Evidence-Based Reviews

Break the ‘fear circuit’ in resistant panic disorder

Current Psychiatry. 2003 November;2(11):12-22

References

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2. Coplan JD, Lydiard RB. Brain circuits in panic disorder. Biol Psychiatry 1998;44:1264-76.

3. Sheehan DV. The anxiety disease. New York: Charles Scribner and Sons, 1983;151.-

4. Rapaport MH, Wolkow RM, Clary CM. Methodologies and outcomes from the sertraline multicenter flexible-dose trials. Psychopharmacol Bull 1998;34:183-9.

5. Otto MW. Psychosocial approach to treatment-resistant anxiety disorders (presentation). Chantilly, VA: Anxiety Disorders Association of America conference on novel approaches to treatment of refractory anxiety disorders, June 15-16, 2003.

6. Gorman JM, Shear MK, McIntyre JS, Zarin DA. American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. Am J Psychiatry 1998;155(May supplement).

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8. Simon NM, Safrens SA, Otto MW, et al. Outcome with pharmacotherapy in a naturalistic study of panic disorder. J Affect Disord 2002;69:201-8.

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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.^8,9Table 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

Class/agent	Possibly effective (mg/d)	Probably effective (mg/d)	High dosage (mg/d)	Initial dosage (mg/d)	Confidence level
SSRIs
Citalopram	<20	20-60	>60	10	++
Escitalopram	<10	10-30	>30	5	++++
Fluoxetine	<40	40-80	>80	10	++
Fluvoxamine	<150	150-300	>300	25	++++
Paroxetine*	<40	40-60	>60	5-10	++++
Sertraline*	<150	150-300	>300	12.5-25	++++
SNRI
Venlafaxine	<150	150-300	>300	18.75-37.5	++
Benzodiazepines
Alprazolam*	<2	2-8	>8	0.5-1.0	++++
Clonazepam*	<1	2-4	>4	0.25-0.5	++++
Tricyclics
Clomipramine	<100	100-200	>200	10	++++
Desipramine	<150	150-300	>300	10	++
Imipramine	<150	150-300	>300	10	++++
MAOIs
Phenelzine	<45	45-90	>90	15	+++
Tranylcypromine	<30	30-70	>70	10	+
Antiepileptics
Gabapentin	100-200	600-3,400			++
Valproate (VPA)	250-500	1,000-2,000			++
* FDA-approved for treating panic disorder
Confidence:
+ (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.