Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia

  • A. T. Gloster
  • H. U. WittchenEmail author
  • F. Einsle
  • M. Höfler
  • T. Lang
  • S. Helbig-Lang
  • T. Fydrich
  • L. Fehm
  • A. O. Hamm
  • J. Richter
  • G. W. Alpers
  • A. L. Gerlach
  • A. Ströhle
  • T. Kircher
  • J. Deckert
  • P. Zwanzger
  • V. Arolt


Cognitive behavioral therapy (CBT) is efficacious for panic disorder with agoraphobia (PD/A). Nevertheless, the active ingredients of treatment and the mechanisms through which CBT achieves its effects remain largely unknown. The mechanisms of action in CBT (MAC) study was established to investigate these questions in 369 patients diagnosed with PD/A. The MAC study utilized a multi-center, randomized controlled design, with two active treatment conditions in which the administration of exposure was varied, and a wait-list control group. The special feature of MAC is the way in which imbedded experimental, psychophysiological, and neurobiological paradigms were included to elucidate therapeutic and psychopathological processes. This paper describes the aims and goals of the MAC study and the methods utilized to achieve them. All aspects of the research design (e.g., assessments, treatment, experimental procedures) were implemented so as to facilitate the detection of active therapeutic components, and the mediators and moderators of therapeutic change. To this end, clinical, behavioral, physiological, experimental, and genetic data were collected and will be integrated.


Panic disorder Agoraphobia CBT Exposure therapy Mechanisms Methods 


Conflict of interest statement

The following authors report no conflicts of interest concerning the content of this paper: A. Gloster, H.-U. Wittchen, F. Einsle, M. Höfler, T. Lang, S. Helbig-Lang, T. Fydrich, L. Fehm, A. Hamm, J. Richter, G. Alpers, A. Gerlach, J. Deckert, P. Zwanzger, and V. Arolt. A. Ströhle received research funding from the German Federal Ministry of Education and Research, the European Commission (FP6) and Lundbeck, and speaker honoraria from Pfizer, Eli Lilly & Co, Wyeth and Lundbeck. A. Ströhle was the recipient of educational grants by the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds and the Eli Lilly International Foundation. T. Kircher received fees for educational programs from Janssen-Cilag, Eli Lilly, Servier, Lundbeck, Bristol Myers Squibb, Pfizer, and AstraZeneca; travel support/sponsorship for congresses from Servier; speaker’s honoraria from Janssen-Cilag; and research grants from Pfizer and Lundbeck.


