Dr. Feusner is psychobiology research fellow, Dr. Cameron is associate clinical professor, and Dr. Bystritsky is professor of psychiatry and behavioral sciences and director of the Anxiety Disorders Program at the David Geffen School of Medicine at the University of California–Los Angeles.

Disclosure: Dr. Feusner receives grant support from the National Institutes of Health. Dr. Cameron reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Bystritsky is a consultant to Jazz; on the speaker’s bureau of Forest; and receives grant support from Cephalon, GlaxoSmithKline, Merck, Pfizer, and Wyeth.

Please direct all correspondence to Alexander Bystritsky, MD, PhD, Department of Psychiatry and Biobehavioral Sciences, 300 UCLA Medical Plaza, Rm. 2335,

Los Angeles, CA 90095-8346; Tel: 310-206-5133; Fax: 310-206-8387; E-mail: abystritsky@mednet.ucla.edu.


 

 

Abstract

Panic disorder affects millions of people worldwide, causing considerable suffering and loss of productivity. It is often associated with other psychiatric and substance use disorders. Fortunately, understanding the neurobiological, behavioral, and psychological factors involved in panic disorder has helped guide the development of effective pharmacotherapies and psychotherapies. The antidepressant class of selective serotonin reuptake inhibitors is a first-line defense, based on efficacy data, safety, and ease of use. However, there is also strong evidence for the efficacy of tricyclic antidepressants, benzodiazepines, and monoamine oxidase inhibitors. Cognitive-behavioral therapy (CBT) is most evidently the psychotherapy of choice for panic disorder, and can result in the maintenance of long-term improvements. Selection of treatment for the individual patient depends on the severity of illness, comorbid conditions, patient choice, and availability of psychotherapy. Pharmacotherapy and CBT combined in a rational and coordinated manner provides the best outcome.  

 

Introduction

Panic disorder is a prevalent and disabling condition, affecting 3% to 8% of the world’s population.1 The hallmark of the disorder is recurrent panic attacks, which are sudden episodes of acute apprehension or intense fear that occur without any apparent cause. During the panic attack, any of the symptoms listed in Table 1 can occur. These intense attacks usually last no more than a few minutes, but, in rare instances, can return in waves for up to 2 hours. In order to meet  Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)2 criteria for panic disorder, an individual must experience panic attacks as well as at least 1 month of persistent fear of having an additional attack, worry about the implications of the attack, or have a significant change in behavior as a result of the attacks.

Panic disorder often affects individuals in early to mid adulthood. The median onset is 24 years of age, although most do not seek treatment until their mid 30s.3,4 However, panic attacks can also begin in late adolescence. Twice as many women as men suffer from panic disorder.5 The course is typically chronic, although often waxing and waning.2

Agoraphobia is a common complication and consequence that occurs in approximately 50% of people with panic disorder. In the United States, an estimated 5.3% of the population, mostly women, suffer from agoraphobia.6 Patients suffering from agoraphobia are afraid of being in situations from which escape might be difficult, or in which help might be unavailable or embarrassing if they suddenly had a panic attack.2 In addition to the fear of experiencing a panic attack, many agoraphobics are afraid of what others will think of them after witnessing them having an attack. It is common for the agoraphobic to avoid crowded public places such as grocery stores, department stores, or restaurants. Enclosed or confined places, such as tunnels, bridges, or the hairdresser’s chair, may also be avoided. Individuals may feel trapped when using public transportation, such as trains, buses, subways, and planes, and may therefore avoid them. Individuals with panic and agoraphobia may also fear being at home alone in case a panic attack occurs and they will need help. The fears usually result in travel restrictions, the need to be accompanied by others when leaving home or staying at home, and being partially or completely house bound.

