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

Gottschalk, Michael G. ; Richter, Jan ; Ziegler, Christiane ; Schiele, Miriam A. ; Mann, Julia ; Geiger, Maximilian J. ; Schartner, Christoph ; Homola, György A. ; Alpers, Georg W. ; Büchel, Christian ; Fehm, Lydia ; Fydrich, Thomas ; Gerlach, Alexander L. ; Gloster, Andrew T. ; Helbig-Lang, Sylvia ; Kalisch, Raffael ; Kircher, Tilo ; Lang, Thomas ; Lonsdorf, Tina B. ; Pané-Farré, Christiane A. ; Ströhle, Andreas ; Weber, Heike ; Zwanzger, Peter ; Arolt, Volker ; Romanos, Marcel ; Wittchen, Hans-Ulrich ; Hamm, Alfons O. ; Pauli, Paul ; Reif, Andreas ; Deckert, Jürgen ; Neufang, Susanne ; Höfler, Michael ; Domschke, Katharina

DOI: https://doi.org/10.1038/s41398-019-0415-8
URL: https://www.nature.com/articles/s41398-019-0415-8
Additional URL: https://freidok.uni-freiburg.de/data/149325
Document Type: Article
Year of publication: 2019
The title of a journal, publication series: Translational Psychiatry
Volume: 9
Issue number: Article 75
Page range: 1-13
Place of publication: London
Publishing house: Nature Publ. Group
ISSN: 2158-3188
Publication language: English
Institution: School of Social Sciences > Klinische u. Biologische Psychologie u. Psychotherapie (Alpers 2010-)
Subject: 150 Psychology
Abstract: 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.
Additional information: Online-Ressource

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