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.

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.

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.

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.

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.

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]).

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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 unavailable to the patient's conscious awareness (199–201). In patients with panic disorder, one of the goals of psychodynamic psychotherapy is to uncover and understand the thoughts and feelings associated with panic symptoms as well as the unconscious psychological meanings of these panic symptoms, issues that are theorized to be related to separation, autonomy, self-esteem, anger, or aggression. Understanding of transference and interpretation are used to elucidate these issues as well as related interpersonal conflicts. In addition, the therapist attempts to identify and alter core conflicts in order to reduce vulnerability to future panic symptoms (145). Given the highly individualized nature of these thoughts, feelings, and conflicts, the length and intensity of most psychodynamic psychotherapy also tends to be individualized.

In psychodynamic psychotherapy, symptom relief or resolution is theorized to result from emotional growth and understanding of the various developmental and psychological issues that relate to the patient's symptoms. Examples include both conscious and unconscious problems of self-esteem and self-cohesion, unresolved developmental trauma, and psychic conflict (e.g., unacceptable impulses, unrealistic or harsh issues of self-esteem and conscience, unadaptive psychological defenses). The therapist places the current symptoms in the context of the patient's life history and current realities. The therapist-patient relationship is often used as a vehicle to achieve insightful awareness by bringing the unconscious into consciousness, as well as to facilitate intrapsychic growth. Because psychodynamic therapies are rooted in various psychoanalytic and/or psychodynamic theoretical models, there are a variety of methods for conducting psychodynamic psychotherapy.

Panic-focused psychodynamic psychotherapy is a twice weekly, 12-week manualized treatment program developed by Milrod and associates (145) that has been tested in a randomized controlled trial (146). It focuses on the underlying psychological meaning of panic symptoms and on current social and emotional functioning. Panic-focused psychodynamic psychotherapy is based on the postulate that panic symptoms carry a specific emotional significance that the patient must confront before remission of the panic symptoms can occur. According to this theoretical model, patients with panic disorder are conceptualized as having difficulty separating from important attachment figures and perceiving themselves as autonomous, which is thought to motivate agoraphobic avoidance. The combination of perceiving their environment and relationships as overly dangerous and themselves as inadequate and lacking autonomy triggers high levels of anxiety that perpetuate panic and agoraphobic avoidance. Panic symptoms in turn are thought to reinforce conflicted interpersonal relationships in which the patient feels excessively dependent on significant others and frightened of losing them. Panic-focused psychodynamic psychotherapy focuses on the transference as a mutative therapeutic agent and does not require behavioral exposure to agoraphobic situations. It helps patients to confront the emotional significance of their physical symptoms and recognize that their fears of upcoming catastrophe reflect an internal emotional state rather than reality. Through these techniques, PFPP encourages patients to function more autonomously and may help patients with panic disorder to achieve a greater sense of personal efficacy, yielding improved function and symptomatic relief.

Compared to PFPP, other approaches to psychodynamic psychotherapy often have a wider focus on other psychological and interpersonal issues in the patient's life. These alternative approaches have not been the subject of rigorous research studies. Consequently, evidence for the use of other psychodynamic psychotherapy approaches in panic disorder is limited to case reports and opinions of psychodynamic psychotherapy experts. No studies have compared the efficacy of the different psychodynamic psychotherapy approaches or have compared psychodynamic psychotherapy with other psychosocial treatments in patients with panic disorder.

As with all psychiatric treatments, psychodynamic psychotherapy (including PFPP) should be conducted by appropriately trained therapists, and patients need to understand the rationale, goals, and potential risks and benefits of the treatment. The exploration of memories and important conflicted relationships and the surfacing of unconscious material may sometimes be associated with powerful affects and transient upsets in the therapeutic and other relationships. These occurrences tend to decline in both frequency and intensity as the patient experiences how they relate to and help resolve the symptoms and problems that brought the patient to treatment.

Many patients with panic disorder have complicating co-occurring Axis I and/or Axis II conditions. The broad focus of some forms of psychodynamic psychotherapy may be useful in reducing symptoms or maladaptive behaviors in these associated conditions. For example, some preliminary data showed that PFPP demonstrated superiority to applied relaxation therapy for patients with Cluster C personality disorders, compared to patients without Cluster C personality disorders (202).

Although evidence is limited, psychodynamic techniques have been used in combination with pharmacotherapies or with elements of CBT (145, 203, 204). For example, patients with agoraphobic avoidance may be encouraged to expose themselves to frightening situations and explore the feelings that the exposure aroused to gain a deeper understanding of the conflicts surrounding feared situations. In practice, psychodynamic therapies are often used adjunctively with medication to assist in the resolution of the panic symptoms (204, 205).

The available evidence suggests that supportive psychotherapy is inferior to standard treatments for panic disorder. One controlled study compared the efficacy of emotion-focused therapy, CBT, imipramine, and pill placebo in patients with panic disorder (147). Emotion-focused therapy was described as a short-term psychotherapy that involved empathic listening and supportive strategies. Emotion-focused psychotherapy was based on the theory that unrecognized emotions (typically triggered by interpersonal situations) trigger panic attacks; therefore, patients were encouraged to explore and process their emotional reactions with the aim of resolving panic symptoms. Results suggested that emotion-focused psychotherapy was less effective than CBT and imipramine in treatment of panic disorder and that its effect was approximately equivalent to that of placebo. Therefore, emotion-focused therapy and other supportive psychotherapies that resemble it cannot be recommended as treatments for panic disorder.