Panic disorder is associated with high comorbidity. Common comorbid conditions are major depressive episodes, specific phobias, obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), generalized anxiety disorder, and posttraumatic stress disorder (PTSD).5,7 There are also high rates of substance use disorders, including alcohol, drugs, and both prescribed and non-prescribed medication. Panic disorder co-occurring with major depressive disorder (MDD), alcohol/substance abuse, and personality disorder, considerably increases the probability of a suicide attempt.5,7

Panic disorder often results in a diminished capacity for employment, especially for those with agoraphobia.8 Those who are financially dependent and those who receive either welfare or disability benefits constitute 27% of all panic disorder patients.9 Clearly, panic disorder is a relatively common psychiatric disorder that, especially when accompanied by agoraphobia, can result in considerable suffering and loss of productivity. Fortunately, in the past few decades there have been advances in the recognition and diagnosis of panic disorder as well as development of effective pharmacotherapy and psychotherapy.

 

Assessment

A comprehensive assessment is important in evaluating panic disorder and distinguishing it from other conditions, as panic attacks can occur in other psychiatric and medical disorders. The conditions that most likely need to be considered in assessing patients with panic disorder are listed in Table 2. A thorough medical history as well as a physical exam, laboratory tests, and an electrocardiogram if appropriate can help rule out any causative or concurrent medical problems related to the panic attacks.10 Certain medical problems that may cause panic-like symptoms or trigger panic attacks include, but are not limited to, complex partial seizures, hyperthyroidism, hyperparathyroidism, arrhythmias, asthma, withdrawal from drugs or alcohol, or use of psychostimulants, including caffeine. It is important to assess the presence of medications used for the treatment of medical illnesses as some of them (ie, antiasthmatics) may provoke panic. Assessment of medical status of panic patients who may undergo behavior therapy is specifically important for patients with cardiovascular problems. Collaborative work with the patient’s primary care physician is highly recommended.

 

Other psychiatric conditions are also part of the differential diagnosis, including MDD, bipolar disorder, SAD, specific phobias, OCD, and PTSD. Panic attacks can occur as symptoms of these disorders, or the disorders may exist as comorbidities. Panic attacks that seem to occur spontaneously or in the middle of the night as opposed to being triggered by specific situations or thoughts (such as with a traumatic reminder in someone with PTSD or fearing humiliation in SAD) can help distinguish panic disorder from its counterparts. Another distinguishing feature of panic disorder is fear of internal symptoms rather than fear of an external threat.

 

Theoretical Framework for Treatment

Cognitive-behavioral and biomedical theories have attempted to describe the mechanisms of panic and panic disorder.11,12 A brief synthesis of these theories reveals that panic disorder is likely a combination of an increase in alarm reaction, error in information processing (catastrophic thinking), and abnormal coping strategies to relieve anxiety and provide a sense of security (safety rituals and avoidance). The disorder represents a sequential process where the symptoms start with panic attacks and progress through the stages of abnormal thinking, rituals, and avoidance. These symptom clusters may be “wired” through different neuronal circuits and respond preferentially to different treatments.

Neuroanatomical areas of the brain responsible for alarm reactivity receive an abundance of projections from neurons having their origins in noradrenergic and serotonergic nuclei. Medications that affect serotonergic and noradrenergic systems are likely to influence the structures that are responsible for the alarm reactions and primitive defensive responses (ie, periaqueductal gray, septal areas, amygdala, and parts of orbital frontal cortex). Medications that affect serotonergic and dopaminergic pathways are capable of influencing systems involved in information processing of dangerous stimuli. These include the rostral cingulum and the basal ganglia, and their interaction with limbic areas. γ-aminobutyric acid (GABA)-receptor agonist medications are capable of slowing general reactivity of neurons. However, they can negatively affect information processing and cortical and hippocampal information retention that is necessary for forming new noncatastrophic memories important for deconditioning and desensitization.

Unfortunately, there are currently no Food and Drug Administration-approved medications that directly affect formation of new coping behaviors. It is highly unlikely that the current medications could directly affect complex behaviors such as safety rituals and avoidance. Rather, current medications influence alarm reactivity directly, and these effects over time may indirectly improve patient coping. Conversely, cognitive-behavioral therapy (CBT) directly affects coping strategies and modifies negative thinking. CBT is also capable of influencing alarm reactivity.