  1. 1.
    Alpers GW, Sell R (2008) And yet they correlate: psychophysiological measures predict the outcome of exposure therapy in claustrophobia. J Anxiety Disord 22:1101–1109CrossRefPubMedGoogle Scholar
  2. 2.
    American Psychiatric Association (2000) Diagnostic and statistic manual of mental disorders, text revision, 4th edn. American Psychiatric Association, Washington, DCCrossRefGoogle Scholar
  3. 3.
    Andor F, Glöckner-Rist A, Gerlach AL, Rist F (2008) Symptomspezifische Subgruppen der Panikstörung. Zeitschrift für Klinische Psychologie und Psychotherapie 37:161–171CrossRefGoogle Scholar
  4. 4.
    Arch JJ, Craske MG (2008) Acceptance and commitment therapy and cognitive behavioral therapy for anxiety disorders: different treatments, similar mechanisms? Clin Psychol Sci Pract 15:263–279Google Scholar
  5. 5.
    Arch JJ, Craske MG (2009) First-line treatment: a critical appraisal of cognitive behavioral therapy developments and alternatives. Psychiatr Clin North America 32:525–547CrossRefGoogle Scholar
  6. 6.
    Baker-Morrissette S, Spiegel DA, Heinrichs N (2005) Sensation-focused intensive treatment for panic disorder with moderate to severe agoraphobia. Cogn Behav Pract 12:17–29CrossRefGoogle Scholar
  7. 7.
    Bandelow B (1999) Panic and agoraphobia scale (PAS). Hogrefe & Huber Publishers, AshlandGoogle Scholar
  8. 8.
    Barlow DH, Gorman JM, Shear MK, Woods SW (2000) Cognitive-behavioral therapy, imipramine, or their combination for panic disorder—a randomized controlled trial. JAMA 283:2529–2536CrossRefPubMedGoogle Scholar
  9. 9.
    Beck AT, Steer RA, Brown GK (1996) Manual for the BDI-II. The Psychological Corporation, San AntonioGoogle Scholar
  10. 10.
    Blümel I, Jansen A, Kellermann T, Schüppen A, Kohn N, Gerlach A et al. (2009) Neural correlates of aversive conditioning (submitted)Google Scholar
  11. 11.
    Bond FW, Hayes SC, Baer RA, Carpenter KM, Orcutt HK, Waltz T et al. (2007) Preliminary psychometric properties of the acceptance and action questionnaire—II: a revised measure of psychological flexibility and acceptance (in review)Google Scholar
  12. 12.
    Chambless DL (1985) The mobility inventory for agoraphobia. Behav Res Ther 23:35–44CrossRefPubMedGoogle Scholar
  13. 13.
    Chambless DL, Caputo GC, Bright P, Gallagher R (1984) Assessment of fear of fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions questionnaire. J Consult Clin Psychol 52:1090–1097CrossRefPubMedGoogle Scholar
  14. 14.
    Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE et al (2003) International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 35:1381–1395CrossRefPubMedGoogle Scholar
  15. 15.
    Craske MG, Barlow DH (2007) Mastery of your anxiety and panic. University Press, OxfordGoogle Scholar
  16. 16.
    Craske MG, Kircanski K, Zelikowsky M, Mystkowski J, Chowdhury N, Baker A (2008) Optimizing inhibitory learning during exposure therapy. Behav Res Ther 46:5–27CrossRefPubMedGoogle Scholar
  17. 17.
    Crawford JR, Henry JD (2004) The positive and negative affect schedule (PANAS): construct validity, measurement properties and normative data in a large non-clinical sample. British Journal of Clinical Psychology 43:245–265CrossRefPubMedGoogle Scholar
  18. 18.
    Davis M (2006) Neural systems involved in fear and anxiety measured with fear-potentiated startle. Am Psychol 61:741–756CrossRefPubMedGoogle Scholar
  19. 19.
    Deckert J, Catalano M, Syagailo Y, Bosi M, Okladnova O, Di Bella D et al (1999) Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 8:621–624CrossRefPubMedGoogle Scholar
  20. 20.
    Derogatis LR (1993) Brief symptom inventory (BSI) administration, scoring, and procedures manual, 3rd edn. National Computer Systems, MinneapolisGoogle Scholar
  21. 21.
    Domschke K, Braun M, Ohrmann P, Suslow T, Kugel H, Bauer J et al (2006) Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal and amygdala activation measured with 3T fMRI in panic disorder. Int J Neuropsychopharmacol 9:349–355CrossRefPubMedGoogle Scholar
  22. 22.
    Domschke K, Hohoff C, Jacob C, Maier W, Fritze J, Bandelow B et al (2008) Chromosome 4q31-34 panic disorder risk locus: association of neuropeptide Y Y5 receptor variants. Am J Med Genet B Neuropsychiatr Genet 147B:510–516CrossRefPubMedGoogle Scholar
  23. 23.
    Domschke K, Ohrmann P, Braun M, Suslow T, Bauer J, Hohoff C et al (2008) Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res 163:13–20CrossRefPubMedGoogle Scholar
  24. 24.
    Gloster A, Einsle F, Lang T, Hauke T, Wittchen H-U (2009) The therapist adherence and competency rating scales for panic disorder with agoraphobia (in preparation)Google Scholar
  25. 25.
    Gloster AT, Klotsche J, Helbig S, Einsle F, Lang T, Hummel K et al. (2009) Expanding the assessment domain in agoraphobia: mobility inventory-expanded (MI-E) and mobility inventory 7-day (MI-7) versions (in preparation)Google Scholar
  26. 26.
    Gorman JM, Kent JM, Sullivan GM, Coplan JD (2000) Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 157:493–505CrossRefPubMedGoogle Scholar
  27. 27.
    Gorman JM, Liebowitz MR, Fyer AJ, Stein J (1989) A neuroanatomical hypothesis for panic disorder. Am J Psychiatry 146:148–161PubMedGoogle Scholar
  28. 28.
