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Evidence-Based Reviews

Break the ‘fear circuit’ in resistant panic disorder

Calming the brain’s overactive alarm network may require high medication dosages, intense cognitive therapy, or both.

Vol. 2, No. 11 / November 2003

When initial therapy fails to control a patient’s panic attacks, a neuroanatomic model of anxiety disorders may help. This model proposes that panic sufferers have an abnormally sensitive brain “fear circuit.” 1 It suggests why both medications and cognitive-behavioral therapy (CBT) are effective for treating panic disorder (PD) and can be used as a guide to more successful treatment.

This article explains the fear circuit model and describes how to determine whether initial drug treatment of panic symptoms has been adequate. It offers evidence-and experience-based dosing ranges, augmentation strategies, tips for antidepressant titration, and solutions to the most common inadequate response problems.


Panic disorder may occur with or without agoraphobia. The diagnosis requires recurrent, unexpected panic attacks (Table 1), with at least one attack followed by 1 month or more of:

  • persistent concern about having additional attacks
  • worry about the implications of the attack
  • or significant change in behavior related to the attack.

Panic disorder is usually accompanied by phobic avoidance and anticipatory anxiety, and it often coexists with other psychiatric disorders. Anxiety disorders may share a common genetic vulnerability. Childhood experiences, gender, and life events may increase or decrease the probability that a biologically vulnerable individual will develop an anxiety disorder or depression. 1

Table 1

Panic attacks: The core symptom of panic disorder

A panic attack is a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and peak within 10 minutes:

  • Palpitations, pounding heart, or accelerated heart rate
  • Sweating
  • Trembling or shaking
  • Sensations of shortness of breath or smothering
  • Feeling of choking
  • Chest pain or discomfort
  • Nausea or abdominal distress
  • Feeling dizzy, unsteady, lightheaded, or faint
  • Derealization (feelings of unreality) or depersonalization (being detached from oneself)
  • Fear of losing control or going crazy
  • Fear of dying
  • Paresthesias (numbness or tingling sensations)
  • Chills or hot flushes

Source: DSM-IV-TR

Fear circuit model. PD’s pathophysiology is not completely understood, but evidence suggests that an overactive brain alarm network may increase vulnerability for PD (Box). 1,2 Individual patients require different intensities of treatment to normalize their panic symptoms:

Mild to moderate PD (characterized by little or no avoidance and no comorbid disorders) often responds to either medication or CBT. A single intervention—such as using CBT to enhance the cortical inhibitory effects or using medication to reduce the amygdala’s reactivity—may suffice for symptomatic relief.

Severe or complicated PD (characterized by frequent panic attacks, significant agoraphobia, and comorbid anxiety disorders or depression) may require high medication dosages, intense CBT/exposure therapy, or both to normalize more severely disrupted communication among the fear circuit’s components.


The goal of treatment is remission: a return to functioning without illness-related impairment or loss of quality of life, as if the patient had never been ill. In clinical practice, we can use validated, patient-rated assessment tools to document improvement in panic-related impairment, patient satisfaction, and quality of life—the real targets of treatment. Two useful tools are the Sheehan Disability Scale3 and the Quality of Life Enjoyment and Satisfaction Questionnaire.4

With adequate treatment, achieving remission can take several months or more; without it, remission may never occur. The following guidelines can help ensure that you provide adequate treatment.

What is adequate CBT? When patients’ symptoms fail to respond to CBT, the first step is to examine whether inadequate treatment is the culprit. At least 10 weekly CBT sessions administered by a “qualified professional” has been suggested as an adequate CBT trial for PD. 5 Unfortunately, qualified CBT therapists are not always available. If CBT referral is not an option, clinicians can provide patients with at least some elements of CBT, such as education about PD, information resources, and self-exposure instruction as indicated. For more information on CBT for PD, see Related Resources.

What is adequate drug treatment? Noncompliance with medication because a patient fears adverse effects or has insufficient information can easily thwart treatment. Before treatment begins, therefore, it is important to establish your credibility. Provide the patient with information about PD, its treatment options, and what to expect so that he or she can collaborate in treatment (Table 2).


