5HTT is associated with the phenotype psychological flexibility: results from a randomized clinical trial

  • Andrew T. GlosterEmail author
  • Alexander L. Gerlach
  • Alfons Hamm
  • Michael Höfler
  • Georg W. Alpers
  • Tilo Kircher
  • Andreas Ströhle
  • Thomas Lang
  • Hans-Ulrich Wittchen
  • Jürgen Deckert
  • Andreas Reif
Original Paper


Adaption to changing environments is evolutionarily advantageous. Studies that link genetic and phenotypic expression of flexible adjustment to one’s context are largely lacking. In this study, we tested the importance of psychological flexibility, or goal-related context sensitivity, in an interaction between psychotherapy outcome for panic disorder with agoraphobia (PD/AG) and a genetic polymorphism. Given the established role of the 5HTT-LPR polymorphism in behavioral flexibility, we tested whether this polymorphism (short group vs. long group) impacted therapy response as a function of various endophenotypes (i.e., psychological flexibility, panic, agoraphobic avoidance, and anxiety sensitivity). Patients with PD/AG were recruited from a large multicenter randomized controlled clinical trial on cognitive-behavioral therapy. Pre- to post-treatment changes by 5HTT polymorphism were analyzed. 5HTT polymorphism status differentiated pre- to post-treatment changes in the endophenotype psychological flexibility (effect size difference d = 0.4, p < 0.05), but none of the specific symptom-related endophenotypes consistently for both the intent-to-treat sample (n = 228) and the treatment completers (n = 194). Based on the consistency of these findings with existing theory on behavioral flexibility, the specificity of the results across phenotypes, and the consistency of results across analyses (i.e., completer and intent to treat), we conclude that 5HTT polymorphism and the endophenotype psychological flexibility are important variables for the treatment of PD/AG. The endophenotype psychological flexibility may help bridge genetic and psychological literatures. Despite the limitation of the post hoc nature of these analyses, further study is clearly warranted.


5HTT Psychological flexibility Psychotherapy Panic disorder Agoraphobia Evolution 



We are grateful to all individuals who participated in this study. This work is part of the German multicenter trial “Mechanisms of Action in CBT (MAC).” The MAC study is funded by the German Federal Ministry of Education and Research (BMBF; Project No. 01GV0615) as part of the BMBF Psychotherapy Research Funding Initiative. The Principal Investigators (PI) of the centers with respective areas of responsibility in the MAC study are as follows: V. Arolt (Münster: Overall MAC Program Coordination), H.U. Wittchen (Dresden: Principal Investigator (PI) for the Randomized Clinical Trial and Manual Development), A. Hamm (Greifswald: PI for Psychophysiology), A.L. Gerlach (Münster: PI for Psychophysiology and Panic subtypes), A. Ströhle (Berlin: PI for Experimental Pharmacology), T. Kircher (Marburg: PI for functional neuroimaging), and J. Deckert (Würzburg: PI for Genetics). Additional site directors in the RTC component of the program are G.W. Alpers (Würzburg), T. Fydrich and L.Fehm (Berlin-Adlershof), and T. Lang (Bremen). The study was further supported by the DFG (SFB TRR 58 Z02 to JD and AR, C02 to JD, B06 to AR; DE357/4-1 to JD and AR; RTG 1256, to ARand JD). T. Töpner and C. Gagel are credited for excellent technical assistance.

Conflict of interest

Drs. Gloster, Gerlach, Hamm, Höfler, Alpers, Kircher, Lang, Deckert & Reif report no conflicts of interest. Dr. Ströhle received research funding from the German Federal Ministry of Education and Research, the European Commission (FP6) and Lundbeck, and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth and UCB. He was a consultant for Actelion. Educational grants were given by the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds, the Eli Lilly International Foundation, Janssen-Cilag, Pfizer and Eli Lilly & Co. Dr. Wittchen is or has been on advisory boards of Servier, Pfizer, and Lundbeck. He also has received via his university grant support by Novartis, Lundbeck and Pfizer. Travel compensation for scientific meetings was received from Servier, Pfizer, Lundbeck, and Novartis.