    Guy W (1976) Clinical global impression. In: Guy W (ed) ECDEU assessment manual for psychopharmacology, revised. National Insitute of Mental Health, Rockville, pp 217–222Google Scholar
  29. 29.
    Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50–55PubMedGoogle Scholar
  30. 30.
    Hayes SC (2008) Climbing our hills: a beginning conversation on the comparison of acceptance and commitment therapy and traditional cognitive behavioral therapy. Clin Psychol Sci Pract 15:286–295Google Scholar
  31. 31.
    Hofmann SG, Alpers GW, Pauli P (2009) Phenomenology of panic and phobic disorders. In: Antony MM, Stein MB (eds) Oxford handbook of anxiety and related disorders. Oxford University Press, New York, pp 34–46Google Scholar
  32. 32.
    Hueweler R, Kandil FI, Alpers GW, Gerlach AL (2009) The impact of visual flow stimuli on anxiety, dizziness, and body sway in persons with and without fear of heights. Behav Res Therapy 47:345–352CrossRefGoogle Scholar
  33. 33.
    Koch EI, Gloster AT, Waller SA (2007) Exposure treatments for panic disorder with and without agoraphobia. In: Richard DCS, Lauterbach DL (eds) Handbook of exposure therapies. Elsevier, Burlington, pp 221–245Google Scholar
  34. 34.
    Lang T, Helbig-Lang S, Westphal D, Gloster AT, Wittchen HU (2009) Kognitiv-behaviorale Behandlung der Panikstörung mit Agoraphobie. Ein Therapiemanual. Hogrefe, GöttingenGoogle Scholar
  35. 35.
    Lonsdorf TB, Weike AI, Nikamo P, Schalling M, Hamm AO, Öhman A (2009) Genetic gating of human fear learning and extinction–Possible implications for gene-environment interaction in anxiety disorder. Psychol Sci 20:198–206CrossRefPubMedGoogle Scholar
  36. 36.
    McHugh RK, Smits JAJ, Otto MW (2009) Empirically supported treatments for panic disorder. Psychiatr Clin North AmGoogle Scholar
  37. 37.
    Melzig CA, Michalowski JM, Holtz K, Hamm AO (2008) Anticipation of interoceptive threat in highly anxiety sensitive persons. Behav Res Ther 46:1126–1134CrossRefPubMedGoogle Scholar
  38. 38.
    Neudeck P, Wittchen H-U (2005) Die Vernachlässigung der Expositionsverfahren- ein Verstoß gegen die Regeln der Kunst!. In: Neudeck P, Wittchen H-U (eds) Konfrontationstherapie bei psychischen Störungen. Hogrefe, Göttingen, pp 7–14Google Scholar
  39. 39.
    Rabin R, de Charro F (1999, 2001) EQ-5D: a measure of health status from the EuroQol Group. Paper presented at the 12th Medical Symposium of the Yrjo-Jahnsson-Foundation, FinlandGoogle Scholar
  40. 40.
    Radomsky AS, Rachman S, Thordarsona DS, McIsaaca HK, Teachman BA (1999) The claustrophobia questionnaire. J Anxiety Disord 15:287–297CrossRefGoogle Scholar
  41. 41.
    Reiss S, Peterson RA, Gursky DM, McNally RJ (1986) Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Therapy 24:1–8CrossRefGoogle Scholar
  42. 42.
    Richard DCS, Lauterbach D, Gloster AT (2007) Description, mechanisms of action, and assessment. In: Richard DCS, Lauterbach DL (eds) Handbook of exposure therapies. Elsevier, Burlington, pp 1–28CrossRefGoogle Scholar
  43. 43.
    Shadish WR, Cook TD, Campbell DT (2002) Experimental and quasi-experimental designs for generalized causal inference. Houghton-Mifflin, BostonGoogle Scholar
  44. 44.
    Shear MK, Vander Bilt J, Rucci P, Endicott J, Lydiard B, Otto MW et al (2001) Reliability and validity of a structured interview guide for the Hamilton anxiety rating scale (SIGH-A). Depress Anxiety 13(4):166–178CrossRefPubMedGoogle Scholar
  45. 45.
    Sheehan DV (1983) The anxiety disease. Charles Scribner’s Sons, New YorkGoogle Scholar
  46. 46.
    Wittchen H-U, Gloster AT (2009) Developments in the treatment and diagnosis of anxiety disorders. Psychiatr Clin North Am 32:xix–xiiiGoogle Scholar
  47. 47.
    Wittchen H-U, Pfister H (1997) DIA-X Interview. Instruktionsmanual zur Durchführung von DIA-X-Interviews (Instruction manual for the DIA-X-Interview). Swets & Zeitlinger, FrankfurtGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • A. T. Gloster
    • 1
  • H. U. Wittchen
    • 1
    • 12
    Email author
  • F. Einsle
    • 1
  • M. Höfler
    • 1
  • T. Lang
    • 1
    • 2
    • 3
  • S. Helbig-Lang
    • 1
    • 2
  • T. Fydrich
    • 4
  • L. Fehm
    • 4
  • A. O. Hamm
    • 5
  • J. Richter
    • 5
  • G. W. Alpers
    • 6
  • A. L. Gerlach
    • 7
  • A. Ströhle
    • 8
  • T. Kircher
    • 9
  • J. Deckert
    • 10
  • P. Zwanzger
    • 11
  • V. Arolt
    • 11
  1. 1.Dresden University of TechnologyDresdenGermany
  2. 2.University of BremenBremenGermany
  3. 3.Christoph-Donier Foundation for Clinical PsychologyMarburgGermnay
  4. 4.Humboldt UniversityBerlinGermany
  5. 5.Greifswald Ernst-Moritz-Arndt UniversityGreifswaldGermany
  6. 6.Department of PsychologyUniversity of WürzburgWürzburgGermany
  7. 7.Department of PsychologyUniversity of MünsterMünsterGermany
  8. 8.Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin BerlinBerlinGermany
  9. 9.Philipps UniversityMarburgGermany
  10. 10.Department of Psychiatry, Psychosomatics and PsychotherapyUniversity of WürzburgWürzburgGermany
  11. 11.Department of PsychiatryUniversity of MünsterMünsterGermany
  12. 12.Department of Psychology, Institute of Clinical Psychology and PsychotherapyTechnische Universität DresdenDresdenGermany

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