Pharmacotherapy and CBT, rationally applied in combination and taking into account their direct and indirect effects, should be more effective than either treatment alone. However, this theoretical framework is incomplete. The intricacy of the neuronal circuits and neurotransmitters and their relation to complex behaviors is not yet fully understood.

 

Pharmacotherapy

Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatment for panic disorder based on their efficacy, tolerability, ability to treat common comorbid depression and anxiety disorders, and lack of abuse potential. Sertraline, fluoxetine, and paroxetine all have FDA indications for the treatment of panic disorder, but fluvoxamine, citalopram, and escitalopram are considered equally effective.   

Several meta-analyses have demonstrated that SSRIs are generally as or more effective than other pharmacotherapies.13 Boyer14 analyzed 27 randomized, placebo-controlled studies and found that SSRIs were superior to imipramine and alprazolam. Otto and colleagues13 performed an effect-size analysis of 12 placebo-controlled trials of SSRIs for the treatment of panic and compared it to a meta-analysis on non-SSRI antidepressants. They found that SSRIs were as effective as other antidepressants (both with effect sizes of 0.55), and dropout rates were similar. Another meta-analysis examined 43 randomized and open, nonrandomized trials and compared effect sizes between SSRIs and tricyclic antidepressants (TCAs). Effect sizes were similar but dropout rates were lower for SSRIs (18%) versus TCAs (31%).15 TCAs and clomipramine have been demonstrated to be efficacious in panic patients but are generally less tolerated than SSRIs.16,17

Benzodiazepines have the longest history of proven efficacy in panic disorder. In several controlled trials, alprazolam, lorazepam, and clonazepam were effective for panic disorder.18-21 Meta-analyses show benefits of benzodiazepines.22-27 Most studies, with the exception of a study by van Balkom and colleagues,25 showed similar effect sizes as the antidepressants. However, outcome measures were not consistent across studies. The benefits of the benzodiazepines are that they have a rapid onset of action and generally favorable side-effect profile. They can be used in maintenance, regular dosing, or on an as-needed basis. The downsides are the propensity for development of physiological dependence, tolerance, and cognitive side effects at higher doses. Compared to the antidepressants, they are not able to treat common comorbid depressive disorders.

Several older controlled studies have shown monoamine oxidase inhibitors (MAOIs) to be efficacious for panic disorder treatment.28,29 Sheehan and colleagues,29 in a placebo-controlled, double-blind study, found that phenelzine and imipramine groups showed significant improvement, with phenelzine superior to imipramine on some measures. MOAIs, however, are often problematic due to a heavy burden of side effects and dietary restrictions. The reversible monoamine oxidase inhibitors (RIMAs) such as moclobemide and brofaromine, do not require dietary restriction, and have been demonstrated in some (but not all30) controlled studies to be beneficial in panic disorder.31-34 Neither are currently available in the US.

Other pharmacologic agents may also be effective in panic disorder, although they have not yet been studied as extensively. Two small, controlled trials showed benefits in treatment with mirtazapine.35,36 GABA-ergic anticonvulsants, such as valproic acid37,38 and gabapentin,39 have shown promise in small trials, although gabapentin was more effective than placebo only for more severely ill patients.

 

Medication Treatment Considerations

Clinical trial data assist in understanding which group of medications are effective for panic disorder, and serve as a starting point for which medication is likely to benefit a particular patient. Selection of specific medications frequently depends on whether patients have received prior pharmacotherapy for the treatment of a mood and anxiety disorder, on previous reaction to medication, and on severity and acuity of their illness state.

