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Review
. 2016 Apr 13;4(4):CD011004.
doi: 10.1002/14651858.CD011004.pub2.

Psychological therapies for panic disorder with or without agoraphobia in adults: a network meta-analysis

Alessandro Pompoli  1 , Toshi A Furukawa, Hissei Imai, Aran Tajika, Orestis Efthimiou, Georgia Salanti
Affiliations
Review

Psychological therapies for panic disorder with or without agoraphobia in adults: a network meta-analysis

Alessandro Pompoli et al. Cochrane Database Syst Rev. .

Abstract

Background: Panic disorder is characterised by the presence of recurrent unexpected panic attacks, discrete periods of fear or anxiety that have a rapid onset and include symptoms such as racing heart, chest pain, sweating and shaking. Panic disorder is common in the general population, with a lifetime prevalence of 1% to 4%. A previous Cochrane meta-analysis suggested that psychological therapy (either alone or combined with pharmacotherapy) can be chosen as a first-line treatment for panic disorder with or without agoraphobia. However, it is not yet clear whether certain psychological therapies can be considered superior to others. In order to answer this question, in this review we performed a network meta-analysis (NMA), in which we compared eight different forms of psychological therapy and three forms of a control condition.

Objectives: To assess the comparative efficacy and acceptability of different psychological therapies and different control conditions for panic disorder, with or without agoraphobia, in adults.

Search methods: We conducted the main searches in the CCDANCTR electronic databases (studies and references registers), all years to 16 March 2015. We conducted complementary searches in PubMed and trials registries. Supplementary searches included reference lists of included studies, citation indexes, personal communication to the authors of all included studies and grey literature searches in OpenSIGLE. We applied no restrictions on date, language or publication status.

Selection criteria: We included all relevant randomised controlled trials (RCTs) focusing on adults with a formal diagnosis of panic disorder with or without agoraphobia. We considered the following psychological therapies: psychoeducation (PE), supportive psychotherapy (SP), physiological therapies (PT), behaviour therapy (BT), cognitive therapy (CT), cognitive behaviour therapy (CBT), third-wave CBT (3W) and psychodynamic therapies (PD). We included both individual and group formats. Therapies had to be administered face-to-face. The comparator interventions considered for this review were: no treatment (NT), wait list (WL) and attention/psychological placebo (APP). For this review we considered four short-term (ST) outcomes (ST-remission, ST-response, ST-dropouts, ST-improvement on a continuous scale) and one long-term (LT) outcome (LT-remission/response).

Data collection and analysis: As a first step, we conducted a systematic search of all relevant papers according to the inclusion criteria. For each outcome, we then constructed a treatment network in order to clarify the extent to which each type of therapy and each comparison had been investigated in the available literature. Then, for each available comparison, we conducted a random-effects meta-analysis. Subsequently, we performed a network meta-analysis in order to synthesise the available direct evidence with indirect evidence, and to obtain an overall effect size estimate for each possible pair of therapies in the network. Finally, we calculated a probabilistic ranking of the different psychological therapies and control conditions for each outcome.

Main results: We identified 1432 references; after screening, we included 60 studies in the final qualitative analyses. Among these, 54 (including 3021 patients) were also included in the quantitative analyses. With respect to the analyses for the first of our primary outcomes, (short-term remission), the most studied of the included psychological therapies was CBT (32 studies), followed by BT (12 studies), PT (10 studies), CT (three studies), SP (three studies) and PD (two studies).The quality of the evidence for the entire network was found to be low for all outcomes. The quality of the evidence for CBT vs NT, CBT vs SP and CBT vs PD was low to very low, depending on the outcome. The majority of the included studies were at unclear risk of bias with regard to the randomisation process. We found almost half of the included studies to be at high risk of attrition bias and detection bias. We also found selective outcome reporting bias to be present and we strongly suspected publication bias. Finally, we found almost half of the included studies to be at high risk of researcher allegiance bias.Overall the networks appeared to be well connected, but were generally underpowered to detect any important disagreement between direct and indirect evidence. The results showed the superiority of psychological therapies over the WL condition, although this finding was amplified by evident small study effects (SSE). The NMAs for ST-remission, ST-response and ST-improvement on a continuous scale showed well-replicated evidence in favour of CBT, as well as some sparse but relevant evidence in favour of PD and SP, over other therapies. In terms of ST-dropouts, PD and 3W showed better tolerability over other psychological therapies in the short term. In the long term, CBT and PD showed the highest level of remission/response, suggesting that the effects of these two treatments may be more stable with respect to other psychological therapies. However, all the mentioned differences among active treatments must be interpreted while taking into account that in most cases the effect sizes were small and/or results were imprecise.