Eye movement desensitization and reprocessing was originally developed as a treatment for posttraumatic stress disorder (206), but it has been studied as a possible treatment for panic disorder. Eye movement desensitization and reprocessing involves reprocessing distressing memories while engaging in guided eye movement. When applied to panic disorder, EMDR targets distressing memories such as the memory of the first panic attack and life events that the patient associates with panic disorder (207).

Empirical data on the use of EMDR in treating panic disorder are limited. In one trial, six sessions of EMDR were superior to a waiting-list control at posttreatment; however, the investigators questioned the clinical significance of the treatment's effect because very few patients who received EMDR showed substantial functional recovery at 3-month follow-up (207). Another study found EMDR to be equivalent in its effects to a credible attention-placebo control (208). Eye movement desensitization and reprocessing therefore cannot be recommended as a treatment for panic disorder at this time.

Clinical experience suggests that possible benefits of a group format for treating panic disorder include 1) decreasing shame and stigma by providing experiences with others who have similar symptoms and difficulties; 2) providing opportunities for modeling, inspiration, and reinforcement by other group members; and 3) providing a naturally occurring exposure environment for patients who fear having panic symptoms in social situations. Most approaches to group therapy have not been empirically tested for panic disorder. However, group CBT for panic disorder has been shown to be effective in controlled studies and therefore can be recommended with confidence as a treatment for panic disorder (137, 176–179). When considering a patient for inclusion in a CBT group, the therapist should consider the severity of the patient's panic disorder, co-occurring disorders, level of insight, interpersonal skills, and the patient's preference for a group versus individual format.

There is limited evidence from a small uncontrolled trial for the effectiveness of group mindfulness-based stress reduction for patients with panic disorder (209, 210). This modality includes training in meditation and relaxation strategies. Other types of groups, such as medication support groups, may provide useful adjunctive experiences for patients with panic disorder but have not been tested empirically.

Patients with panic disorder have symptoms that can disrupt day-to-day patterns of relationships and may place a family member in a caretaker or rescuer role. Increased dependency needs of patients with panic disorder may lead to frustration in family members, and relationships may be jeopardized. Results are mixed with regard to whether panic disorder is associated with increased incidence of relationship dysfunction or whether relationship dysfunction affects outcome of standard treatments for panic disorder (180).

The scant available literature suggests that marital therapy alone is less effective than established treatments in relieving panic symptoms (211). Based on the available data, couples or family therapy alone cannot be recommended as a treatment for panic disorder. In contrast, partner-assisted exposure therapy for panic disorder has been shown to reduce symptoms of panic disorder in several studies (180). Other studies have documented benefits of including patients' significant others in group-based CBT (177, 212, 213) and of adding couples-based communication training to exposure treatment (214). Therefore, including a significant other in CBT or exposure-based treatment may be a useful approach for some patients.

When pursuing other treatments for panic disorder (e.g., pharmacotherapy), educating significant others about the nature of the disorder and enlisting them to improve treatment adherence may also be helpful. However, no empirical studies of involving partners or family members in other types of treatment have been published.

Patient support groups may be helpful for some patients with panic disorder. Patients who participate in support groups have the opportunity to learn that they are not unique in experiencing panic attacks and to share ways of coping with the illness. Family members of patients with panic disorder also may benefit from the educational aspects of patient support groups. In deciding to refer a patient or family member to a support group, it is important that the psychiatrist obtain information about the nature of the group and the credentials of its leader(s). Support groups are not a substitute for effective treatment; rather, they are complementary.

A review of research on a variety of self-help and alternative treatments for anxiety disorders concluded that there was no evidence for efficacy of most of these treatments for panic disorder (215). Treatments evaluated included natural products (e.g., kava, St. John's wort, inositol), other physical treatments (e.g., acupuncture, massage), and lifestyle treatments (e.g., yoga, relaxation). Most of the treatments had never been formally tested in patients with panic disorder. Very preliminary support is available for the efficacy of the glucose isomer inositol in treatment of panic disorder; however, inositol is rarely used clinically, and more extensive clinical research is necessary to establish its efficacy (216, 217). Evidence of efficacy has also been found for relaxation training (215). Although one controlled study found applied relaxation to be as effective as CBT and exposure therapy (218), a recent meta-analysis suggested that relaxation training is less effective than CBT for patients with panic disorder (219).

Because medications from four classes—SSRIs, SNRIs, TCAs, and benzodiazepines—are roughly comparable in efficacy, the decision regarding which medication to choose for panic disorder mainly involves considerations of side effects, cost, prior treatment history, the presence of co-occurring general medical and other psychiatric conditions, and the strength of the evidence base for the particular medication in treatment of panic disorder. Medication choice can also be influenced by pharmacological properties such as medication half-life, drug metabolism (e.g., effects of cytochrome P450 isoenzymes), and the potential for drug interactions. These latter factors are particularly important when treating older adults and individuals taking multiple medications.

Selective serotonin reuptake inhibitors or SNRIs are likely to be the best choice of pharmacotherapy for many patients with panic disorder, though SSRIs have a larger evidence base and are more likely to be chosen as a first-line treatment. Although SSRIs and SNRIs do carry a risk of sexual side effects, they lack the significant cardiovascular and anticholinergic side effects associated with TCAs, which are particularly troublesome for older patients and for patients with general medical conditions. Although cost was previously a concern, most SSRIs are now available in less expensive generic forms. For patients with co-occurring depression, SSRIs, SNRIs, and TCAs are preferable to benzodiazepines as monotherapies because, in contrast to benzodiazepines, these agents will likely alleviate the depressive symptoms. Because they have no liability for abuse, SSRIs, SNRIs, and TCAs are also preferable to benzodiazepines in individuals with current or prior substance use disorders.

