Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy

Molecular Psychiatry volume 19, pages 122–128 (2014)Cite this article

Subjects

Abstract

Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011; 21: 655–679.

    Article  CAS  PubMed  Google Scholar 

  2. Domschke K, Reif A . Behavioral genetics of affective and anxiety disorders. Curr Top Behav Neurosci 2012; 12: 463–502.

    Article  PubMed  Google Scholar 

  3. Erhardt A, Czibere L, Roeske D, Lucae S, Unschuld PG, Ripke S et al. TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies. Mol Psychiatry 2011; 16: 647–663.

    Article  CAS  PubMed  Google Scholar 

  4. Domschke K, Reif A, Weber H, Richter J, Hohoff C, Ohrmann P et al. Neuropeptide S receptor gene — converging evidence for a role in panic disorder. Mol Psychiatry 2011; 16: 938–948.

    Article  CAS  PubMed  Google Scholar 

  5. Leygraf A, Hohoff C, Freitag C, Willis-Owen SA, Krakowitzky P, Fritze J et al. Rgs 2 gene polymorphisms as modulators of anxiety in humans? J Neural Transm 2006; 113: 1921–1925.

    Article  CAS  PubMed  Google Scholar 

  6. Buigues J, Vallejo J . Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. J Clin Psychiatry 1987; 48: 55–59.

    CAS  PubMed  Google Scholar 

  7. Tyrer P, Shawcross C . Monoamine oxidase inhibitors in anxiety disorders. J Psychiatr Res 1988; 22 (Suppl 1): 87–98.

    Article  PubMed  Google Scholar 

  8. Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP et al. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Exp Ophthalmol 2006; 34: 682–688.

    Article  PubMed  Google Scholar 

  9. Halpin C, Owen G, Gutierrez-Espeleta GA, Sims K, Rehm HL . Audiologic features of Norrie disease. Ann Otol Rhinol Laryngol 2005; 114: 533–538.

    Article  PubMed  Google Scholar 

  10. Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA . Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 1993; 262: 578–580.

    Article  CAS  PubMed  Google Scholar 

  11. Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 1995; 268: 1763–1766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D et al. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999; 8: 621–624.

    Article  CAS  PubMed  Google Scholar 

  13. Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103: 273–279.

    Article  CAS  PubMed  Google Scholar 

  14. Jonsson EG, Norton N, Gustavsson JP, Oreland L, Owen MJ, Sedvall GC . A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers. J Psychiatr Res 2000; 34: 239–244.

    Article  CAS  PubMed  Google Scholar 

  15. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW et al. Role of genotype in the cycle of violence in maltreated children. Science 2002; 297: 851–854.

    Article  CAS  PubMed  Google Scholar 

  16. Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW et al. MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis. Mol Psychiatry 2006; 11: 903–913.

    CAS  PubMed  Google Scholar 

  17. Reif A, Rosler M, Freitag CM, Schneider M, Eujen A, Kissling C et al. Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment. Neuropsychopharmacology 2007; 32: 2375–2383.

    Article  CAS  PubMed  Google Scholar 

  18. Maron E, Lang A, Tasa G, Liivlaid L, Toru I, Must A et al. Associations between serotonin-related gene polymorphisms and panic disorder. Int J Neuropsychopharmacol 2005; 8: 261–266.

    Article  CAS  PubMed  Google Scholar 

  19. Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepien G, Grzywacz A et al. Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res 2004; 128: 21–26.

    Article  CAS  PubMed  Google Scholar 

  20. Gibbons A . American Association of Physical Anthropologists meeting. Tracking the evolutionary history of a "warrior" gene. Science 2004; 304: 818.

    Article  CAS  PubMed  Google Scholar 

  21. McDermott R, Tingley D, Cowden J, Frazzetto G, Johnson DD . Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation. Proc Natl Acad Sci USA 2009; 106: 2118–2123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eisenberger NI, Way BM, Taylor SE, Welch WT, Lieberman MD . Understanding genetic risk for aggression: clues from the brain’s response to social exclusion. Biol Psychiatry 2007; 61: 1100–1108.

    Article  PubMed  Google Scholar 

  23. Meyer-Lindenberg A, Buckholtz JW, Kolachana B, A R Hariri, Pezawas L, Blasi G et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc Natl Acad Sci USA 2006; 103: 6269–6274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gloster AT, Wittchen HU, Einsle F, Hofler M, Lang T, Helbig-Lang S et al. 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 2009; 259 (Suppl 2): S155–S166.

    Article  PubMed  Google Scholar 

  25. Eley TC, Hudson JL, Creswell C, Tropeano M, Lester KJ, Cooper P et al. Therapygenetics: the 5HTTLPR and response to psychological therapy. Mol Psychiatry 2012; 17: 236–237.