How an abnormal ‘fear circuit’ may trigger panic attacks

An inherited, abnormally active brain alarm mechanism—or “fear circuit”—may explain panic disorder, according to a theoretical neuroanatomic model.1 Its hub is the central nucleus of the amygdala, which coordinates fear responses via pathways communicating with the hippocampus, thalamus, hypothalamus, brainstem, and cortical processing areas.

The amygdala mediates acute emotional responses, including fear and anxiety. The hypothalamus mediates physiologic changes connected with emotions, such as release of stress hormones and some changes in heart rate. The prefrontal cortex is involved in thinking and memory and may be instrumental in predicting the consequences of rewards or punishments. In vulnerable individuals, defects in coordinating the sensory input among these brain regions may cause the central nucleus to discharge, resulting in a panic attack.

Medication and cognitive-behavioral therapy may reduce fear circuit reactivity and prevent panic attacks by acting at different components of the fear circuit. When the amygdala’s central nucleus no longer overreacts to sensory input, anticipatory anxiety and phobic avoidance usually dissipate over time. 2,3 Thus, the fear circuit model integrates the clinical observation that both cognitive-behavioral therapy and medication are effective for treating panic. 1

Abnormal interactions among components of this oversensitive fear circuit also may occur in social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, and depression.1 In these disorders, communication patterns among the parts of the hypothesized circuit may be disrupted in different ways. The clinical observation that anxious individuals often become depressed when under stress is consistent with this model and with the literature.

Antidepressants are preferred as first-line treatment of PD, even in nondepressed patients. Selective serotonin reuptake inhibitors (SSRIs) are recommended for PD because of their comparable efficacy and tolerability compared with older antipanic agents. 6 SSRIs are also effective against other anxiety disorders likely to co-occur with PD. 7

Many panic patients are exquisitely sensitive to activation by initial antidepressant dosages. Activation rarely occurs in other disorders, so its appearance suggests that your diagnosis is correct. Clinical strategies to help you manage antidepressant titration are suggested in Table 3.

Table 2

Prescription for success in treating panic disorder

Relieve patient of perceived burden of being ill
Explain the disorder’s familial/genetic origins
Describe the fear circuit model
Include spouse or significant other in treatment

Build patient-physician collaboration
Explain potential medication side effects
Describe the usual pattern of symptom relief (stop panic attacks → reduce anticipatory anxiety → decrease phobia)
Estimate a time frame for improvement
Map out next steps if first try is unsuccessful
Be available, especially at first

Address patient’s long-term medication concerns
Discuss safety, long-term efficacy
Frame treatment as a pathway to independence from panic attacks
Use analogy of diabetes or hypertension to explain that medication is for managing symptoms, rather than a cure
Discuss tapering medication after sustained improvement (12 to 18 months) to determine continued need for medication

In clinical settings, two naturalistic studies suggested that more-favorable outcomes are associated with antipanic medication dosages shown in Table 4 as “possibly effective”—and that most patients with poor medication response received inadequate treatment.8,9 Table 4 ’s dosages come from those two studies—published before the efficacy studies of SSRIs in PD—and from later studies of SSRIs and the selective norepinephrine-serotonin reuptake inhibitor (SNRI) venlafaxine.7,8,10

The lower end of the “probably effective” range in Table 4 represents the lowest dose levels generally expected to be effective for PD. Not all agents in the table are FDA-approved for PD, nor are the dosages of approved agents necessarily “within labeling.” Some patients’ symptoms may resolve at higher or lower dosages.

Table 3

Tips to help the patient tolerate antidepressant titration

Be pre-emptive
Before starting therapy, explain that low initial dosing and flexible titration help to control unpleasant but medically safe “jitteriness” known as antidepressant-induced activation
Tell the patient that activation rarely occurs in disorders other than PD (“Its appearance suggests that the diagnosis is correct and that we’re likely on the right track”)

Be reassuring
Tell the patient, “You control the gas peddle—I’ll help you steer” (to an effective dose)

Be cautious
Start with 25 to 50% of the usual antidepressant initial dosage for depression (Table 4); if too activating, reduce and advance more gradually
Activation usually dissipates in 1 to 2 weeks; over time, larger dosage increments are often possible

Be attentive
Use benzodiazepines or beta blockers as needed to attenuate activation

Some patients require months to reach and maintain the “probably effective” dosage for at least 6 weeks. Short-term benzodiazepines can be used to control panic symptoms during antidepressant titration, then tapered off.11 We categorize patients who are unable to tolerate an “adequate dose” as not having had a therapeutic trial—not as treatment failures.