Benzodiazepines are often used for treatment of panic disorder, and some studies suggest that these medications are still used with greater frequency than the SSRIs (220). Although consideration must be given to potential side effects of benzodiazepines (e.g., sedation, memory difficulties, increased rates of falls or motor vehicle accidents), one advantage of benzodiazepines is their earlier onset of action as compared to antidepressants (101, 221). Because demonstration of some improvement often takes 4–6 weeks with SSRIs, SNRIs, and TCAs, benzodiazepines may be useful for patients with very distressing or impairing symptoms in whom rapid symptom control is critical. Furthermore, several studies suggest that the short-term (4–6 week) addition of benzodiazepines (alprazolam and clonazepam) to antidepressants produces a more rapid therapeutic response (100, 222, 223). Consequently, benzodiazepines may be used along with antidepressants to help control symptoms until the antidepressant takes effect, followed by slow tapering of the benzodiazepine. With benzodiazepines, the benefit of more rapid response to treatment must be balanced against the possibility that the patient may have difficulty tolerating the tapering and discontinuation of benzodiazepine; with ongoing use, all benzodiazepines will produce physiological dependence in most patients. To reduce the possibility of physiological dependence, psychiatrists sometimes prescribe benzodiazepines on an as-needed (p.r.n.) basis. Unfortunately, this practice has a number of adverse effects. Irregular use promotes fluctuating blood levels that may aggravate anxiety. One study also showed worse CBT outcomes in participants using benzodiazepines on a p.r.n. basis compared to those taking benzodiazepines on a regular schedule and those not taking benzodiazepines (224). Because many individuals may end up taking as-needed medication on an almost daily basis, it may be preferable to encourage regular use rather than use linked to or associated with surges of anxiety.

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

When implementing treatment with SSRIs, SNRIs, and TCAs, it is helpful to educate patients about the likely time course of treatment effects. In addition, some patients with panic disorder may be hypersensitive to medication side effects at treatment initiation. Thus, it is recommended that starting doses of SSRIs, SNRIs, and TCAs be approximately half of those given to depressed patients (225). 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.

Table 5 summarizes usual dosing for antidepressant and benzodiazepine pharmacotherapy for panic disorder.

With antidepressant medications, concerns have been raised about the potential for treatment-related increases in self-harming or suicidal behaviors. Based primarily on data in children and adolescents (226), the FDA has issued warnings that apply to all antidepressants, which indicate that the risk of increased suicidal thinking and behavior in patients under the age of 25 must be balanced with the clinical need for pharmacotherapy (227). No deaths from suicide occurred in any of the pediatric clinical trials, but pooled analyses of 24 placebo-controlled trials of nine antidepressants in pediatric patients with a variety of psychiatric disorders showed a risk of suicidal thinking and behavior during the first few months of antidepressant treatment that was approximately twice that of patients receiving placebo (4% in the active treatment groups vs. 2% in the placebo groups) (226, 228, 229). A more recent meta-analysis suggested that benefits of antidepressant treatment were greater than the risks of increased suicidal ideation or behaviors across indications, including anxiety disorders (230). In adults, antidepressant treatment does not appear to be associated with an increase in suicide risk per se (227, 231, 232).

Although some evidence from meta-analyses of randomized controlled trials (primarily in patients with depression) suggests an increased likelihood of self-harming behaviors (231) or suicide attempts (233), these results may be confounded by the difficulty in calculating precise suicide risks from meta-analytic data (234). In a pooled analysis of placebo-controlled trials involving adults with major depressive disorder or other psychiatric disorders that included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in more than 77,000 patients, a reduction of suicidal thinking and behavior was seen in adults older than age 65 years who received antidepressants, compared to placebo, and adults between ages 25 and 65 years showed no change in risk with antidepressant treatment (227). Furthermore, studies using other methods showed no increases in the likelihood of suicide or suicide attempts with antidepressant treatment (235–237), and an additional study noted a small increase in the likelihood of self-harm but no increase in the risk of suicide (238). In addition, most, but not all (239, 240) studies of the relationship between antidepressant prescription rates and rates of suicide and suicide attempts suggest that increases in SSRI prescriptions are associated with decreases in suicide and suicide attempt rates in a variety of patient populations (241–248) and that decreases in SSRI prescriptions are associated with increases in suicide rates (249). Nevertheless, it is conceivable that side effects (e.g., anxiety, agitation, insomnia, irritability) may increase the chance of self-harming behaviors in some individuals (234, 250). Thus, careful monitoring for such side effects as well as for evidence of self-harming or suicidal thoughts or behaviors is important in adults as well, particularly in the early phases of treatment and after increases in antidepressant dose. Against these small risks, the benefits of antidepressant treatment must always be considered (230, 251–253) and weighed against the corresponding risks and benefits of other options for the treatment of panic disorder. Additional information may be found at the web sites of the FDA (http://www.fda.gov/cder/drug/antidepressants/default.htm), the APA (http://www.psych.org), and the American Academy of Child and Adolescent Psychiatry (http://www.aacap.org).