Authors' conclusions: There is no high-quality, unequivocal evidence to support one psychological therapy over the others for the treatment of panic disorder with or without agoraphobia in adults. However, the results show that CBT - the most extensively studied among the included psychological therapies - was often superior to other therapies, although the effect size was small and the level of precision was often insufficient or clinically irrelevant. In the only two studies available that explored PD, this treatment showed promising results, although further research is needed in order to better explore the relative efficacy of PD with respect to CBT. Furthermore, PD appeared to be the best tolerated (in terms of ST-dropouts) among psychological treatments. Unexpectedly, we found some evidence in support of the possible viability of non-specific supportive psychotherapy for the treatment of panic disorder; however, the results concerning SP should be interpreted cautiously because of the sparsity of evidence regarding this treatment and, as in the case of PD, further research is needed to explore this issue. Behaviour therapy did not appear to be a valid alternative to CBT as a first-line treatment for patients with panic disorder with or without agoraphobia.

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Conflict of interest statement

AP has no competing interests.

TAF has received honoraria for speaking at CME meetings sponsored by Asahi Kasei, Eli Lilly, GlaxoSmithKline, Mochida, MSD, Otsuka, Pfizer, Shionogi and Tanabe‐Mitsubishi. He is a diplomate of the Academy of Cognitive Therapy. He has received royalties from Igaku‐Shoin, Seiwa‐Shoten and Nihon Bunka Kagaku‐sha. He is on the advisory board for Sekisui Chemicals and Takeda Science Foundation. The Japanese Ministry of Education, Science, and Technology, the Japanese Ministry of Health, Labor and Welfare, and the Japan Foundation for Neuroscience and Mental Health have funded his research projects.

HI has no competing interests.

AT has received honoraria for speaking at a meeting sponsored by Eli Lilly.

OE has no competing interests.

GS has no competing interests.

