Next-Step Strategies for Panic Disorder Refractory to Initial Pharmacotherapy: A 3-Phase Randomized Clinical Trial
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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 (beta [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 (t(17) = 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: clinicaltrials.gov Identifier: NCT00118417.
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A randomized controlled trial by Simon et al. suggested that maintaining medium recommended doses of sertraline/escitalopram for an additional 6 weeks in patients who did not achieve remission during the previous 6 weeks can facilitate additional significant improvement, whereas increasing to maximum doses did not.
“RCT conducted by Simon et al. [9•, 19] suggested that maintaining medium recommended doses of sertraline/escitalopram for additional 6 weeks in patients who did not achieve remission during the previous 6 weeks of treatment can facilitate additional, significant improvement, whereas increase to the maximum doses did not do so.”
From Management of Treatment-Resistant Panic Disorder (2017) · cites this paper as [19]
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Experimental — accuracy not yet measuredThe most recent comprehensive systematic review on pharmacological/non-pharmacological interventions in treatment-resistant panic disorder, covering studies published from 1980 to the beginning of 2015, included 11 studies, only two of which were double-blind randomized controlled trials.
“The most recent, comprehensive systematic review on pharmacological/non-pharmacological interventions in patients with TRPD, covering studies published from 1980 to the beginning of 2015 [9•], included 11 studies, only two of which were double-blind randomized controlled trials (RCTs) [16, 19].”
From Management of Treatment-Resistant Panic Disorder (2017) · cites this paper as [19]
In a small sample of panic disorder patients not remitted after 6 weeks of sertraline or escitalopram, 6 subsequent weeks of higher dosages of the same medications did not improve panic/anxiety symptoms compared with adjunctive placebo.
“in a small sample of patients with PD who had not achieved remission after 6 weeks of treatment with sertraline (up to 100 mg/day) or escitalopram (up to 15 mg/day), 6 subsequent weeks of a higher dosage of the same medications (150–200 mg/day or 20–30 mg/day, respectively) did not improve panic/anxiety symptoms in comparison to adjunctive placebo [19].”
From Management of Treatment-Resistant Panic Disorder (2017) · cites this paper as [19]
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References 36 · Cited by 45
Research works printed but not linked: 3
- [14]Simon NM Pollack MH Treatment Refractory Panic Disorder. Psychiatric Clinics of North America: Annual of Drug Therapy Philadelphia, PA WB Saunders 1999
- [17]Craske MG Barlow DH Mastery of Your Anxiety and Panic: Therapist Guide (Kindle Edition) New York, NY Oxford University Press 2006
- [39]Craske MG Golinelli D Stein MB Roy-Byrne P Bystritsky A Sherbourne C Does the addition of cognitive behavioral therapy improve panic disorder treatment outcome relative to medication alone in the primary-care setting? Psychol Med 2005 Nov 35 11 1645 1654 16219122
- Authors
- Simon, N. M., Otto, M. W., Worthington, J. J., Hoge, E. A., Thompson, E. H., LeBeau, R. T., Moshier, S. J., Zalta, A. K., & Pollack, M. H.
- Affiliations
- Massachusetts General Hospital (US)
- Boston University (US)
- Harvard University (US)
- Corresponding author
- Simon, Naomi M.
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2009-10-06
- Volume
- 70
- Issue
- 11
- Pages
- 1563-1570
- ISSN
- 0160-6689 (ISSN-L)
- PMC
- PMC2995303
- OpenAlex
- W2071972290
- Cited by
- 45
- References
- 36
- Citations by year
- 2026: 1 · 2025: 2 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 3 · 2012: 5
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (K23MH001831)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
- Social Sciences › Psychology › Clinical Psychology › Personality Disorders and Psychopathology
- Keywords
- panic disorder, medication optimization, sertraline, remission, Panic Disorder Severity Scale, treatment-resistant depression, comorbid depression
- MeSH terms
- Adult, Anticonvulsants, Clonazepam, Combined Modality Therapy, Double-Blind Method, Drug Resistance, Female, Humans, Longitudinal Studies, Male, Placebos, Psychiatric Status Rating Scales, Surveys and Questionnaires, Severity of Illness Index, Stress Disorders, Post-Traumatic, Citalopram, Cognitive Behavioral Therapy, Panic Disorder, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Sertraline, Diagnostic and Statistical Manual of Mental Disorders
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