Six SSRIs are now available in the United States: fluoxetine, sertraline, paroxetine (immediate release [IR] and controlled release [CR] formulations), fluvoxamine, citalopram, and escitalopram. Numerous clinical trials have shown that each of them is effective for panic disorder, and three—fluoxetine, sertraline, and paroxetine (both IR and CR)—carry FDA approval for this indication. There is no evidence of differential efficacy between agents in this class, although differences in side-effect profile (e.g., potential for weight gain, discontinuation-related symptoms), drug half-life, propensity for drug interactions, and availability of generic formulations may be clinically relevant (254, 255).

Recommended starting and therapeutic doses are summarized in Table 5. As is the case with TCAs, some patients with panic disorder experience an initial feeling of increased anxiety, jitteriness, shakiness, and agitation when beginning treatment with an SSRI. For that reason, the initial dose should be lower than that usually prescribed to patients with depression. The recommended starting doses for SSRIs are as follows: 10 mg/day or less of fluoxetine, 25 mg/day of sertraline, 10 mg/day of paroxetine IR, 12.5 mg/day of paroxetine CR, 50 mg/day of fluvoxamine, 10 mg/day of citalopram, and 5–10 mg/day of escitalopram. Although some patients may respond to lower doses and some may require higher doses for response, clinical trials suggest that the following are therapeutic doses for the SSRIs: 10–20 mg/day of fluoxetine (74), 20–40 mg/day of paroxetine (73), 50–200 mg/day of sertraline (76), 100–150 mg/day of fluvoxamine (256), 20–30 mg/day of citalopram (71), and 10 mg/day of escitalopram (86). It is recommended that the initial low dose of the SSRI be maintained for approximately 3–7 days, then gradually increased (e.g., in weekly increments) to a more standard daily dose, adjusting the timing of titration to the individual patient's tolerability (257). Because elimination of SSRIs involves hepatic metabolism, doses may need to be adjusted for patients with liver disease.

Abrupt discontinuation of SSRIs (or SNRIs) can lead to a discontinuation syndrome with neurosensory (e.g., paresthesias, shock-like reactions, myalgias), neuromotor (e.g., tremor, unstable gait, visual disturbances), gastrointestinal (e.g., nausea, diarrhea), neuropsychiatric (e.g., anxiety, irritability), vasomotor (e.g., diaphoresis, flushing), and other manifestations (e.g., insomnia, fatigue, dizziness, headache) (85, 258). Selective serotonin reuptake inhibitors with very long half-lives (e.g., fluoxetine) are less likely to be associated with this discontinuation syndrome. Symptoms of SSRI discontinuation syndrome typically begin within 24 hours, peak about 5 days after withdrawal, and generally resolve within 2 weeks (67, 259). Tapering SSRIs over at least 7–10 days, or a longer period if clinical circumstances permit, can minimize the risk of SSRI discontinuation syndrome. If discontinuation symptoms do occur, reinstatement of the medication at the previous dosage level for a few days, followed by a return to an even slower taper schedule, is the preferred course of action.

In terms of significant side effects, SSRIs are safer than TCAs and MAOIs. They are rarely lethal in overdose and have few serious effects on cardiovascular function. Because they lack clinically significant anticholinergic effects, they can be prescribed to patients with prostatic hypertrophy or narrow-angle glaucoma. The most common side effects of SSRIs are headaches, irritability, nausea and other gastrointestinal issues, insomnia, sexual dysfunction, weight gain, increased anxiety, drowsiness, and tremor. Some of these effects (e.g., nausea) are usually transient, lasting 1–2 weeks. Others (e.g., sexual dysfunction) commonly last for the duration of treatment. Side effects of SSRIs are highly individualized. For example, a particular SSRI may cause insomnia in one patient but somnolence in another. Thus, although comparative studies may tend to favor one medication over another for a particular side effect, a given patient may still experience that particular side effect. Fortunately, there are several SSRIs on the market, and it is usually possible to find one that the patient can tolerate well; this may require a process of engaging in several therapeutic trials until the optimal medication is found for a given patient.

There are scattered reports in the literature of extrapyramidal side effects, but these have not been observed in large multicenter trials and may be idiosyncratic. Some evidence suggests that SSRIs may be associated with an increased likelihood of upper gastrointestinal bleeding, particularly when taken in combination with NSAIDs or with aspirin (260, 261). Use of SSRIs also has been found to be associated with low bone mineral density in male patients age 65 years and older (262), increased rate of bone loss at the hip in older female patients (263), and increased risk of falls and of osteoporotic fractures in patients age 50 years and older (264, 265). In addition, as described earlier in Section II.H, the FDA has warned of the possibility that SSRIs and other antidepressants may increase the risk of suicidal ideation and behavior in patients age 25 years and younger (227).

Venlafaxine ER has been shown to be effective for panic disorder and has FDA approval for this indication (88, 89). Venlafaxine ER has been shown to be effective in the range of 75 to 225 mg/day. As with SSRIs and TCAs, venlafaxine and venlafaxine ER should be initiated gradually to reduce the likelihood of side effects: as described in Table 5, dosing is often initiated at 37.5 mg for the first 3–7 days, then increased to a minimum of 75 mg/day. Although increasing the dose after initial nonresponse or partial response to 150 mg/day is clinically recommended, the timing of such increase or the effectiveness of increasing the dose in those with initial poor or partial response has not been systematically studied. The level of initial response and tolerability should be taken into consideration. In clinical practice, some patients require and tolerate higher doses. Titration to these higher doses should be done gradually, and potential side effects, including blood pressure elevations should be monitored carefully.