No controlled studies of PD have examined the success rate of switching to a second antidepressant after a first one has been ineffective.12 In clinical practice, we may try two different SSRIs and venlafaxine. When switching agents, we usually co-administer the treatments for a few weeks, titrate the second agent upward gradually, then taper and discontinue the first agent over 2 to 4 weeks. We use short-term benzodiazepines as needed.

Partial improvement. Sometimes overall symptoms improve meaningfully, but bothersome panic symptoms remain. Clinical response may improve sufficiently if you raise the medication dosage in increments while monitoring for safety and tolerability. Address medicolegal concerns by documenting in the patient’s chart:

  • your rationale for prescribing dosages that exceed FDA guidelines
  • that you discussed possible risks versus benefits with the patient, and the patient agrees to the treatment.

When in doubt about using dosages that exceed FDA guidelines for patients with unusually resistant panic symptoms, obtain consultation from an expert or colleague.

Table 4

Recommended drug dosages for panic disorder


Possibly effective (mg/d)

Probably effective (mg/d)

High dosage (mg/d)

Initial dosage (mg/d)

Confidence level

































































































Valproate (VPA)






* FDA-approved for treating panic disorder


+ (uncontrolled series)

++ (at least 1 controlled study)

+++ (>1 controlled study)

++++ (Unequivocal)

Using benzodiazepines. As noted above, adjunctive use of benzodiazepines while initiating antidepressant therapy can help extremely anxious or medication-sensitive patients. 11 Many clinicians coadminister benzodiazepines with antidepressants over the longer term. 7 As a primary treatment, benzodiazepines may be useful for patients who could not tolerate or did not respond to at least two or three antidepressant trials.

Table 5

Solving inadequate response to initial SSRI treatment of panic disorder


Differential diagnosis

Suggested solutions

Persistent panic attacks

Unexpected attacks Inadequate treatment or duration
Situational attacks
Medical condition
Other psychiatric disorder

≥Threshold dose for 6 weeks
Try second SSRI
Try venlafaxine
CBT/exposure therapy
Address specific conditions
Rule out social phobia, OCD, PTSD

Persistent nonpanic anxiety

Medication-related Activation (SSRI or SNRI) Akathisia from SSRI
Comorbid GAD
Interdose BZD rebound
BZD or alcohol withdrawal
Residual anxiety

Adjust dosage, add BZD or beta blocker
Adjust dosage, add beta blocker or BZD
Increase antidepressant dosage, add BZD
Switch to longer-acting agent
Assess and treat as indicated
Add/increase BZD

Residual phobia


CBT/exposure, adjust medication

Other disorders

Bipolar disorder
Personality disorders
Medical disorder

Aggressive antidepressant treatment ±BZDs
Mood stabilizer and antidepressant ±BZDs
Specific psychotherapy
Review and modify treatment as indicated

Environmental event or stressor(s)

Review work, family events, patient perception of stressor

Family/spouse interview and education
Environmental hygiene as indicated
Brief adjustment in treatment plan(s) as needed

Poor adherence

Drug sexual side effects
Inadequate patient or family understanding of panic disorder and its treatment

Try bupropion, sildenafil, amantadine, switch agents
Patient/family education
Make resource materials available

BZD: Benzodiazepine

CBT: Cognitive-behavioral therapy

GAD: Generalized anxiety disorder

OCD: Obsessive-compulsive disorder

PTSD: Posttraumatic stress disorder

SNRI: Serotonin-norepinephrine reuptake inhibitor

SSRI: Selective serotonin reuptake inhibitor

Because benzodiazepine monotherapy does not reliably protect against depression, we advise clinicians to encourage patients to self-monitor and report any signs of emerging depression. Avoid benzodiazepines in patients with a history of alcohol or substance abuse. 7

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