SSRIs are currently the treatment of choice for patients who have never received prior pharmacotherapy and have at least moderate severity of illness. In addition to treating anxiety, SSRIs treat the frequently present comorbid MDD and lower the risk of future MDD. All SSRIs are thought to be effective in treating panic disorder and differ only in subtle side-effect profile and in their effects on the cytochrome P450 liver enzyme systems. In general, selection among antidepressants should be based on the patient’s anxiety symptom profile (one should avoid medications with side effects similar to their anxiety symptoms) and history of prior medication side effects. For example, paroxetine, fluvoxamine, or citalopram are more sedating medications and would be preferable SSRIs for patients with prominent activation. In the patient with severe insomnia one might select a sedating tricyclic antidepressant, such as nortriptyline or mirtazapine. Use of a dual-acting medication, such as venlafaxine, may be considered in the early stages of the treatment; however, at present there is no strong evidence from clinical research to support their early use. The clinical experience of the authors of this article is that treatment of uncomplicated panic may be started with small doses and increased to higher doses in patients with more obsessive thought patterns and avoidance.

Patients with panic disorder are often fearful of medication side effects or medications in general. They also have a tendency to have heightened side effects and reactions to side effects.10 This can be particularly problematic with the SSRIs, which often cause transient increases in anxiety, jitteriness, or exacerbation of panic attacks at initiation of treatment. For these reasons, and to minimize the likelihood of patients discontinuing the medications early, it can be helpful to start at very low doses and titrate upwards slowly. If needed, liquid formulations of most SSRIs are available to facilitate starting at very low doses, (eg, as low as fluoxetine 1 mg). However, the patient will at some point most likely need to achieve a dose in the range of what is required for the treatment of MDD.15

Benzodiazepines are not the first choice of treatment for panic disorder because of tolerance, dependency potential, and possible interference with CBT (especially with as-needed use). Therefore, these medications should be reserved for the “emergency” situations (eg, initial panic attacks) or for the reduction of anxiety in extreme or infrequent phobic situations (eg, airplanes, elevators) when the patient has not yet begun CBT. Finally, benzodiazepines can be used for maintenance of the chronic patients with refractory anxiety. If used chronically, these agents should be prescribed using a pharmacokinetically appropriate schedule in order to minimize daily withdrawal or interdose anxiety. Prior history of alcohol and drug abuse should be assessed before beginning treatment, as this may preclude their use.

Benzodiazepines can be initiated concurrently with an antidepressant. This strategy is particularly useful for patients with a history of increased anxiety with initiation of antidepressants or for acute anxiety in need of rapid relief. The benzodiazepine can be initiated with a planned treatment duration of approximately 4 weeks (to allow the antidepressant to take effect), followed by a flexible taper of the benzodiazepine over several weeks. This strategy was tested by Goddard and colleagues,40 who found that the combination of clonazepam and sertraline for 4 weeks followed by a 3-week taper of the clonazepam resulted in more responders than with sertraline and placebo by the first and third week. However, by the end of the 12-week trial there were no differences in the number of responders, and the dropout rates were similar.

 

Psychotherapy

Of the psychotherapeutic modalities, CBT has received the most widespread empirical and theoretical support in controlled studies for panic disorder.12,41-43 CBT is associated with low dropout rates, maintained long-term improvements, and the largest within-group and between-group effect sizes relative to all other comparison conditions.44,45

A recent long-term follow-up found treatment gains were maintained when reassessed at 6–8 years.46

CBT for panic disorder with and without agoraphobia has been described in manuals which have both patient and therapist guide versions.47 The goal of the treatment is to change catastrophic thinking that results when patients misinterpret internal bodily sensations as dangerous. First, the patient is guided through a psychoeducational process of understanding the panic process and the self-regulating nature of the physiology of anxiety. The patient is instructed on breathing and muscle relaxation techniques, which must be practiced at home between sessions. Next, the patient is engaged in monitoring his or her thinking, toward identifying and reappraising anxiety and panic-generating thoughts (cognitive restructuring). Finally, the patient is exposed, both in session and out of session, to bodily sensations that have become conditioned to fear. Through repeated exposure the patient habituates to the feared bodily sensations, thereby unlearning the fear response. The patient learns to confront possible agoraphobic avoidance of situations associated with previous panic attacks and anxiety.

Although considerable and growing research continues to demonstrate that CBT is well tolerated, cost effective, and efficacious in the short and long term, some patients do not benefit from it and there is still a need to improve the treatment.48 Efforts have been made to make CBT more efficient and to dismantle and identify its efficacious treatment components.