Figures

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Ideal network of included treatment and control conditions.
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Study selection process: PRISMA flow diagram
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'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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'Risk of bias' summary. Note that we left the boxes empty when the RoB assessment was not applicable (e.g. in the case of incomplete outcome data in the long term when the study did not report any long term measure that could be included in the analyses).
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Short‐term remission: network plot
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Short‐term remission: forest plot for the comparison WL vs CBT
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Short‐term remission: forest plot for the comparison CBT vs BT
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Short‐term remission: funnel plot for the comparison CBT vs WL
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Short‐term remission: funnel plot for the comparison CBT vs BT
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Short‐term remission: contour‐enhanced funnel plot for the comparison CBT vs WL
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Short‐term remission: inconsistency factors for the network
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Short‐term response: network plot
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Short‐term response: forest plot for the comparison WL vs CBT
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Short‐term response: forest plot for the comparison CBT vs BT
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Short‐term response: funnel plot for the comparison WL vs CBT
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Short‐term response: funnel plot for the comparison CBT vs BT
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Short‐term response: inconsistency factors for the network
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Short‐term dropouts: network plot
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Short‐term dropouts: forest plot for the comparison WL vs CBT
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Short‐term dropouts: forest plot for the comparison CBT vs BT
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Short‐term dropouts: funnel plot for the comparison WL vs CBT
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Short‐term dropouts: funnel plot for the comparison CBT vs BT
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Short‐term dropouts: inconsistency factors for the network
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Short‐term improvement: network plot
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Short‐term improvement: forest plot for the comparison WL vs CBT
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Short‐term improvement: forest plot for the comparison CBT vs BT
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Short‐term improvement: funnel plot for the comparison WL vs CBT
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Short‐term improvement: funnel plot for the comparison CBT vs BT
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Short‐term improvement: inconsistency factors for the network
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Long‐term remission/response: network plot
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Long‐term remission/response: inconsistency factors for the network
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Subgroup analysis: number of treatment sessions, forest plot for the comparison WL vs CBT
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Subgroup analysis: number of treatment sessions, regression line for the comparison WL vs CBT
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Subgroup analysis: number of treatment sessions, forest plot for the comparison CBT vs BT
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Subgroup analysis: number of treatment sessions, regression line for the comparison CBT vs BT
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Subgroup analysis: therapist training, forest plots for the comparison WL vs CBT
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Subgroup analysis: therapist training, forest plot for the comparison CBT vs BT
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Subgroup analysis: percentage of agoraphobic patients, regression line for the comparison WL vs CBT
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Subgroup analysis: percentage of depressed patients, regression line for the comparison WL vs CBT
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Subgroup analysis: percentage of drug‐treated patients, regression line for the comparison WL vs CBT
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Sensitivity analyses: network plot for short‐term remission excluding from the analyses group therapy trials
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Sensitivity analyses: forest plot for the comparison WL vs CBT excluding group therapy trials
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Sensitivity analyses: forest plot for the comparison CBT vs BT excluding group therapy trials
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Sensitivity analyses: funnel plot for the comparison WL vs CBT excluding group therapy trials
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Sensitivity analyses: forest plot for the comparison CBT vs BT excluding group therapy trials
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Sensitivity analyses: inconsistency factors for the network of short‐term remission excluding from the analyses group therapy trials
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Sensitivity analyses: network plot for short‐term remission excluding from the analyses trials in which a concomitant pharmacotherapy is allowed
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Sensitivity analyses: network plot for short‐term remission excluding from the analyses trials in which pharmacotherapy stabilisation was not required
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    1. Meulenbeek P, Spinhoven P, Smit F, Balkom A, Cuijpers P. Cognitive mediation of panic reduction during an early intervention for panic. Acta Psychiatrica Scandinavica 2010;122(1):20‐9. - PubMed
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Meuret 2008 {published data only (unpublished sought but not used)}
    1. Meuret AE, Wilhelm FH, Ritz T, Roth WT. Feedback of end‐tidal pCO2 as a therapeutic approach for panic disorder. Journal of Psychiatric Research 2008;42(7):560‐8. - PMC - PubMed
Meuret 2010 {published data only (unpublished sought but not used)}
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    1. Meuret AE, Rosenfield D, Seidel A, Bhaskara L, Hofmann SG. Respiratory and cognitive mediators of treatment change in panic disorder: evidence for intervention specificity. Journal of Consulting and Clinical Psychology 2010;78(5):691‐704. - PMC - PubMed
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Meyerbroker 2011 {published and unpublished data}
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Milrod 2006a {published and unpublished data}
    1. Klass ET, Milrod BL, Leon AC, Kay SJ, Schwalberg M, Li C, et al. Does interpersonal loss preceding panic disorder onset moderate response to psychotherapy? An exploratory study. Journal of Clinical Psychiatry Diseases of the Nervous System 2009;70(3):406‐11. - PMC - PubMed
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Muncy 1991 {published data only}
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Ost 1993 {published data only (unpublished sought but not used)}
    1. Ost LG, Westling BE, Hellstrom K. Applied relaxation, exposure in vivo and cognitive methods in the treatment of panic disorder with agoraphobia. Behaviour Research and Therapy 1993;31(4):383‐94. - PubMed
Ost 1995 {published data only}
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Ost 2004 {published data only (unpublished sought but not used)}
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Petterson 1996 {published data only}
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Rees 1999 {published data only}
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Reinecke 2013 {published data only}
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Salkovskis 1999 {published data only}
    1. Salkovskis PM, Clark DM, Hackmann A, Wells A, Gelder MG. An experimental investigation of the role of safety‐seeking behaviours in the maintenance of panic disorder with agoraphobia. Behaviour Research and Therapy 1999;37(6):559‐74. - PubMed
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Schmidt 1997a {published data only}
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Schmidt 1997b {published data only (unpublished sought but not used)}
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Scott 1995 {published data only (unpublished sought but not used)}
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Sharp 2004 {published data only}
    1. Sharp DM, Power KG, Swanson V. A comparison of the efficacy and acceptability of group versus individual cognitive behaviour therapy in the treatment of panic disorder and agoraphobia in primary care. Clinical Psychology and Psychotherapy 2004;11(2):73‐82.
Shear 1994 {published data only}
    1. Shear MK, Leon AC, Portera L, Klosko J, Cloitre M. Psychoeducation /reflective listening compared to cognitive‐behavioural treatment in panic disorder. New Research Program and Abstracts ‐ 144th Annual Meeting of the American Psychiatric Association; 1991 May 11‐16. New Orleans, Louisiana, US, 1991.
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Taylor 1982 {published data only (unpublished sought but not used)}
    1. Taylor CB, Kenigsberg ML, Robinson JM. A controlled comparison of relaxation and diazepam in panic disorder. Journal of Clinical Psychiatry 1982;43(10):423‐5. - PubMed
Telch 1993 {published data only}
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Tyrer 1988 {published data only (unpublished sought but not used)}
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Williams 1996 {published data only (unpublished sought but not used)}
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Wollburg 2011 {published data only}
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References to studies excluded from this review