    Article  CAS  PubMed  Google Scholar 

  26. Gloster AT, Wittchen HU, Einsle F, Lang T, Helbig-Lang S, Fydrich T et al. 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 2011; 79: 406–420.

    Article  PubMed  Google Scholar 

  27. Richter J, Hamm AO, Pané-Farré CA, Gerlach AL, Gloster AT, Wittchen H-U et al. Dynamics of defensive reacivity in patients with panic disorder and agoraphobia: implications for the etiology of panic disorder. Biol Psychiatry 2012; 72: 512–520.

    Article  PubMed  Google Scholar 

  28. Reinhardt I, Jansen A, Kellermann T, Schuppen A, Kohn N, Gerlach AL et al. Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders. Eur Arch Psychiatry Clin Neurosci 2010; 260: 443–453.

    Article  PubMed  Google Scholar 

  29. Kircher T, Arolt V, Jansen A, Pyka M, Reinhardt I, Kellermann T et al. Effect of cognitive-behavioral therapy on neural correlates of fear conditioning in panic disorder. Biol Psychiatry, advance online publication, 23 August 2012 (e-pub ahead of print).

  30. Bouton ME, Mineka S, Barlow DH . A modern learning theory perspective on the etiology of panic disorder. Psychol Rev 2001; 108: 4–32.

    Article  CAS  PubMed  Google Scholar 

  31. Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS et al. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatry 2010; 167: 47–55.

    Article  PubMed  Google Scholar 

  32. Lissek S, Rabin SJ, McDowell DJ, Dvir S, Bradford DE, Geraci M et al. Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behav Res Ther 2009; 47: 111–118.

    Article  PubMed  Google Scholar 

  33. Tuescher O, Protopopescu X, Pan H, Cloitre M, Butler T, Goldstein M et al. Differential activity of subgenual cingulate and brainstem in panic disorder and PTSD. J Anxiety Disord 2011; 25: 251–257.

    Article  PubMed  Google Scholar 

  34. Mobbs D, Marchant JL, Hassabis D, Seymour B, Tan G, Gray M et al. From threat to fear: the neural organization of defensive fear systems in humans. J Neurosci 2009; 29: 12236–12243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mobbs D, Petrovic P, Marchant JL, Hassabis D, Weiskopf N, Seymour B et al. When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 2007; 317: 1079–1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee BT, Ham BJ . Monoamine oxidase A-uVNTR genotype affects limbic brain activity in response to affective facial stimuli. Neuroreport 2008; 19: 515–519.

    Article  CAS  PubMed  Google Scholar 

  37. Straube B, Chatterjee A . Space and time in perceptual causality. Front Hum Neurosci 2010; 4: 28.

    PubMed  PubMed Central  Google Scholar 

  38. Mueller D, Cahill SP . Noradrenergic modulation of extinction learning and exposure therapy. Behav Brain Res 2010; 208: 1–11.

    Article  CAS  PubMed  Google Scholar 

  39. Myers KM, Davis M . Mechanisms of fear extinction. Mol Psychiatry 2007; 12: 120–150.

    Article  CAS  PubMed  Google Scholar 

  40. de Quervain DJ, Bentz D, Michael T, Bolt OC, Wiederhold BK, Margraf J et al. Glucocorticoids enhance extinction-based psychotherapy. Proc Natl Acad Sci USA 2011; 108: 6621–6625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Powers MB, Smits JA, Otto MW, Sanders C, Emmelkamp PM . Facilitation of fear extinction in phobic participants with a novel cognitive enhancer: a randomized placebo controlled trial of yohimbine augmentation. J Anxiety Disord 2009; 23: 350–356.

    Article  PubMed  Google Scholar 

  42. Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U et al. Glucocorticoids reduce phobic fear in humans. Proc Natl Acad Sci USA 2006; 103: 5585–5590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sehlmeyer C, Dannlowski U, Schoning S, Kugel H, Pyka M, Pfleiderer B et al. Neural correlates of trait anxiety in fear extinction. Psychol Med 2011; 41: 789–798.

    Article  CAS  PubMed  Google Scholar 

  44. Svensson TH . Stress, central neurotransmitters, and the mechanism of action of alpha 2-adrenoceptor agonists. J Cardiovasc Pharmacol 1987; 10 (Suppl 12): S88–S92.

    CAS  PubMed  Google Scholar 

  45. LeDoux J . The amygdala. Curr Biol 2007; 17: R868–R874.

    Article  CAS  PubMed  Google Scholar 

  46. Graeff FG, Guimaraes FS, De Andrade TG, Deakin JF . Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 1996; 54: 129–141.