Venlafaxine ER is generally well tolerated and has a side effect profile similar to the SSRIs. The most common side effects of SNRIs in studies of panic disorder include nausea, dry mouth, constipation, anorexia, insomnia, sweating, somnolence, tremor, and sexual dysfunction. Because a small proportion of individuals may develop sustained hypertension, an effect that may be dose related, it is reasonable to assess blood pressure prior to and during treatment, particularly when venlafaxine ER is titrated to higher doses. In addition to the concerns and debate regarding the relationship between antidepressants and increased suicidality, described earlier in Section II.H, some observational studies found that venlafaxine ER was associated with higher rates of lethal overdose than SSRIs (266–268). However, later studies suggested that this finding may be attributable to confounding patient factors (e.g., patients prescribed venlafaxine displayed more pretreatment suicide risk factors) (269, 270).

No systematic data are currently available supporting the use of another SNRI, duloxetine, in panic disorder, although its mechanism of action, which is similar to that of venlafaxine, suggests it might be an effective agent.

Abrupt discontinuation of SNRIs can produce a discontinuation syndrome similar to that associated with SSRIs. Symptoms can include dizziness, headache, and nausea (271). Tapering the SNRI over at least 7–10 days, or a longer period if clinical circumstances permit, can minimize the risk of a discontinuation syndrome.

Imipramine is effective for panic disorder and is the most well studied of the TCAs (90–92, 94–102, 104, 105, 107, 108, 111). Clomipramine also has considerable empirical support (70, 72, 79, 93, 102, 103, 109, 110). Although few controlled studies have evaluated other TCAs for panic disorder, those that have are generally supportive of the efficacy of desipramine (106) and nortriptyline (112). Given the equivalency of TCAs in treating depression, there is little reason to expect other TCAs to work less well for panic disorder. However, TCAs that are more noradrenergic (e.g., desipramine, maprotiline) may be less effective than agents that are more serotonergic (272).

Psychiatrists have often noticed, and research studies have occasionally shown, that some patients with panic disorder are hypersensitive to both the beneficial and adverse effects of TCAs (91, 106). Patients sometimes experience a stimulating response, including anxiety, agitation, or insomnia, when treatment with antidepressant medication of any class is initiated. For this reason, it is recommended that, similar to the SSRIs and SNRIs, TCAs be started for patients with panic disorder at doses substantially lower than those for patients with depression or other psychiatric conditions. One common strategy is to begin with only 10 mg/day of imipramine or its equivalent and gradually titrate the dose upward over the ensuing weeks.

Few studies have rigorously addressed the optimum dose of TCAs for panic disorder. Results of clinical trials suggest that it is reasonable to titrate the imipramine dose of patients with panic disorder to approximately 100 mg/day and wait for at least 4 weeks to see whether there is a response. If tolerated, the dose can then be increased to as high as 300 mg/day if initial response is either absent or inadequate (108). Evidence suggests that clomipramine may be effective in somewhat lower doses than imipramine; clomipramine can generally be used effectively in doses ranging from 50 to 150 mg/day (93, 102). Although there is no evidence of a correlation between blood levels of TCAs and clinical response in panic disorder, blood level monitoring may be helpful for patients who display inadequate response despite seemingly adequate doses or for patients who display signs of toxicity despite doses that are in the therapeutic range.

The most common side effects of TCAs as reported in clinical trials for panic disorder are 1) anticholinergic effects, including dry mouth, constipation, difficulty urinating, increased heart rate, and blurry vision; 2) increased sweating; 3) sleep disturbance; 4) orthostatic hypotension and dizziness; 5) fatigue and weakness; 6) cognitive disturbance; 7) weight gain, especially for long-term users; and 8) sexual dysfunction (273). Higher doses of TCAs are associated with a higher dropout rate in research studies (108), and one naturalistic follow-up study found that one-third of patients prescribed TCAs discontinued them because of side effects (274).

Tricyclic antidepressants should not be prescribed for patients with panic disorder who also have acute narrow-angle glaucoma or clinically significant prostatic hypertrophy. The risk of falls may be increased by TCAs, particularly among elderly patients, because of orthostasis. Because patients with preexisting cardiac conduction abnormalities may experience significant or fatal arrhythmia with TCA treatment (275), a baseline electrocardiogram should be considered before initiating a TCA. Overdoses with TCAs can lead to significant cardiac toxicity and fatality (275). For this reason and because of the concerns and debate regarding the relationship between antidepressants and increased suicidality (see discussion earlier in Section II.H), TCAs should be used judiciously in suicidal patients.

Alprazolam has the largest number of clinical trials supporting its efficacy for treatment of panic disorder and is FDA approved for this indication (104, 116, 118, 122, 123, 126, 276, 277). The data support the efficacy of alprazolam in treating multiple dimensions of illness (i.e., preventing panic attacks, reducing anticipatory anxiety and avoidance) in patients with panic disorder. However, because of its short half-life, frequent (3–4 times daily) dosing is required, which creates practical difficulty for many patients and results in more rapid and profound withdrawal symptoms with missed doses. A sustained-release form of alprazolam is also FDA approved based on two placebo-controlled studies (125, 129). Although this formulation is approved for once daily dosing, clinical experience suggests that twice daily dosing of alprazolam, sustained release, may be required to maximize efficacy.

