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
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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.
Domschke K, Reif A . Behavioral genetics of affective and anxiety disorders. Curr Top Behav Neurosci 2012; 12: 463–502.
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.
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.
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.
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.
Tyrer P, Shawcross C . Monoamine oxidase inhibitors in anxiety disorders. J Psychiatr Res 1988; 22 (Suppl 1): 87–98.
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.
Halpin C, Owen G, Gutierrez-Espeleta GA, Sims K, Rehm HL . Audiologic features of Norrie disease. Ann Otol Rhinol Laryngol 2005; 114: 533–538.
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.
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.
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.
Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103: 273–279.
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.
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.
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.
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.
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.
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.
Gibbons A . American Association of Physical Anthropologists meeting. Tracking the evolutionary history of a "warrior" gene. Science 2004; 304: 818.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Bouton ME, Mineka S, Barlow DH . A modern learning theory perspective on the etiology of panic disorder. Psychol Rev 2001; 108: 4–32.
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.
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.
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.
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.
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.
Lee BT, Ham BJ . Monoamine oxidase A-uVNTR genotype affects limbic brain activity in response to affective facial stimuli. Neuroreport 2008; 19: 515–519.
Straube B, Chatterjee A . Space and time in perceptual causality. Front Hum Neurosci 2010; 4: 28.
Mueller D, Cahill SP . Noradrenergic modulation of extinction learning and exposure therapy. Behav Brain Res 2010; 208: 1–11.
Myers KM, Davis M . Mechanisms of fear extinction. Mol Psychiatry 2007; 12: 120–150.
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.
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.
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.
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.
Svensson TH . Stress, central neurotransmitters, and the mechanism of action of alpha 2-adrenoceptor agonists. J Cardiovasc Pharmacol 1987; 10 (Suppl 12): S88–S92.
LeDoux J . The amygdala. Curr Biol 2007; 17: R868–R874.
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.
Deakin JF, Graeff FG . 5-HT and mechanisms of defence. J Psychopharmacol 1991; 5: 305–315.
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
Authors and Affiliations
Corresponding author
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
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2012.172
Keywords
This article is cited by
-
Parental rejection in early adolescence predicts a persistent ADHD symptom trajectory across adolescence
European Child & Adolescent Psychiatry (2023)
-
Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits
Molecular Psychiatry (2022)
-
Associations of age, sex, sexual abuse, and genotype with monoamine oxidase a gene methylation
Journal of Neural Transmission (2021)
-
Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms
European Archives of Psychiatry and Clinical Neuroscience (2019)
-
Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
Translational Psychiatry (2019)