the focus of CBT shifts, and development of a specific relapse prevention plan becomes an integral part of treatment. The therapist normalizes fluctuations in anxiety and anticipates that the patient may experience periods of increased anxiety (including occasional panic attacks) in the future. The therapist and patient collaborate to anticipate potential triggers for these periods of increased anxiety (e.g., work stress, moving to an unfamiliar place) and to develop an individualized relapse prevention plan that the patient can follow if symptoms recur. This plan typically involves a return to more intensive practice of CBT skills that were previously helpful such as exposure and cognitive restructuring. If symptoms do not improve with the implementation of the practice plan, the therapist and patient can consider the option of "booster sessions" (i.e., a short course of CBT to help the patient reinstitute skills that were previously helpful). If efforts to boost response are unsuccessful, the psychiatrist should consider trying a different treatment modality or referring the patient to another qualified professional.

There is little evidence to suggest that CBT and commonly prescribed medications for panic disorder either enhance or counteract one another in the acute term. One randomized controlled trial found that fluvoxamine plus exposure therapy was superior to either alone in treatment of panic disorder with moderate to severe agoraphobia (68); however, this result has not been replicated. In contrast, another study found that, 6 months after treatments were withdrawn, patients who responded to a combination of imipramine and CBT for panic disorder displayed poorer maintenance of response than those who received CBT alone or CBT plus placebo (111). This finding raises some concern that simultaneously initiating medication and CBT may negatively affect the durability of the effects of CBT after treatments are withdrawn. This topic requires further study before firm conclusions can be drawn. Concern also exists about possible decreases in the efficacy of CBT if combined with benzodiazepines, although there is a dearth of systematic empirical data on this topic (190). One large randomized controlled trial showed that although adding alprazolam to exposure therapy marginally enhanced gains during acute treatment, patients who received the combination relapsed more after treatment withdrawal compared to those who received exposure plus placebo (149). Another small study showed that patients taking benzodiazepines had poorer memory for the educational material presented in CBT than patients who were taking no medications (161). Clinical experience suggests that p.r.n. ("as needed") use of benzodiazepines to block anxiety symptoms can be difficult to reconcile with certain components of CBT, and many CBT therapists discourage p.r.n. benzodiazepine use as soon as the patient has developed other anxiety management skills.

Cognitive-behavioral therapy for panic disorder has been shown to be effective in treating not only the targeted panic disorder but also in reducing the rates and severity of some co-occurring conditions (191–194).

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2. Psychodynamic psychotherapy

The goal of psychodynamic psychotherapy is to achieve remission of panic disorder symptoms through a therapeutic process that encourages exploration of feelings and past and present traumatic experiences. The core principles of psychodynamic psychotherapy are 1) the appreciation that much of mental life is unconscious, 2) childhood experiences in concert with genetic and constitutional factors shape adult personality, and 3) individual symptoms and behaviors may serve multiple functions (195).

Many studies suggest that acute stressors, or "life events," occur just prior to panic disorder onset (196–198). According to psychodynamic theory, the psychological meaning of these events as well as symptoms, behaviors, and coping styles are determined by complex forces that may be unavail