Evidence-Based Reviews

Break the ‘fear circuit’ in resistant panic disorder

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

References

1. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revisited. Am J Psychiatry 2000;157:493-505.

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).

7. Lydiard RB, Otto MW, Milrod B. Panic disorder treatment. In: Gabbard, GO (ed). Treatment of psychiatric disorders (3rd ed). Washington, DC: American Psychiatric Press, Inc, 2001;1447-82.

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.

9. Yonkers KA, Ellison J, Shera D, et al. Description of antipanic therapy in a prospective longitudinal study. J Clin Psychopharmacol 1996;16:223-32.

10. Pollack MH, Worthington JJ, 3rd, Otto MW, et al. Venlafaxine for panic disorder: results from a double-blind, placebo-controlled study. Psychopharmacol Bull 1996;32:667-70.

11. Goddard AW, Brouette T, Almai A, et al. Early coadministration of clonazepam with sertraline for panic disorder. Arch Gen Psychiatry 2001;58:681-6.

12. Simon NM. Pharmacological 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.

13. Hoffart A, Due-Madsen J, Lande B, et al. Clomipramine in the treatment of agoraphobic inpatients resistant to behavioral therapy. J Clin Psychiatry 1993;54:481-7.

14. Kampman M, Keijsers GP, Hoogduin CA, Hendriks GJ. A randomized, double-blind, placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. J Clin Psychiatry 2002;63:772-7.

15. Hirschmann S, Dannon PN, Iancu I, et al. Pindolol augmentation in patients with treatment-resistant panic disorder: a double-blind, placebo-controlled trial. J Clin Psychopharmacol 2000;20:556-9.

16. Hollifield M, Thompson P, Uhlenluth E. Potential efficacy and safety of olanzapine in refractory panic disorder (presentation). San Francisco: American Psychiatric Association annual meeting, 2003.

17. Tiffon L, Coplan J, Papp L, Gorman J. Augmentation strategies with tricyclic or fluoxetine treatment in seven partially responsive panic disorder patients. J Clin Psychiatry 1994;55:66-9.

18. Dannon PN, Iancu I, Grunhaus L. The efficacy of reboxetine in treatment-refractory patients with panic disorder: an open-label study. Hum Psychopharmacol 2002;17:329-33.

19. Chiu S. Gabapentin treatment response in SSRI-refractory panic disorder (presentation) San Francisco: American Psychiatric Association annual meeting, 2003.

20. Marazziti D, Presta S, Pfanner C, et al. Pramipexole augmentation in panic with agoraphobia. Am J Psychiatry 2001;158:498-9.

Table 5

Solving inadequate response to initial SSRI treatment of panic disorder

Problem	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	Agoraphobia	CBT/exposure, adjust medication
Other disorders	Depression 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

Other agents. Once the mainstay of antipanic treatment, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are seldom used today because of their side effects, toxicity in overdose, and—for MAOIs—tyramine-restricted diet. Their usefulness in resistant panic is probably limited to last-ditch efforts.

DISSECTING TREATMENT FAILURE

In uncomplicated PD, lack of improvement after two or more adequate medication trials is unusual. If you observe minimal or no improvement, review carefully for other causes of anxiety or factors that can complicate PD treatment (Table 5).

If no other cause for the persistent symptom(s) is apparent, the fear circuit model may help you decide how to modify or enhance medication treatment, add CBT, or both.

For example:

If panic attacks persist, advancing the medication dosage (if tolerated and acceptably safe) may help. Consider increasing the dosage, augmenting, or switching to a different agent.
If persistent attacks are consistently cued to feared situations, try intervening with moreaggressive exposure therapy. Consider whether other disorders such as unrecognized social anxiety disorder, obsessive-compulsive disorder (OCD), or posttraumatic stress disorder (PTSD) may be perpetuating the fearful avoidance.
If the patient is depressed, consider that depression-related social withdrawal may be causing the avoidance symptoms. Aggressive antidepressant pharmacotherapy is strongly suggested.

AUGMENTATION STRATEGIES

Medication for CBT failure. Only two controlled studies have examined adding an adequate dose of medication after patients failed to respond to exposure/CBT alone:

One study of 18 hospitalized patients with agoraphobia who failed a course of behavioral psychodynamic therapy reported improvement when clomipramine, 150 mg/d, was given for 3 weeks.¹³
In a study of 43 patients who failed initial CBT, greater improvement was reported in patients who received CBT plus paroxetine, 40 mg/d, compared with those who received placebo while continuing CBT.¹⁴

Augmentation in drug therapy. Only one controlled study has examined augmentation therapy after lack of response to an SSRI—in this case 8 weeks of fluoxetine after two undefined “antidepressant failures.” When pindolol, 2.5 mg tid, or placebo were added to the fluoxetine therapy, the 13 patients who received pindolol improved clinically and statistically more on several standardized ratings than the 12 who received placebo.¹⁵

An 8-week, open-label trial showed beneficial effects of olanzapine, up to 20 mg/d, in patients with well-described treatment-resistant PD.¹⁶

Other well-described treatment adjustments reported to benefit nonresponsive PD include:

Adding fluoxetine to a TCA or adding a TCA to fluoxetine, for TCA/SSRI combination therapy¹⁷
Switching to the selective norepinephrine reuptake inhibitor reboxetine, 2 to 8 mg/d for 6 weeks after inadequate paroxetine or fluoxetine response (average of 8 weeks, maximum dosage 40 mg/d).¹⁸ (Note: Reboxetine is not available in the United States.)
Using open-label gabapentin, 600 to 2,400 mg/d, after two SSRI treatment failures.¹⁹
Adding the dopamine receptor agonist pramipexole, 1.0 to 1.5 mg/d, to various antipanic medications.²⁰

Augmenting an SSRI with pindolol or supplementing unsuccessful behavioral treatment with “probably effective” dosages of paroxetine or clomipramine could be recommended with some confidence, although more definitive studies are needed. As outlined above, some strategies^17-20 might be considered if a patient fails to respond to two or more adequate medication trials. Anecdotal reports are difficult to assess but may be clinically useful when other treatment options have been exhausted.

Related resources

Barlow DH. Anxiety and its disorders: the nature and treatment of anxiety and panic New York: Guilford Press, 1988.
Craske MG, DeCola JP, Sachs AD, Pontillo DC. Panic control treatment of agoraphobia. J Anxiety Disord 2003;17:321-33.
National Institute for Mental Health: Panic Disorder http://www.nimh.nih.gov/publicat/fearandtrauma.cfm
Anxiety Disorders Association of America http://www.adaa.org/