  1. 1.
    Darwin C (1859) On the origin of species. Oxford World’s Classics, OxfordGoogle Scholar
  2. 2.
    Jablonka E, Lamb MJ (2005) Evolution in four dimensions: genetic, epigenetic, behavioral, and symbolic variation in the history of life. MIT Press, CambridgeGoogle Scholar
  3. 3.
    Homberg JR, Lesch KP (2011) Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry 69:513–519PubMedCrossRefGoogle Scholar
  4. 4.
    Hayes SC, Luoma JB, Bond FW, Masuda A, Lillis J (2006) Acceptance and commitment therapy: model, processes and outcomes. Behav Res Ther 44:1–25PubMedCrossRefGoogle Scholar
  5. 5.
    Wilson DS, Hayes SC, Biglan A, Embry DD (2014) Evolving the future: toward a science od intentional change. Behav Brain Sci 37:395–416PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Williams KE, Ciarrochi J, Heaven PCL (2012) Inflexible parents, inflexible kids: a 6-year longitudinal study of parenting style and the development of psychological flexibility in adolescents. J Youth Adolesc 41:1053–1066PubMedCrossRefGoogle Scholar
  7. 7.
    Hayes SC, Strosahl KD, Wilson KG (2012) Acceptance and commitment therapy: the process and practice of mindful change. Guilford, New YorkGoogle Scholar
  8. 8.
    Kashdan TB, Rottenberg J (2010) Psychological flexibility as a fundamental aspect of health. Clin Psychol Rev 30:865–878PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Gloster AT, Klotsche J, Chaker S, Hummel KV, Hoyer J (2011) Assessing psychological flexibility: What does it add above and beyond existing constructs? Psychol Assess 23:970–982PubMedCrossRefGoogle Scholar
  10. 10.
    Latzman RD, Masuda A (2013) Examining mindfulness and psychological inflexibility within the framework of big five personality. Personal Individ Differ 55:129–134CrossRefGoogle Scholar
  11. 11.
    Kämpfe C, Gloster AT, Wittchen HU, Helbig-Lang S, Lang T, Gerlach AL, Richter J, Alpers GW, Fehm L, Kircher T, Hamm AO, Ströhle A, Deckert J (2012) Experiential avoidance and anxiety sensitivity in patients with panic disorder and agoraphobia: Do both constructs measure the same? Int J Clin Health Psychol 12:5–22Google Scholar
  12. 12.
    Ruiz FJ (2012) Acceptance and commitment therapy versus traditional cognitive behavioral therapy: a systematic review and meta-analysis of current empirical evidence. Int J Psychol Psychol Therapy 12:333–357Google Scholar
  13. 13.
    Gloster AT, Klotsche J, Gerlach AL, Hamm A, Strohle A, Gauggel S, Kircher T, Alpers GW, Deckert J, Wittchen HU (2014) Timing matters: change depends on the stage of treatment in cognitive behavioral therapy for panic disorder with agoraphobia. J Consult Clin Psychol 82:141–153PubMedCrossRefGoogle Scholar
  14. 14.
    Levin ME, Hildebrandt MJ, Lillis J, Hayes SC (2012) The impact of treatment components suggested by the psychological flexibility model: a meta-analysis of laboratory-based component studies. Behav Ther 43:741–756PubMedCrossRefGoogle Scholar
  15. 15.
    Canli T, Lesch KP (2007) Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci 10:1103–1109PubMedCrossRefGoogle Scholar
  16. 16.
    Lesch KP, Waider J (2012) Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron 76:175–191PubMedCrossRefGoogle Scholar
  17. 17.
    Uher R, McGuffin P (2008) The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry 13:131–146PubMedCrossRefGoogle Scholar
  18. 18.
    Uher R, McGuffin P (2010) The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Mol Psychiatry 15:18–22PubMedCrossRefGoogle Scholar
  19. 19.
    Enge S, Fleischhauer M, Lesch KP, Reif A, Strobel A (2011) Serotonergic modulation in executive functioning: linking genetic variations to working memory performance. Neuropsychologia 49:3776–3785PubMedCrossRefGoogle Scholar
  20. 20.
