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Therapygenetics: anterior cingulate cortex–amygdala coupling is associated with 5-HTTLPR and treatment response in panic disorder with agoraphobia

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Variation in the 5′-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ≥50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.

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Acknowledgments

This work is part of the German multicentre 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; neuroimaging study: project no. 01GV0611) as part of the BMBF Psychotherapy Research Funding Initiative. Greifswald (coordinating site for Psychophysiology): Christiane Melzig, Jan Richter, Susan Richter, Matthias von Rad; Berlin-Charité (coordinating Centre for Experimental Pharmacology): Harald Bruhn, Anja Siegmund, Meline Stoy, André Wittmann; Berlin-Adlershof: Irene Schulz; Münster (Overall MAC Program Coordination, Genetics and Functional Neuroimaging): Andreas Behnken, Katharina Domschke, Adrianna Ewert, Carsten Konrad, Bettina Pfleiderer, Christina Uhlmann, Peter Zwanzger; Münster (coordinating site for psychophysiology and subtyping): Judith Eidecker, Swantje Koller, Fred Rist, Anna Vossbeck-Elsebusch; Marburg/Aachen (coordinating centre for functional neuroimaging): Barbara Drüke, Sonja Eskens, Thomas Forkmann, Siegfried Gauggel, Susan Gruber, Andreas Jansen, Thilo Kellermann, Isabelle Reinhardt, Nina Vercamer-Fabri; Dresden (coordinating site for data collection, analysis, and the RCT): Franziska Einsle, Christine Froehlich, Andrew T. Gloster, Christina Hauke, Simone Heinze, Michael Hoefler, Ulrike Lueken, Peter Neudeck, Stephanie Preiß, Dorte Westphal; Würzburg Psychiatry Department (coordinating centre for genetics): Andreas Reif, Caro Gagel; Würzburg Psychology Department: Julia Duerner, Hedwig Eisenbarth, Antje B. M. Gerdes, Harald Krebs, Paul Pauli, Silvia Schad, Nina Steinhäuser; Bremen: Veronika Bamann, Sylvia Helbig-Lang, Anne Kordt, Pia Ley, Franz Petermann, Eva-Maria Schroeder. Additional support was provided by the coordinating centre for clinical studies in Dresden (KKS Dresden): Xina Graehlert and Marko Käppler.

Conflict of interest

The following authors report no conflicts of interest concerning the content of this paper: U. Lueken, B. Straube, A. Wittmann, B. Pfleiderer. V. Arolt is member of 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 unrestricted educational programs from Janssen-Cilag, Eli Lilly, Servier, Lundbeck, Bristol Myers Squibb and Pfizer; and research grants from Pfizer and Lundbeck. C. Konrad received fees for an educational program from esparma GmbH/Aristo Pharma GmbH, Lilly Deutschland GmbH, Servier Deutschland GmbH, and MagVenture GmbH. A. Reif has received research support from PsyNova and research grants from Astra Zeneca. A. 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, 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.

Ethical standard

The RCT project was approved by the Ethics Committee of the Medical Faculty of the Technische Universität Dresden (EK 164082006). The neuroimaging components were approved by the Ethics Committee of the Medical Faculty of the Rheinisch-Westfaehlische Hochschule University Aachen (EK 073/07) and at all local sites. The experimental pharmacology study was approved by the Ethics Committee of the state of Berlin (EudraCT: 2006-00-4860-29). The study was registered with the ISRCTN: ISRCTN80046034.

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Authors and Affiliations

  1. Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Chemnitzer Straße 46, 01187, Dresden, Germany

    Ulrike Lueken & Hans-Ulrich Wittchen

  2. Department of Psychology, Neuroimaging Center, Technische Universität Dresden, Dresden, Germany

    Ulrike Lueken & Hans-Ulrich Wittchen

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

    Benjamin Straube, Carsten Konrad & Tilo Kircher

  4. Department of Psychiatry and Psychotherapy, Campus Charité Mitte Charité–University Medicine Berlin, Berlin, Germany

    Andreas Ströhle & André Wittmann

  5. Department of Clinical Radiology, University Hospital Münster, Münster, Germany

    Bettina Pfleiderer

  6. Department of Psychiatry and Psychotherapy, University Hospital Münster, Münster, Germany

    Volker Arolt

  7. Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany

    Jürgen Deckert & Andreas Reif

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  1. Ulrike Lueken
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Correspondence to Ulrike Lueken.

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Principal investigators (PI) with respective areas of responsibility in the MAC study are V. Arolt (Münster: Overall MAC Program Coordination), H.U. Wittchen (Dresden: Principal Investigator (PI) for the Randomised 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 RCT component of the programme are G.W. Alpers (Würzburg), T. Fydrich and L. Fehm (Berlin-Adlershof), and T. Lang (Bremen).

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Lueken, U., Straube, B., Wittchen, HU. et al. Therapygenetics: anterior cingulate cortex–amygdala coupling is associated with 5-HTTLPR and treatment response in panic disorder with agoraphobia. J Neural Transm 122, 135–144 (2015). https://doi.org/10.1007/s00702-014-1311-2

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