    Article  CAS  PubMed  Google Scholar 

  47. Deakin JF, Graeff FG . 5-HT and mechanisms of defence. J Psychopharmacol 1991; 5: 305–315.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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 (PIs) of the centers with respective areas of responsibility in the MAC study are: V Arolt (Münster: Overall MAC Program Coordination), HU Wittchen (Dresden: PI for the Randomized Clinical Trial and Manual Development), A Hamm (Greifswald: PI for Psychophysiology), AL 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 GW Alpers (Würzburg), T Fydrich and L Fehm (Berlin-Adlershof) and T Lang (Bremen). For staff members by site, see Supplementary Material. The study was further supported by the DFG (Grant RE1632/5-1 and KFO 125 to AR; SFB TRR 58 Z02 to JD, PP and AR; C02 to JD and KD; DE357/4-1 to JD, AR, JR and AH; RTG 1256 to AR, JD and PP). T Töpner, N Steigerwald, C Gagel and J Auer are credited for excellent technical assistance.

Author information

Author notes

  1. A Reif and J Richter: Both authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Psychiatric Neurobiology and Bipolar Disorder Program, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany

    A Reif, H Weber, K Domschke & J Deckert

  2. Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany

    J Richter & A Hamm

  3. Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany

    B Straube, A Jansen, M Pyka, C Konrad & T Kircher

  4. Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany

    M Höfler, U Lueken, A T Gloster & H-U Wittchen

  5. Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany

    K Domschke, C Konrad & V Arolt

  6. Department of Psychology, Humboldt-University Berlin, Berlin, Germany

    L Fehm

  7. Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Berlin, Germany

    A Ströhle & A Wittmann

  8. Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany

    A Gerlach

  9. Department of Psychiatry and Psychotherapy, RWTH- Aachen, Aachen, Germany

    I Reinhardt

  10. Department of Clinical Radiology, University of Münster, Münster, Germany

    B Pfleiderer

  11. Chair of Clinical and Biological Psychology, School of Social Sciences and Otto-Selz-Institute, University of Mannheim, Mannheim, Germany

    G W Alpers

  12. Department of Psychology, University of Würzburg, Würzburg, Germany

    P Pauli

  13. Christoph-Dornier-Stiftung for Clinical Psychology, Institute Bremen, Bremen, Germany

    T Lang

Authors
  1. A Reif
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Richter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Straube
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Höfler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U Lueken
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A T Gloster
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Domschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Fehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Ströhle
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Jansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Gerlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Pyka
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. I Reinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C Konrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. A Wittmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. B Pfleiderer
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. G W Alpers
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. P Pauli
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. T Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. V Arolt
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. H-U Wittchen
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. A Hamm
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. T Kircher
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. J Deckert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Reif.

Ethics declarations

Competing interests

V Arolt is a member of the advisory boards and/or gave presentations for the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer and Wyeth. He also received research grants from Astra-Zeneca, Lundbeck and Servier. He chaired the committee for the ‘Wyeth Research Award Depression and Anxiety’. J Deckert received in the past 3 years honoraria by Janssen, Bristol Myers-Squibb, Wyeth, Lundbeck, Astra-Zeneca and Pfizer and Grant Support by Medice, Lundbeck and AstraZeneca. T Kircher received fees for educational programs from Janssen-Cilag, Eli Lilly, Servier, Lundbeck, Bristol Myers Squibb, Pfizer and Astra-Zeneca; travel support/sponsorship for congresses from Servier; speaker’s honoraria from Janssen-Cilag; and research grants from Pfizer and Lundbeck. C Konrad received fees for educational programs from Esparma GmbH/Aristo Pharma GmbH, Lilly Deutschland GmbH, Servier Deutschland GmbH and MagVenture GmbH. A Reif has received research support from PsyNova, and A Reif and K Domschke have received research grants from Astra Zeneca. K Domschke has received honoraria for scientific talks from Pfizer, Lilly and Bristol-Myers Squibb and has been a consultant for Johnson&Johnson. A Ströhle received research funding from Lundbeck, and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth and UCB. Educational grants were given by the Stifterverband für die Deutsche Wissenschaft, the Berlin Brandenburgische Akademie der Wissenschaften, the Boehringer Ingelheim Fonds and the Eli Lilly International Foundation. H-U Wittchen has served as a general consultant (non-product related) for Pfizer, Organon, Servier and EssexPharma and has received grant funding for his institution from Sanofi Aventis, Pfizer, Lundbeck, Novartis, Essex Pharma, Servier and Wyeth. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reif, A., Richter, J., Straube, B. et al. MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy. Mol Psychiatry 19, 122–128 (2014). https://doi.org/10.1038/mp.2012.172

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2012.172

Keywords

This article is cited by

Search

Advanced search

Quick links