    Enge S, Fleischhauer M, Lesch KP, Strobel A (2011) On the role of serotonin and effort in voluntary attention: evidence of genetic variation in n1 modulation. Behav Brain Res 216:122–128PubMedCrossRefGoogle Scholar
  21. 21.
    Enge S, Fleischhauer M, Lesch KP, Reif A, Strobel A (2012) Variation in key genes of serotonin and norepinephrine function predicts gamma-band activity during goal-directed attention. Cereb Cortex 24:1195–1205PubMedCrossRefGoogle Scholar
  22. 22.
    Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R (2009) Vulnerability genes or plasticity genes? Mol Psychiatry 14:746–754PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Hayes SC, Sanford BT (2014) Cooperation came first: evolution and human cognition. J Exp Anal Behav 101:112–129PubMedCrossRefGoogle Scholar
  24. 24.
    Pauli P, Conzelmann A, Mucha RF, Weyers P, Baehne CG, Fallgatter AJ, Jacob CP, Lesch KP (2010) Affect-modulated startle reflex and dopamine d4 receptor gene variation. Psychophysiology 47:25–33PubMedCrossRefGoogle Scholar
  25. 25.
    Gloster AT, Lang T, Georgi N, Wittchen HU (submitted) How patients decide to engage in exposure predicts attrition: the importance of willingnessGoogle Scholar
  26. 26.
    Gloster AT, Wittchen HU, Einsle F, Hofler M, Lang T, Helbig-Lang S, Fydrich T, Fehm L, Hamm AO, Richter J, Alpers GW, Gerlach AL, Strohle A, Kircher T, Deckert J, Zwanzger P, Arolt V (2009) Mechanism of action in cbt (mac): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia. Eur Arch Psychiatry Clin Neurosci 259(Suppl 2):S155–S166PubMedCrossRefGoogle Scholar
  27. 27.
    Gloster AT, Wittchen HU, Einsle F, Lang T, Helbig-Lang S, Fydrich T, Fehm L, Hamm AO, Richter J, Alpers GW, Gerlach AL, Strohle A, Kircher T, Deckert J, Zwanzger P, Hofler M, Arolt V (2011) Psychological treatment for panic disorder with agoraphobia: a randomized controlled trial to examine the role of therapist-guided exposure in situ in cbt. J Consult Clin Psychol 79:406–420PubMedCrossRefGoogle Scholar
  28. 28.
    Lang T, Helbig-Lang S, Westphal D, Gloster AT, Wittchen HU (2012) Expostitionsbasierte therapie der panikstörung mit agoraphobie. Ein behandlungsmanual. Hogrefe, GöttingenGoogle Scholar
  29. 29.
    Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-httlpr) shows ten novel allelic variants. Mol Psychiatry 5:32–38PubMedCrossRefGoogle Scholar
  30. 30.
    Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL (2006) Simultaneous genotyping of four functional loci of human slc6a4, with a reappraisal of 5-httlpr and rs25531. Mol Psychiatry 11:224–226PubMedCrossRefGoogle Scholar
  31. 31.
    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  32. 32.
    Bond FW, Hayes SC, Baer RA, Carpenter KM, Guenole N, Orcutt HK, Waltz T, Zettle RD (2011) Preliminary psychometric properties of the acceptance and action questionnaire-ii: a revised measure of psychological inflexibility and experiential avoidance. Behav Ther 42:676–688PubMedCrossRefGoogle Scholar
  33. 33.
    Shear MK, Vander Bilt J, Rucci P, Endicott J, Lydiard B, Otto MW, Pollack MH, Chandler L, Williams J, Ali A, Frank DM (2001) Reliability and validity of a structured interview guide for the Hamilton anxiety rating scale (sigh-a). Depress Anxiety 13:166–178PubMedCrossRefGoogle Scholar
  34. 34.
    Guy W (1976) Ecdeu assessment manual for psychopharmacology. U.S. Department of Health, Education, and Welfare, RockwilleGoogle Scholar
  35. 35.
    Barlow DH, Gorman JM, Shear MK, Woods SW (2000) Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial. J Am Med Assoc 283:2529–2536CrossRefGoogle Scholar
  36. 36.
    Chambless DL, Caputo GC, Jasin SE, Gracely EJ, Williams C (1985) The mobility inventory for agoraphobia. Behav Res Ther 23:35–44PubMedCrossRefGoogle Scholar
  37. 37.