It is necessary to be flexible in choosing the alprazolam dose for an individual patient. Most patients require three to four doses per day to avoid breakthrough or rebound symptoms, although some may achieve symptom control with two doses of alprazolam per day. For patients who have not taken alprazolam in the past, the starting dose should be 0.25 mg three or four times daily. The dose should be titrated up to 2–3 mg/day over the first week or two, but an increase to as high as 5–6 mg/day may in rare instances be necessary to obtain symptom control. Although the literature on alprazolam, sustained release, is much more sparse, most studies have tested doses in the range of 2–4 mg/day. The manufacturer's recommendation for alprazolam treatment of panic disorder notes that doses above 4 mg/day are usually necessary and that doses up to 10 mg/day are sometimes required. However, very few studies have empirically evaluated dose requirements, and those studies that have been conducted have produced mixed results regarding the advantages of higher doses (e.g., 6 mg/day) over lower doses (e.g., 2 mg/day) (95, 278).

Clonazepam is also FDA approved for the treatment of panic disorder, and several clinical trials support its efficacy (122, 131, 132). Its longer half-life results in less severe withdrawal symptoms with missed doses and usually allows once or twice a day administration. These factors lead some psychiatrists to prefer clonazepam over other benzodiazepines for the long-term maintenance treatment of panic disorder, largely because of the ease of clonazepam dosing.

For patients without prior clonazepam treatment, starting doses are usually in the range of 0.5–1 mg/day and may be titrated to higher doses as needed. Studies of clonazepam suggest that daily doses of 1–2 mg offer the best balance of therapeutic benefits and side effects. These doses are the equivalent of 2–4 mg of alprazolam or less. Patients can usually be switched from alprazolam to clonazepam by taking the total daily alprazolam dose in milligrams and administering half that daily dose in milligrams of clonazepam (usually as twice daily or bedtime-only treatment).

Results of several studies suggest a relationship between alprazolam and clonazepam blood levels and treatment response (279–281). In patients who do not respond to usual dose titrations, dose adjustment may be facilitated by monitoring of alprazolam and clonazepam blood levels, although this is rarely done.

Additional studies suggest that other benzodiazepines (e.g., diazepam, lorazepam), when given in equivalent doses, may be as effective as alprazolam in the treatment of panic disorder (113–116, 119–121, 124, 127, 128, 130, 282).

In general, benzodiazepines seem to be well tolerated by patients with panic disorder, with very few serious side effects. When side effects of benzodiazepines do occur in patients with panic disorder, they appear similar to those reported when benzodiazepines are used for other indications. Side effects include primarily sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness. Geriatric patients taking benzodiazepines may be at higher risk for falls and fractures because of these side effects (283–287).

Because of an increased risk of motor vehicle accidents in association with benzodiazepine use (288), patients should be warned about driving or operating heavy machinery while taking benzodiazepines, particularly when these medications are started or with dose increases. Patients should also be advised about the additive effects of benzodiazepines and alcohol, in particular combined sedative and respiratory effects. Although patients may be able to safely drink small amounts of alcohol, they should consume alcohol slowly and exercise extra caution when doing so (e.g., avoid operating vehicles).

For patients in stable recovery from substance use disorders, there is not an absolute contraindication to benzodiazepine use, but the decision to use benzodiazepines should be made cautiously. In patients in early remission or with active substance use disorders, concerns regarding potential misuse of the benzodiazepine or relapse of the substance use disorder are greater; in these circumstances other treatments for panic disorder that have a lower abuse potential are recommended for first-line use (289–291). If benzodiazepines are felt to be necessary after careful consideration of other treatment options, the psychiatrist should closely monitor their use (e.g., dispense in limited quantities and on a time-limited basis, supervise medication administration, track prescription refills or use pill counts to assess medication adherence, increase office visit frequency to monitor the ongoing medical necessity for and the patient's response to the medication). In addition, selection of an agent that is more slowly absorbed (e.g., oxazepam, clorazepate) may limit the potential for abuse (291).

Cognitive effects of benzodiazepines have been the subject of debate and some empirical research (292–294). It is clear that benzodiazepines at higher doses can cause memory impairment (101). One meta-analysis concluded that long-term benzodiazepine users performed worse than control participants on numerous domains of cognitive functioning (295). However, another review concluded that the literature as a whole does not provide convincing evidence of cumulative long-term cognitive effects of benzodiazepines in anxious patients (296). Nevertheless, patients should be monitored for the development of cognitive impairment, which may be more problematic at higher doses and in patients performing complex information-processing tasks at work. Caution is indicated when prescribing benzodiazepines to elderly patients or those with preexisting cognitive impairment.

Monoamine oxidase inhibitors are widely regarded as effective for panic disorder. However, there have been virtually no studies involving the use of MAOIs for panic disorder since the introduction of the panic disorder diagnosis in DSM-III in 1980. One study included patients with what would now be called panic disorder and found phenelzine to be effective (297). The commonly held belief that MAOIs are actually more potent antipanic agents than TCAs has never been convincingly proven in the scientific literature and is only supported by clinical anecdote. There has been considerable clinical interest in medications that are reversible inhibitors of monoamine oxidase A, because these medications do not generally require adherence to the low-tyramine diet that is mandatory for patients treated with phenelzine, tranylcypromine, or isocarboxazid. However, none of these medications is currently approved for use in the United States in either oral or patch form, although moclobemide is available in other countries, including Canada. Four studies have examined the effectiveness of moclobemide in panic disorder, and the results are mixed and only modestly encouraging (298–301). Although the monoamine oxidase B inhibitor selegiline is available in the United States, there are no data to support its efficacy for the treatment of panic disorder.

