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Panic Disorder: Effective Treatment Options S. ATEZAZ SAEED, M.D., and TIMOTHY J. BRUCE, PH.D. University of Illinois College of Medicine at Peoria, Peoria, Illinois

A patient information handout on panic disorder and agoraphobia, written by the authors of this article, is provided on page 2419.

Panic disorder is a distressing and debilitating condition with a familial tendency; it may be associated with situational (agoraphobic) avoidance. The diagnosis of panic disorder requires recurrent, unexpected panic attacks and at least one of the following characteristics: persistent concern about having an additional attack (anticipatory anxiety); worry about the implications of an attack or its consequences (e.g., a catastrophic medical or mental consequence) and making a significant change in behavior as a consequence of the attacks. A variety of pharmacologic interventions is available, as are nonpharmacologic cognitive or cognitive-behavioral therapies that have demonstrated safety and efficacy in the treatment of panic disorder. Early detection and thoughtful selection of appropriate first-line interventions can help these patients, who often have been impaired for years, regain their confidence and ability to function in society.

TABLE 1 Symptoms of Panic Attacks Neurologic symptoms Dizzy, light-headed or unsteady feeling Paresthesias Trembling/shaking Fainting Cardiac symptoms Chest pain or discomfort Palpitations, heart pounding or tachycardia Sweating Respiratory symptoms Shortness of breath Feeling of smothering or choking Gastrointestinal symptoms Nausea Abdominal distress Psychologic symptoms Derealization/depersonalization Fear of losing control, going crazy or dying Miscellaneous symptoms Chills or hot flushes

Panic disorder is an anxiety disorder characterized by unexpected panic attacks. It is often associated with situational (agoraphobic) avoidance stemming from fear of further attacks.¹ Epidemiologic studies suggest that panic disorder, with or without agoraphobia, has a lifetime prevalence between 1.5 and 3.0 percent¹ and a familial tendency. It can run a chronic, relapsing course and can produce significant disability and personal distress. Panic disorder is commonly seen in the family practice setting, but it often eludes detection or is misdiagnosed because its clinical presentation mimics that of other medical conditions.² A large body of evidence shows that panic disorder responds to various pharmacotherapies and to cognitive and cognitive-behavioral therapies. Early recognition and prompt, appropriate treatment are the keys to managing this disorder effectively.

Identifying Panic Disorder With and Without Agoraphobia

Panic disorder is characterized by the unexpected, "out of the blue" panic attack. A panic attack is defined as a discrete episode of intense symptoms that peak within 10 minutes and primarily involve sympathetic nervous system manifestations. According to criteria given in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV),¹ a panic attack must include at least four of the symptoms listed in Table 1.

A diagnosis of panic disorder is made if the patient has experienced recurrent, unexpected panic attacks and shows at least one of the following characteristics: (1) persistent concern about having another attack (anticipatory anxiety); (2) worry about the implications of an attack or its consequences (e.g., suffering a catastrophic medical or mental consequence), or (3) a significant change in behavior related to the attacks.

A panic attack is defined as a discrete episode of intense symptoms that peak within 10 minutes and primarily involve sympathetic nervous system manifestations.

In clinical populations, panic disorder is usually accompanied by agoraphobia. Agoraphobia refers to avoidance behavior motivated by fear of having another panic attack. It may involve activities that patients fear could provoke an attack, situations where escape may not be readily available or routine activities during which patients are not accompanied by a "safe person" whom they believe could help in case of an attack. Table 2 lists common types of agoraphobic fear and avoidance.

TABLE 2 Examples of Activities And Situations that May Be Avoided by Patients with Agoraphobia Being far away from home Being without the company of a "safe" person Physical exertion that patients believe could provoke a panic attack Going to places where escape is not readily available (e.g., restaurants, theaters, stores, public transportation) Driving Places where embarrassment could be a consequence of suffering a panic attack (e.g., social gatherings) Ingesting substances that patients believe could provoke panic (e.g., foods, medicines, alcohol, caffeine)

Clinical Management of Panic Disorder

Patients presenting with panic-like symptoms should receive a thorough initial evaluation that goes beyond assessment of their primary somatic complaints. Areas of initial evaluation are outlined in Table 3. Several authors^3,4 have recommended a specific work-up for these patients to reduce unnecessary assessments. Panic disorder can be treated effectively with pharmacotherapy, cognitive and cognitive-behavioral therapies or a combination of therapies.

