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Evidence-Based Reviews

Panic disorder: Break the fear circuit

For most patients, CBT, antidepressants, or a combination of both is effective

Vol. 11, No. 11 / November 2012

Dr. Dunlop: State-of-the-art treatment for panic disorder

Ms. K, a 24-year-old waitress who lives with her boyfriend, was referred by her primary care physician for evaluation of panic attacks that began “out of nowhere” at work approximately 6 months ago. The unpredictable attacks occur multiple times per week, causing her to leave work and cancel shifts.

Ms. K reports that before the panic attacks began, she felt happy in her relationship, enjoyed hobbies, and was hopeful about the future. However, she has become concerned that a potentially catastrophic illness is causing her panic attacks. She researches her symptoms on the Internet, and is preoccupied with the possibility of sudden death due to an undiagnosed heart condition. Multiple visits to the emergency room have not identified any physical abnormalities. Her primary care doctor prescribed alprazolam, 0.5 mg as needed for panic attacks, which she reports is helpful, “but only in the moment of the attacks.” Ms. K avoids alcohol and illicit substances and limits her caffeine intake. She is not willing to accept that her life “feels so limited.” Her dream of earning a nursing degree and eventually starting a family now seems unattainable.

Panic disorder (PD) occurs in 3% to 5% of adults, with women affected at roughly twice the rate of men.1 Causing a broad range of distress and varying degrees of impairment, PD commonly occurs with other psychiatric disorders. For most patients, treatment is effective, but those who do not respond to initial approaches require a thoughtful, stepped approach to care. Key considerations include establishing an accurate diagnosis, clarifying comorbid illnesses, ascertaining patient beliefs and expectations, and providing appropriately dosed and maintained treatments.

Panic attacks vs PD

Panic attacks consist of rapid onset of intense anxiety, with prominent somatic symptoms, that peaks within 10 minutes (Figure).2 Attacks in which <4 of the listed symptoms occur are considered limited-symptom panic attacks.

Figure: Body locations of panic attack symptoms
Diagnosis of a panic attack requires the sudden development of intense fear or discomfort characterized by ≥4 of the 13 symptoms listed above that peaks in intensity within 10 minutes of onset
Source: Reference 2

Panic attacks can occur with various disorders, including other anxiety disorders, mood disorders, and substance intoxication or withdrawal. Because serious medical conditions can present with panic-like symptoms, the initial occurrence of such symptoms warrants consideration of physiological causes. For a Box2 that describes the differential diagnosis of panic attacks, see this article at


Differential diagnosis of panic attacks

To meet diagnostic criteria for panic disorder, panic attacks must initially occur “out of the blue,” meaning no specific object or situation induced the attack. The differential diagnosis of panic attacks includes assessing for other psychiatric disorders that may involve panic attacks. Evaluation requires considering the context in which the panic attacks occur, including their start date, pattern of attacks, instigating situations, and associated thoughts.

Social phobia. Attacks occur only during or immediately before a social interaction in which the patient fears embarrassing himself or herself.

Obsessive-compulsive disorder (OCD). Attacks occur when the patient cannot avoid exposure to an obsessional fear or is prevented from performing a ritual that diffuses obsessional anxiety.

Posttraumatic stress disorder (PTSD). Attacks occur when confronted by a trauma-related memory or trigger.

Specific phobia. Attacks occur only when the patient encounters a specifically feared object, place, or situation, unrelated to social phobia, OCD, or PTSD.

Medical conditions. Conditions to consider include—but are not limited to—hyperthyroidism, pulmonary embolism, myocardial infarction, cardiac dysrhythmias, hypoglycemia, asthma, partial complex seizures, and pheochromocytoma.

Source: Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000

A PD diagnosis requires that repeated panic attacks initially must occur from “out of the blue,” meaning no specific object or situation induced the attack. In addition, the diagnosis requires 1 of 3 types of psychological or behavioral changes as a result of the attacks (Table 1).2 Agoraphobia is diagnosed if 1 of the behavioral changes is avoidance of places or situations from which escape might be embarrassing or difficult should an attack occur. A patient can be diagnosed as having PD with agoraphobia, PD without agoraphobia, or agoraphobia without PD (ie, experiences only limited symptom panic attacks, but avoids situations or stimuli associated with them).

Table 1

Definitions of panic disorder and agoraphobia

Panic disorder

  1. Both 1 and 2:
  2. The panic attacks do not arise from the direct physiological effects of substance intoxication (eg, caffeine, cocaine) or withdrawal (eg, cannabis, gamma-hydroxybutyrate) or from a general medical condition
  3. The panic attacks are not better accounted for by another mental disorder


Anxiety about, or avoidance of, being in places or situations from which escape might be difficult or embarrassing, or in which help may not be available in the event of having an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations that include being outside the home alone, being in a crowd, standing in a line, being on a bridge, or traveling in a bus, train, or automobile

Source: Reference 2

Comorbidities are common in patients with PD and predict greater difficulty achieving remission (Box).1,3-6


Comorbidities: How they affect panic disorder treatment

The most common psychiatric conditions that co-occur with panic disorder (PD) are other anxiety disorders, mood disorders, personality disorders, and substance use disorders.1 Carefully assess the severity and degree of impairment or distress arising from each condition to prioritize treatment goals. For example, treating panic attacks would be a lower priority in a patient with untreated bipolar disorder.