Doses of phenelzine in controlled trials for illnesses that resemble panic disorder have tended to be low, often no higher than 45 mg/day (297, 302). Some authors have commented that higher doses may be more effective. Doses of phenelzine up to 90 mg/day and of tranylcypromine up to 60 mg/day are said by experienced psychiatrists to be necessary for some patients with panic disorder. Patients rarely get significant benefit before several weeks have elapsed, and periods up to 12 weeks may be necessary before the full effectiveness of the medication can be judged. No maintenance studies of MAOIs for panic disorder have been published. Hence, the optimal length of treatment that provides the least chance of relapse has not been established.

Adverse effects are a major concern with MAOIs, and these medications are generally reserved for use when a patient has not responded to several other treatments. The complexity of these medications suggests that they should be prescribed by physicians with experience in monitoring MAOI treatment. A major risk of taking an MAOI is the induction of a hypertensive crisis with ingestion of tyramine. Hence, patients taking phenelzine or tranylcypromine must adhere to a special low-tyramine diet (303). Certain medications, including but not limited to sympathomimetic amines and decongestants, can also precipitate a hypertensive crisis and must not be used with MAOIs. Another serious drug-drug interaction to be avoided is the "serotonin syndrome," which can be fatal and is characterized by confusion, agitation, hyperthermia, and other autonomic unstable vital signs (e.g., shivering, diaphoresis, nausea, diarrhea) and neuromuscular signs (e.g., tremor, hyperreflexia, clonus, myoclonus, ataxia) (304). Serotonin syndrome can occur when MAOIs are used with other antidepressants (particularly SSRIs); the antibiotic linezolid; the analgesics meperidine, fentanyl, and tramadol; the over-the-counter medication dextromethorphan; and other medications acting on serotonin such as buspirone, fenfluramine, sibutramine, and the anti-migraine triptan medications (305, 306). Even when the risks of hypertensive crises and serotonin syndrome are obviated by strict adherence to dietary and medication restrictions, MAOIs have substantial adverse effects. These include hypotension (sometimes leading to syncope), weight gain, sexual dysfunction, paresthesia, myoclonic jerks, dry mouth, edema, and a paradoxical syndrome of excessive daytime sleepiness, nocturnal insomnia, and shorter sleep length.

There is minimal support for the use of trazodone in panic disorder. It appears less effective than imipramine and alprazolam and does not enhance outcome when used to augment CBT (221, 307, 308). Although there are a few small uncontrolled studies showing benefits of nefazodone in some patients with panic disorder (309–311), its use has been limited by concerns about liver toxicity (312). Thus, neither trazodone nor nefazodone can be recommended as a first-line treatment for panic disorder.

Bupropion (including extended release formulations) was effective in one small trial (313) and ineffective in another (314). Although it might be useful in some cases, given the limited and mixed systematic data regarding its efficacy, bupropion cannot be recommended as a first-line treatment for panic disorder.

A few open short-term studies support the potential efficacy of mirtazapine for panic disorder (315–319), and a comparison of mirtazapine and paroxetine in a very small randomized controlled trial involving 27 patients suggested similar efficacy of the two medications (320). However, mirtazapine should not be considered a first-line treatment for panic disorder because tolerability issues have been noted, with common side effects including somnolence and weight gain. In addition, there are no available data from large controlled studies supporting its efficacy in panic disorder.

The concerns and debate regarding the relationship between antidepressants and increased suicidality have been reviewed earlier in Section II.H and may apply to the other antidepressants discussed in this section.

There are limited data concerning the use of anticonvulsant medications in the treatment of panic disorder. One randomized controlled trial of gabapentin provided partial support for its efficacy and safety in panic disorder (321), but no further research has been conducted. Thus, gabapentin should not be considered a first-line treatment but may be useful in individual circumstances, either alone or as an adjunct to antidepressants. Small open-label studies have suggested that valproic acid may benefit some patients with panic disorder (322–324), but this medication has significant side effects (325), and controlled investigations are needed before it can be recommended. One small open-label study of levetiracetam (326) and very preliminary case report data for tiagabine (327) and vigabatrin (327) suggest that these agents may be worthy of further study in panic disorder. However, controlled trials are needed before any of these medications can be recommended as treatments for panic disorder. A small placebo-controlled trial suggested that carbamazepine was not effective for panic disorder (328).

First-generation (i.e., typical) antipsychotic medications are rarely appropriate in the treatment of panic disorder. There is no evidence that they are effective, and the risk of neurological side effects outweighs any potential benefit. Among the second-generation (i.e., atypical) antipsychotics, there is limited positive evidence for olanzapine (329) and adjunctive risperidone (330), suggesting the possibility that second-generation antipsychotics may be useful for patients with severe, treatment-resistant panic disorder. At present, however, evidence for efficacy is limited, and there is growing concern about side effects of second-generation antipsychotics, including weight gain, poor glycemic control, and metabolic syndrome (331). Consequently, at this time these agents cannot be broadly recommended for patients with panic disorder, although they may have a role in individual circumstances.