The National Institutes of Health Consensus Development Conference on Treatment of Panic Disorder⁵ recommends that patients who are diagnosed with panic disorder should be provided with a description of indicated treatment options and the advantages and disadvantages of each option. Treatment selection should then be made with the patient's input and in consideration of the severity of the presenting complaints, and the patient's specific history and preferences. The following sections outline treatment options for patients with panic disorder and their known advantages and disadvantages. Considerations for selecting treatment also are presented.

TABLE 3 Areas of Evaluation for Patients with Panic Symptoms Criteria for an unexpected panic attack Agoraphobic avoidance Use of caffeine and other anxiety-provoking substances Substance-use history Medical history to eliminate organic etiology Psychiatric comorbidity (e.g., depression, interpersonal conflicts) Previous assessments and treatments (psychiatric, medical) Family history

Drug Therapy

Table 4 lists pharmacologic agents used to treat panic disorder and their common therapeutic dosage ranges.

Tricyclic Antidepressants
Imipramine (Tofranil) is the medication for panic disorder that has been most thoroughly studied, with at least 10 double-blind, placebo-controlled studies supporting its efficacy in the acute treatment of panic disorder.⁶ Clomipramine (Anafranil) has shown similar results in several double-blind trials as well. Other tricyclic antidepressants that have shown promise are listed in Table 4.

TABLE 4 Drugs Used For Treating Panic Disorder Drug Dosage range Tricyclic antidepressants Imipramine (Tofranil) Clomipramine (Anafranil) Nortriptyline (Pamelor) Desipramine (Norpramin) 50 to 300 mg per day 25 to 250 mg per day 25 to 100 mg per day 25 to 300 mg per day SSRIs Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Fluvoxamine (Luvox) 20 to 80 mg per day 10 to 50 mg per day 50 to 200 mg per day 50 to 300 mg per day MAOIs Phenelzine (Nardil) Tranylcypromine (Parnate) 45 to 90 mg per day 30 to 60 mg per day Benzodiazepines Alprazolam (Xanax) Lorazepam (Ativan) Clonazepam (Klonopin) 2 to 10 mg per day 2 to 6 mg per day 1 to 3 mg per day SSRIs=selective serotonin reuptake inhibitors; MAOIs=monoamine oxidase inhibitors.

The onset of therapeutic action for tricyclic antidepressants typically takes three to four weeks. The average length of treatment is approximately six months but depends on several factors, including the efficiency with which panic suppression is achieved and agoraphobic avoidance, if any, is overcome. In obtaining an optimal response, the physician may find it helpful to assess plasma levels. For example, a therapeutic response should be evident at a level greater than 150 ng per mL (imipramine and desipramine [Norpramin] combined) in patients receiving imipramine.

Approximately one fourth of patients cannot tolerate the side effects of tricyclic antidepressants. Side effects are commonly anticholinergic (constipation, dry mouth, blurred vision and urinary retention), histaminergic (sedation and weight gain) or adrenergic (orthostatic hypotension).

One of the most burdensome adverse effects for patients with panic disorder, who often fear their own bodily sensations, is the "activation syndrome" that occurs on initial titration in approximately 25 to 40 percent of patients. The syndrome often can be mitigated by education, reassurances and initiating a low starting dosage (e.g., 10 mg of imipramine per day), then increasing gradually and flexibly at a rate of approximately 10 mg every two to three days until a dosage of 50 to 75 mg is achieved. An increment of 25 mg every two to four days from that point is usually well tolerated.

Since patients with panic disorder are often very sensitive to side effect symptoms, they may need more reassurance throughout pharmacotherapy than other patients. Physicians should also be aware that a withdrawal syndrome following abrupt cessation of these agents has been described.⁷

Imipramine and clomipramine are considered first-line treatment options for panic disorder. Some advantages and disadvantages of these agents are listed in Table 5.

TABLE 5 Selected Advantages and Disadvantages of Major Treatment Modalities in Patients with Panic Disorder TCAs SSRIs MAOIs BZDs CBT Advantages Antidepressant effect Generic form available Established efficacy Favorable side-effect profile Not habit forming Maintenance of gains + + + + + +/- + + + + + + + + + + N/A + Disadvantages Potential toxicity Weight gain Sexual dysfunction Anticholinergic effects Orthostatic hypotension Cardiovascular effects Dependence/abuse Withdrawal syndrome Multiple dosing/sessions Delayed onset Cost Limited availability Dietary restrictions + + + + + + +/- + + +/- + +/- + + + + + + + + + + + + + + TCAs=tricyclic antidepressants; SSRIs=selective serotonin reuptake inhibitors; MAOIs=monoamine oxidase inhibitors; BZDs=benzodiazepines; CBT=cognitive-behavioral therapy.

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