Assessing comorbid substance abuse is important in selecting PD treatments. Benzodiazepines should almost always be avoided in patients with a history of drug abuse—illicit or prescribed. Although complete abstinence should not be a prerequisite for beginning PD treatment, detoxification and concomitant substance abuse treatment are essential.3

Comorbid mood disorders also affect the course of PD treatment. Antidepressants are effective for treating depression and PD, whereas benzodiazepines are not effective for depression.4 Antidepressants in patients with bipolar disorder are controversial because these medications might induce mixed or elevated mood states or rapid cycling. In these complicated patients, consider antidepressants lower in the treatment algorithm.5

Other conditions to consider before beginning treatment include pregnancy or the possibility of becoming pregnant in the near future and suicidal ideation. PD is associated with increased risk for suicidal ideation and progression to suicide attempts, particularly in patients with a comorbid mood or psychotic disorder.6 In addition, consider the potential impact of medications on comorbid medical conditions.

Treatment begins with education

The goal of treatment is remission of symptoms, ideally including an absence of panic attacks, agoraphobic avoidance, and anticipatory anxiety.1 The Panic Disorder Severity Scale self-report is a validated measure of panic symptoms that may be useful in clinical practice.7

The first step in treatment is educating patients about panic attacks, framing them as an overreactive fear circuit in the brain that produces physical symptoms that are not dangerous. Using a brain model that shows the location of the amygdala, hippocampus, and prefrontal cortex—which play crucial roles in generating and controlling anxiety and fear—can make this discussion more concrete.8 Although highly simplified, such models allow clinicians to demonstrate that excessive reactivity of limbic regions can be reduced by both top-down (cortico-limbic connections via cognitive-behavioral therapy [CBT]) and bottom-up (pharmacotherapy directly acting on limbic structures) approaches. Such discussions lead to treatment recommendations for CBT, pharmacotherapy, or their combination.

No single treatment has emerged as the definitive “best” for PD, and no reliable predictors can guide specific treatment for an individual.3 Combining CBT with pharmacotherapy produces higher short-term response rates than either treatment alone, but in the long term, combination treatment does not appear to be superior to CBT alone.9 Base the initial treatment selection for PD on patient preference, treatment availability and cost, and comorbid medical and psychiatric conditions. For an Algorithm to guide treatment decisions, see this article at

Algorithm: Treatment for panic disorder: A suggested algorithm
aPoor response to an SSRI should lead to a switch to venlafaxine extended-release, and vice versa
bBenzodiazepines are relatively contraindicated in geriatric patients and patients with a history of substance abuse or dependence
CBT: cognitive-behavioral therapy; MAOI: monoamine oxidase inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; Ven XR: venlafaxine extended-release

First-line treatments

Psychotherapy. CBT is the most efficacious psychotherapy for PD. Twelve to 15 sessions of CBT has demonstrated efficacy for PD, with additional effects on comorbid anxiety and depressive symptoms.10 No large clinical trials of CBT have used cognitive restructuring alone; all have included at least some component of exposure that requires the patient to confront feared physical sensations. Gains during treatment may be steady and gradual or sudden and uneven, with rapid improvement in some but not all symptoms. CBT and pharmacotherapy have demonstrated similar levels of benefit in short-term trials, but CBT has proven superior in most9 but not all11 trials evaluating long-term outcomes, particularly compared with pharmacotherapy that is discontinued during follow-up. Although less studied, group CBT also may be considered if a patient cannot afford individual CBT.

Pharmacotherapy. Evidence supports selective serotonin reuptake inhibitors (SSRIs), venlafaxine extended-release (XR), benzodiazepines, and tricyclic antidepressants (TCAs) as effective treatments for PD.3 No class of medication has demonstrated superiority over others in short-term treatment.3,12 Because of the medical risks associated with benzodiazepines and TCAs, an SSRI or venlafaxine XR should be the first medication option for most patients. Fluoxetine, paroxetine, sertraline, and venlafaxine XR are FDA-approved for PD. Paroxetine is associated with weight gain and may increase the risk for panic recurrence upon discontinuation more than sertraline, making it a less favorable option for many patients.13 Start doses at half the normal starting dose used for treating major depressive disorder and continue for 4 to 7 days, then increase to the minimal effective dose. For a Table3 that lists dosing recommendations for antidepressants to treat PD, see this article at If there is no improvement by 4 weeks, increase the dose every 2 to 4 weeks until remission is achieved or side effects prevent further dose increases.


Recommended doses for antidepressants used to treat panic disorder


Starting dose (mg/d)

Therapeutic range (mg/d)




20 to 40



10 to 40


5 to 10

20 to 80



100 to 300



20 to 80

   Paroxetine CR


25 to 50



100 to 200



20 to 30

60 to 120

   Venlafaxine XR


150 to 225



10 to 25

100 to 300



100 to 300




45 to 90

CR: controlled release; MAOI: monoamine oxidase inhibitor; SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; XR: extended release
Source: American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. 2nd ed. Washington, DC: American Psychiatric Association; 2009

Treatment nonresponse. True non-response needs to be distinguished from poor response caused by inadequate treatment delivery, eg, patients not completing homework assignments in CBT or not adhering to pharmacotherapy. Asking patients about adverse effects or personal and family beliefs about treatment may reveal reasons for nonadherence.

Second-line treatments

Little data are available to guide next-step treatment options in patients who don’t achieve remission from their initial treatment. Patients who benefit from an SSRI, venlafaxine XR, or CBT but still have symptoms should be started on combination treatment. For a patient who experiences complete non-response to the initial treatment, discontinue the first treatment and switch to the other modality. In general, completely ineffective treatments should be discontinued when another treatment is added, but when partial improvement (>30%) occurs, continue the original treatment and augment it with another approach.

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