Andersson 2011 {published and unpublished data}
    1. Andersson G. Internet‐administrated treatment of anxiety symptoms for young adults. https://clinicaltrials.gov/ct2/show/NCT01402258 2011 (accessed 16 March 2015).
Barlow 2000a {published data only}
    1. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive‐behavioral therapy, imipramine, or their combination for panic disorder. a randomized controlled trial. JAMA 2000;283(19):2529‐36. - PubMed
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    1. Barlow DH, Gorman JM, Shear MK, Woods SW. ERRATUM: Cognitive‐behavioral therapy, imipramine, or their combination for panic disorder. a randomized controlled trial. JAMA 2001;284(20):2597. - PubMed
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Bélanger 2006 {published and unpublished data}
    1. Bélanger C, Vaillancourt L, Dulude D, Archambault M, Rochfort J, Pecknold J, et al. The differential effect of two behavioral therapies on attentional processes of subjects presenting panic disorder [L'effet différentiel de deux thérapies comportementales sur les processus attentionnels de sujets présentant un trouble panique]. Revue Francophone de Clinique Comportamentale et Cognitive 2008;13(2):11‐23.
Benecke 2014 {published data only}
    1. Benecke C. Psychoanalytic therapy (PT) and cognitive‐behavioral therapy (CBT) in outpatients with anxiety (panic disorder/agoraphobia) and comorbid personality disorders: a multicenter prospective randomized superiority trial. http://www.isrctn.com/ISRCTN12449681 2014 (accessed 16 March 2015).
Borden 1986 {published data only}
    1. Clum GA, Watkins PL, Borden JW, Broyles S, Hayes J. A comparison of guided imaginal coping and imaginal exposure in the treatment of panic disorder. Journal of Rational‐Emotive & Cognitive‐Behavior Therapy 1993;11(4):179.
Elsesser 2002 {published and unpublished data}
    1. Elsesser K, Mosch A, Sartory G. Brief psychological treatment for the relief of panic disorder. Behavioural and Cognitive Psychotherapy 2002;30(4):423‐30.
Fava 1997 {published data only (unpublished sought but not used)}
    1. Fava GA, Savron G, Zielezny M, Grandi S, Rafanelli C, Conti S. Overcoming resistance to exposure in panic disorder with agoraphobia. Acta Psychiatrica Scandinavica 1997;95(4):306‐12. - PubMed
Gloster 2010a {published data only (unpublished sought but not used)}
    1. Gloster AT. Acceptance and commitment therapy (ACT) for treatment‐resistant panic disorder with agoraphobia. http://www.isrctn.com/ISRCTN12042066 2010 (accessed 16 March 2015).
Ito 2001 {published data only}
    1. Ito LM, Araujo LA, Tess VLC, Barros‐Neto TP, Asbahr FR, Marks I. Self‐exposure therapy for panic disorder with agoraphobia. British Journal of Psychiatry 2001;178(4):331‐6. - PubMed
Michelson 1996 {published data only}
    1. Michelson LK, Marchione KE, Greenwald MT, Testa S, Marchione NJ. A comparative outcome and follow‐up investigation of panic disorder with agoraphobia: the relative and combined efficacy of cognitive therapy, relaxation training, and therapist‐assisted exposure. Journal of Anxiety Disorders 1996;10(5):297‐330.
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Teusch 1996 {published data only (unpublished sought but not used)}
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Zane 1993 {published data only (unpublished sought but not used)}
    1. Zane G, Williams SL. Performance‐related anxiety in agoraphobia: treatment procedures and cognitive mechanisms of change. Behavior Therapy 1993;196:625‐43.