The available scant literature suggests that beta-adrenergic blocking agents (e.g., propranolol, atenolol) are ineffective for panic disorder (115, 332, 333). However, these agents continue to be used occasionally by psychiatrists who have observed that they can help reduce somatic sensations (e.g., palpitations) in some patients. There is limited evidence supporting the potential efficacy of a particular beta-blocker, pindolol, as augmentation for patients with SSRI-resistant panic disorder (334). Given the frequent side effects associated with beta-adrenergic blocking agents (e.g., fatigue, sleep disturbance, and possibly, the worsening of depression), these agents should not be considered in the routine treatment of panic disorder.

Although historically there was interest in treating panic attacks with calcium channel blockers, they are rarely used clinically, and efficacy data are very limited (335). Similarly, there are limited data suggesting clonidine may have mild and/or transient effects only (336, 337). Thus, calcium channel blockers and clonidine cannot be recommended as first-line or adjunctive treatments for panic disorder.

The available data suggest that buspirone monotherapy is not effective for panic disorder (338, 339) and does not enhance the efficacy of CBT (340). Although it is sometimes used clinically in individual circumstances as an augmentation strategy for patients with panic disorder, there are no published data except case reports (341) to support this practice.

There are few data on optimum length of treatment following response. Studies of acute treatment for panic disorder have been conducted over 6–12 weeks, with some studies including long-term follow-up periods of 1 to 2 years. Studies of CBT (which include some of the longer follow-up intervals) suggest that the majority of patients maintain benefits derived from a short-term course of CBT. Some clinical trials have included several months of maintenance CBT (i.e., monthly "booster sessions" focused on relapse prevention), which may have helped sustain positive response to CBT. However, the incremental benefit of periodic booster sessions has yet to be empirically proven. In general, CBT can be discontinued after 10–15 sessions (or sooner if the patient responds quickly) with specific instructions for continued independent practice of CBT skills. Many clinicians and patients also find addition of several monthly booster sessions useful.

With each of the antidepressant medications, therapeutic effects are generally maintained for as long as medication is continued. For responders to an SSRI or a TCA, clinical experience and some data suggest that continuing treatment for 6 months or more after acute response can lead to further symptom reduction and decreased risk of recurrence (70, 85, 99, 104, 342, 343). Although no empirical data are available addressing this question, clinical experience suggests patients with treatment-resistant panic disorder or prior relapse with treatment discontinuation may require longer term treatment. For venlafaxine ER, there are minimal systematic data addressing the optimum length of treatment following response, although discontinuation of venlafaxine ER after only 12 weeks of treatment has been shown to result in an increased likelihood of relapse (344).

Before advising a taper of effective medication, the psychiatrist should consider whether the patient is currently motivated to discontinue the medication as well as the duration of the patient's symptom remission. The timing of medication discontinuation is often influenced by factors such as the presence of psychosocial stressors or supports, the stability of co-occurring conditions, and the availability of alternative treatment options. Discussion of medication taper should also include the possible outcomes of tapering, which include the potential recurrence of panic symptoms, potential withdrawal symptoms, or both. 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. Similarly, discontinuation of psychosocial treatment should be planned collaboratively with the patient. Before terminating treatment, clinicians providing CBT help patients develop personalized relapse prevention plans. They also frequently offer patients the option of scheduling "booster sessions" focused on maintaining and enhancing treatment gains.

If an SSRI, SNRI, or TCA is to be discontinued, most psychiatrists and patients prefer to taper medications over a period of several weeks or months. This both allows for an opportunity to monitor for the possible reemergence of panic symptoms as well as decreases the likelihood of discontinuation effects, particularly for those patients who are taking higher doses or after prolonged use. However, under more urgent conditions (e.g., the patient is pregnant and wants to discontinue medications immediately), these medications can be discontinued much more quickly.

There are fewer data examining the issue of benzodiazepine discontinuation, but existing studies support continuing benzodiazepine treatment to prevent recurrence (99, 104). Clinical experience also suggests that many patients can be maintained with stable doses of benzodiazepines for many years with no recurrence of symptoms. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, there is no evidence for significant dose escalation in patients with panic disorder or with long-term benzodiazepine use (294, 345–347).

The approach to benzodiazepine discontinuation also involves a gradual tapering of dose. 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 (348–350). Although is it commonly believed that benzodiazepines with shorter half-lives produce more severe withdrawal symptoms than those with longer half-lives, most studies suggest that half-life is less of a factor than the use of a gradual taper schedule (126, 351). In addition, withdrawal symptoms can occur after relatively short-term periods of treatment and have been observed after as little as 6–8 weeks of treatment with alprazolam (352). The likelihood of discontinuation effects may be increased in patients with panic disorder who have traits such as high anxiety sensitivity and high levels of avoidance (353); for such patients, close monitoring should be performed and special care should be taken during the discontinuation process. Cognitive-behavioral therapy, which counteracts tendencies to amplify bodily sensations and catastrophize discontinuation symptoms, has been found to effectively facilitate withdrawal from benzodiazepines (354–357).

There is also some evidence for the utility of concurrent psychotherapy to maintain response after discontinuation of antidepressants. One small controlled study showed that combining brief psychodynamic psychotherapy and clomipramine reduced the likelihood of relapse of panic disorder after clomipramine discontinuation (156). Furthermore, in a meta-analysis of antidepressant pharmacotherapy and psychotherapy (in which nearly all psychotherapy studies administered CBT), combination treatment was more effective than antidepressants alone after treatment had been withdrawn (160).