Data on utilization of healthcare services and medication have shown significant reductions in costs following CBT for panic disorder.49 CBT for panic disorder has been effectively and efficiently transported to the primary care setting. In a randomized, controlled study, mid-level behavioral health specialists trained to deliver CBT and pharmacotherapy were significantly more effective in treating primary care panic disorder than treatment as usual.50

Recent research has been conducted to increase self-directed therapy, reduce therapy frequency, and further streamline CBT delivery in innovative ways. Forty patients with panic disorder with agoraphobia were randomly assigned to either a traditional 12-session CBT group or a 4-session traditional treatment group plus a virtual reality component.51 Both groups were equally effective at treatment end, although the virtual reality group was less effective at 6-month follow-up. Using a manualized treatment program, panic disorder patients received either four sessions of group CBT or one meeting with a therapist plus three telephone contacts.52 Although the authors suggested that certain comorbid conditions negatively impacted self-directed treatment outcomes, the findings of the study (ie, higher end-state functioning in telephone condition) add to the viability of self-directed treatment options. An international multicenter trial reported that CBT delivered by brief computer-augmentation was as effective as extended therapist-delivered CBT, providing some support for the use of computers as an adjunct to effective CBT.53

A final emerging area in the evolution of CBT are mindfulness-based approaches. Mindfulness- or acceptance-based approaches are being hailed as the third wave in CBT54 (the first wave was strict behavioral approaches; the second wave was cognitive approaches). Mindfulness is a type of meditation that has been adapted from Buddhist psychology. One definition of mindfulness is “awareness of present experience with acceptance.”55 Mindfulness-based CBT has been applied to the treatment of panic disorder and other anxiety disorders,56 but it requires further carefully controlled research.57

CBT currently provides well-established treatments for panic disorder. It continues to be developed and evaluated, spawning innovating treatments that await further evaluation.

 

Combining Treatment Modalities

Several studies have been conducted to understand the importance of combined medication and CBT, versus either alone. A meta-analysis found combination treatments of CBT and medication, including benzodiazepines and/or antidepressants, superior to control groups, while exposure was not effective alone.25 In addition, the combined behavioral therapy and antidepressant group was superior to medications alone or psychotherapeutic interventions alone for agoraphobic avoidance. In another meta-analysis, Gould and colleagues24 showed that pharmacologic and CBT treatments were superior to control conditions, but that CBT had the largest effect sizes and the lowest attrition rates. A 1-year follow-up study, employing a time-series design, found that 89% of the participants were symptom free after receiving CBT, and that they also reduced their use of benzodiazepines. A study comparing CBT and pharmacologic treatment found all treatments effective, but the CBT group treatment was the most cost effective.58

In a clinic where CBT was accepted as the basic treatment for panic disorder with agoraphobia, it was suggested that psychiatrists appeared to rationally choose whether to add a benzodiazepine or antidepressant, either alone or in combination with each other and the CBT. Psychiatrists generally used combination treatments for more severe disorders, while CBT alone was often chosen when cognitive components were more pronounced than other symptoms. Benzodiazepines were often chosen for more somatically oriented patients with prominent panic attacks. Those choices resulted in substantial clinical improvements.59

If both CBT and medication are being used, coordination between the treatments is crucial. Completely blocking anxiety may prevent patients from receiving benefits from therapy and does not promote development of new ways of coping. Gradual reduction and stopping of medication can be attempted after 2–3 months of complete resolution of symptoms.

 

Treatment Algorithm

The treatment of panic disorder can proceed in a stepwise process, starting with treatments of proven efficacy and low rates of adverse events. Full response should be defined as not only a resolution of panic attacks, but also a resolution of the fear of panic and avoidant behaviors. The steps of the treatment are listed in the suggested (but not empirically tested) Algorithm.