References to studies awaiting assessment

Bressi 2010a {published data only (unpublished sought but not used)}
    1. Bressi C, Ciabatti M, Nocito EP, Catenacci E, Porcellana, M, Invernizzi G, et al. A preliminary longitudinal study on the importance of early intervention in panic disorder [conference abstract]. Journal of Psychosomatic Research [abstracts from the 19th European Congress of Psychiatry, EPA 2011 Vienna Austria, 12‐15 Mar]. 2011:610.
Foley 2006 {published data only (unpublished sought but not used)}
    1. Foley D, Baille A, Renner P. 29th Australian Association for Cognitive and Behaviour Therapy Annual Conference. Manly, 18‐23 October 2006:43.
Franklin 1990 {published data only}
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Irgens 2009 {published data only (unpublished sought but not used)}
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Margraf 1991 {published data only (unpublished sought but not used)}
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Milrod 2006b {published data only (unpublished sought but not used)}
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Richards 1997 {published data only (unpublished sought but not used)}
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Roache 1998 {published data only (unpublished sought but not used)}
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Strauss 1997 {published data only (unpublished sought but not used)}
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Vincelli 2003 {published data only (unpublished sought but not used)}
    1. Vincelli F, Anolli L, Bouchard S, Wiederhold BK, Zurloni V, Riva G. Experiential cognitive therapy in the treatment of panic disorders with agoraphobia: a controlled study. Cyberpsychology and Behavior 2003;6(3):321‐8. - PubMed
Vincelli 2004 {published data only (unpublished sought but not used)}
    1. Vincelli F, Molinari E, Riva G. CBT Virtual Reality Assisted for the Treatment of Panic Disorders with Agoraphobia: A Controlled Study. 35th International Meeting of the Society for Psychotherapy Research. Rome, 16‐19 June 2004:35.

References to ongoing studies

Barlow 2010 {published data only (unpublished sought but not used)}
    1. Barlow DH. Efficacy evaluation of a unified transdiagnostic treatment for anxiety disorders. https://clinicaltrials.gov/ct2/show/NCT01243606 2010 (accessed 16 March 2015).
Caspi 2012 {published data only (unpublished sought but not used)}
    1. Caspi A. The assessment and treatment of balance impairment using virtual reality (VR) in panic disorder patients. https://clinicaltrials.gov/ct2/show/NCT01677429 2012 (accessed 16 March 2015).
Gensichen 2012 {published data only (unpublished sought but not used)}
    1. Gensichen J. Evaluation of a practice team‐supported, self‐managed exposure training for patients with panic disorder and agoraphobia in primary care [Jena‐PARADISE (Patient Activation foR Anxiety DISordErs)]. http://www.isrctn.com/ISRCTN64669297 2012 (accessed 16 March 2015).
    1. Gensichen J, Hiller TS, Breitbart J, Teismann T, Brettschneider C, Schumacher U, Piwtorak A, König HH, Hoyer H, Schneider N, Schelle M, Blank W, Thiel P, Wensing M, Margraf J. Evaluation of a practice team‐supported exposure training for patients with panic disorder with or without agoraphobia in primary care ‐ study protocol of a cluster randomised controlled superiority trial [2014]. Trials 2014;15:112. - PMC - PubMed
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Teismann 2012 {published data only}
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