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Original Research

Next-Step Strategies for Panic Disorder Refractory to Initial Pharmacotherapy: A 3-Phase Randomized Clinical Trial

Naomi M. Simon, MD, MSc; Michael W. Otto, PhD; John J. Worthington, MD; Elizabeth A. Hoge, MD; Elizabeth H. Thompson, BA; Richard T. LeBeau, BA; Samantha J. Moshier, BA; Alyson K. Zalta, MA; and Mark H. Pollack, MD

Published: October 6, 2009

Article Abstract

Background: More data are needed to guide next-step interventions for panic disorder refractory to initial intervention.

Method: This 24-week randomized clinical trial (RCT) enrolled 46 patients with DSM-IV-defined panic disorder from November 2000 to April 2005 and consisted of 3 phases. Patients who failed to
meet remission criteria were eligible for randomization in the next treatment phase. Phase 1 was a 6-week lead-in with open-label sertraline flexibly dosed to 100 mg (or escitalopram equivalent) to
prospectively define treatment refractoriness (lack
of remission). Phase 2 was a 6-week double-blind RCT of (1) increased-dose selective serotonin reuptake inhibitor (SSRI) versus (2) continued SSRI plus placebo. Phase 3 was a 12-week RCT of added cognitive-behavioral therapy (CBT) compared to "medication optimization" with SSRI plus clonazepam. Primary endpoints were remission and change in Panic Disorder Severity Scale (PDSS) score in the intent-to-treat sample in each phase.

Results: In phase 1, 20.5% (8/39) of the patients achieved remission, and only baseline severity predicted endpoint PDSS score (β [SE]‘ ‰=‘ ‰1.04 [0.15], t‘ ‰=‘ ‰6.76, P‘ ‰<‘ ‰.001). In phase 2, increasing the SSRI dose did not result in greater improvement or remission rates (placebo 15% [n‘ ‰=‘ ‰2] vs increased dose 9% [n‘ ‰=‘ ‰1]: Fisher exact test P‘ ‰=‘ ‰NS). In phase 3, remission was minimal (medication optimization‘ ‰=‘ ‰11% [n‘ ‰=‘ ‰1]; CBT‘ ‰=‘ ‰10% [n‘ ‰=‘ ‰1]), with a lack of group difference in PDSS score reduction (t17‘ ‰=‘ ‰0.51, P‘ ‰>‘ ‰.60) consistent with a small effect size (d‘ ‰=‘ ‰0.24).

Conclusions: Although power was limited and larger studies are needed, we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose. Further, augmentation with CBT or medication optimization with clonazepam augmentation in nonremitted panic after 12 weeks of an SSRI did not differ, suggesting that both are reasonable next-step options. However, low overall remission rates in this comorbid refractory population suggest that better predictors of response to specific treatments over time and additional interventions are needed.

Trial Registration: Identifier: NCT00118417

Submitted: June 20, 2008; accepted October 9, 2008.

Online ahead of print: October 6, 2009.

Corresponding author: Naomi M. Simon, MD, MSc, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, Simches Research Building, 2nd Floor, 185 Cambridge St, Boston, MA 02114 (

Volume: 70

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