    Chambless DL, Sharpless BA, Rodriguez D, McCarthy KS, Milrod BL, Khalsa SR, Barber JP (2011) Psychometric properties of the mobility inventory for agoraphobia: convergent, discriminant, and criterion-related validity. Behav Ther 42:689–699PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Reiss S, Peterson RA, Gursky DM, McNally RJ (1986) Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Ther 24:1–8PubMedCrossRefGoogle Scholar
  39. 39.
    Alpers GW, Pauli P (2001) Angstsensitivitäts-index. Julius-Maximilians Universität, WürzburgGoogle Scholar
  40. 40.
    Smits JA, Powers MB, Cho Y, Telch MJ (2004) Mechanism of change in cognitive-behavioral treatment of panic disorder: evidence for the fear of fear mediational hypothesis. J Consult Clin Psychol 72:646–652PubMedCrossRefGoogle Scholar
  41. 41.
    Bryant RA, Felmingham KL, Falconer EM, Pe Benito L, Dobson-Stone C, Pierce KD, Schofield PR (2010) Preliminary evidence of the short allele of the serotonin transporter gene predicting poor response to cognitive behavior therapy in posttraumatic stress disorder. Biol Psychiatry 67:1217–1219PubMedCrossRefGoogle Scholar
  42. 42.
    Eley TC, Hudson JL, Creswell C, Tropeano M, Lester KJ, Cooper P, Farmer A, Lewis CM, Lyneham HJ, Rapee RM, Uher R, Zavos HM, Collier DA (2012) Therapygenetics: the 5httlpr and response to psychological therapy. Mol Psychiatry 17:236–237PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Lonsdorf TB, Ruck C, Bergstrom J, Andersson G, Ohman A, Lindefors N, Schalling M (2010) The comtval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder. BMC Psychiatry 10:99PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Bockting CL, Mocking RJ, Lok A, Koeter MW, Schene AH (2013) Therapygenetics: The 5httlpr as a biomarker for response to psychological therapy? Mol Psychiatry 18:744–745PubMedCrossRefGoogle Scholar
  45. 45.
    Losos JB, Schoener TW, Langerhans RB, Spiller DA (2006) Rapid temporal reversal in predator-driven natural selection. Science 314:1111PubMedCrossRefGoogle Scholar
  46. 46.
    Whelan R, Schlund MW (2013) Reframing relational frame theory research: Gaining a new perspective through the application of novel behavioral and neurophysiological methods. In: Dymond S, Roche B (eds) Advances in relational frame theory: research and application. New Harbinger Publications, OaklandGoogle Scholar
  47. 47.
    Glenn AL (2011) The other allele: exploring the long allele of the serotonin transporter gene as a potential risk factor for psychopathy: a review of the parallels in findings. Neurosci Biobehav Rev 35:612–620PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Andrew T. Gloster
    • 1
    • 2
    Email author
  • Alexander L. Gerlach
    • 3
  • Alfons Hamm
    • 4
  • Michael Höfler
    • 2
  • Georg W. Alpers
    • 5
  • Tilo Kircher
    • 6
  • Andreas Ströhle
    • 7
  • Thomas Lang
    • 8
  • Hans-Ulrich Wittchen
    • 2
  • Jürgen Deckert
    • 9
  • Andreas Reif
    • 9
  1. 1.Division of Clinical Psychology and Epidemiology, Department of PsychologyUniversity of BaselBaselSwitzerland
  2. 2.Institute for Clinical Psychology and PsychotherapyTechnische Universität DresdenDresdenGermany
  3. 3.Department of Psychology, Clinical Psychology and PsychotherapyUniversity of CologneCologneGermany
  4. 4.Department of Clinical and Biological PsychologyErnst Moritz-Arndt University of GreifswaldGreifswaldGermany
  5. 5.Chair of Clinical Psychology, Biological Psychology and Psychotherapy, Department of PsychologyUniversity of MannheimMannheimGermany
  6. 6.Department of Psychiatry and PsychotherapyUniversity of MarburgMarburgGermany
  7. 7.Department of Psychiatry and PsychotherapyCharité-UniversitätsmedizinBerlinGermany
  8. 8.Christoph-Dornier-Foundation for Clinical PsychologyBremenGermany
  9. 9.Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental HealthUniversity of WürzburgWürzburgGermany

Personalised recommendations