 

Step 1

Education is the important first step in treatment, whether the treatment is pharmacotherapy, CBT, or the combination. At the most basic level, this involves explanations that the panic attacks do not signify that something is wrong with the body, and that the panic attacks are not dangerous. As primary care providers and the public are currently more aware of panic attacks, patients may already know that what they are experiencing is anxiety rather than a life-threatening condition such as a heart attack or stroke. The education should include explanations of how the cycle of panic attacks and fear of panic operates, and what kinds of behaviors reinforce the fear of the attacks. The clinician can also educate the patient on expectations regarding medication treatment; panic attacks may resolve, but the avoidance behavior may not change unless addressed directly with the help of a CBT therapist. Useful resources are available on the Internet and information in the form of pamphlets can be ordered from the Anxiety Disorders Association of America (www.adaa.org) and the National Institute of Mental Health (www.nih.nimh.gov). Involving the family can be helpful, especially when avoidance behavior is prominent and/or a family member misinterprets and is fearful of the patient’s panic attacks.

 

Step 2

Step 2 begins with a first-line of medication (SSRI) or CBT. The treatment choice is made during the initial patient session with the physician, in which the patient’s preference for either medication or psychotherapy is taken into consideration, along with the acuity of their current condition and availability of CBT. Patients who have very severe panic disorder accompanied by depression or other anxiety disorders are often less able to initially engage in CBT, and need to be started on antidepressants early. When availability or cost of CBT for the individual patient is problematic, medication treatment may be the only option.

 

Step 3

Step 3 begins after two trials of an SSRI are deemed to be unsuccessful. This step should start with a discussion with the patient about their preferences for switching to another medication or another treatment modality (eg, CBT) or augmenting the current modality by adding another medication or CBT. If the patient has had nonresponse or side effects to two prior SSRIs, the next choice is between other antidepressants (eg, venlafaxine, mirtazapine, or a TCA). A GABA-ergic strategy, such as benzodiazepines or gabapentin, can be used as augmentation if there is a partial response. Alternatively, a sedating atypical antipsychotic, such as olanzapine or quetiapine, can be used concomitantly. These medications are not ordinarily first-line treatments for anxiety disorders. If the patient continues to be treatment refractory, MAOIs may also be tried. MAOIs require dietary restrictions as well as first tapering off other antidepressants.

 

Step 4

Step 4 involves treatments with more intensive CBT or with medications or combinations of treatments that have not yet been tried. An expert consultation is usually recommended. Treatments with less established evidence could be attempted at this step. Combining an intensive CBT program (several times a week) with medication augmentation strategies may also result in a desired effect. Electroconvulsive therapy may be helpful for comorbid panic and depression but not for panic alone.60 Other strategies are under development for the treatment-resistant population, but they have yet to move past early experimental stages.

 

Long-Term Management

While in some patients panic attacks remit in the course of a few months, panic disorder is usually a chronic, waxing and waning condition. However, some patients can achieve complete remission. As per expert consensus guidelines, after 12–24 months of remission (defined as absence of panic attacks, fear of panic, and avoidance, as well as overall well being and lack of disability) the clinician may discuss with the patient the risks and benefits of continuing versus tapering off the medication.61 The risk of relapse may be reduced if the patient has undergone CBT.62 If a course of CBT has been successful, the individual may benefit from once monthly sessions for 3–6 months and “booster” CBT sessions as needed thereafter. Other patients may be left with the symptoms of other disorders, initially masked by the panic attacks. Approximately 20% of patients will not respond to any treatment and need to be maintained in the most comfortable state with medication, therapy, or their combination.63

 

Conclusion

Panic disorder (and the often accompanying agoraphobia) is a relatively common condition that can significantly disrupt the patient’s life in many ways. Knowledge of neuroanatomy and neuropharmacology of these conditions can assist us in better understanding current treatments of these disorders and in selecting the appropriate treatment choices. However, knowledge of neuropharmacology is not enough in selecting treatment for a particular patient. A thorough assessment and understanding of the interplay of multiple psychological and biological factors together with a deep knowledge of evidence from contemporary clinical research can assist the effective management of an individual patient. For the best possible results, psychotherapy (CBT) and pharmacologic treatment may need to be used individually or in a rationally chosen combination for the best possible results.  PP

 

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