Orexin in the anxiety spectrum : association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes

  • Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

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Author:Michael G. Gottschalk, Jan Richter, Christiane Ziegler, Miriam A. Schiele, Julia Mann, Maximilian J. Geiger, Christoph Schartner, György Ádám Homola, Georg W. Alpers, Christian Büchel, Lydia Fehm, Thomas Fydrich, Alexander Gerlach, Andrew T. Gloster, Sylvia Helbig-Lang, Raffael Kalisch, Tilo Kircher, Thomas Lang, Tina B. Lonsdorf, Christiane A. Pané-Farré, Andreas Ströhle, Heike Weber, Peter M. Zwanzger, Volker Arolt, Marcel Romanos, Hans-Ulrich Wittchen, Alfons Hamm, Paul Pauli, Andreas ReifORCiDGND, Jürgen Deckert, Susanne Neufang, Michael Höfler, Katharina Domschke
URN:urn:nbn:de:hebis:30:3-490830
DOI:https://doi.org/10.1038/s41398-019-0415-8
ISSN:2158-3188
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30718541
Parent Title (English):Translational Psychiatry
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/02/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/02/14
Tag:Human behaviour; Molecular neuroscience; Personalized medicine; Predictive markers; Psychiatric disorders
Volume:9
Issue:1, Art. 75
Page Number:13
First Page:1
Last Page:13
Note:
Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:446490849
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0