Gottschalk, Michael G., Richter, Jan ORCID: 0000-0002-7127-6990, Ziegler, Christiane ORCID: 0000-0001-8543-2010, Schiele, Miriam A., Mann, Julia, Geiger, Maximilian J., Schartner, Christoph, Homola, Gyorgy A., Alpers, Geoerg W., Buechel, Christian, Fehm, Lydia ORCID: 0000-0002-0825-8466, Fydrich, Thomas, Gerlach, Alexander L. ORCID: 0000-0001-6794-5349, Gloster, Andrew T., Helbig-Lang, Sylvia, Kalisch, Raffael, Kircher, Tilo ORCID: 0000-0002-2514-2625, Lang, Thomas, Lonsdorf, Tina B., Pane-Farre, Christiane A., Stroehle, Andreas, Weber, Heike, Zwanzger, Peter, Arolt, Volker, Romanos, Marcel ORCID: 0000-0001-7628-8299, Wittchen, Hans-Ulrich, Hamm, Alfons, Pauli, Paul, Reif, Andreas, Deckert, Juergen, Neufang, Susanne, Hoefler, Michael and Domschke, Katharina (2019). Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes. Transl. Psychiatr., 9. NEW YORK: NATURE PUBLISHING GROUP. ISSN 2158-3188

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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 x 10(-7)), particularly in the female subsample (p = 9.8 x 10(-9)). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gottschalk, Michael G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter, JanUNSPECIFIEDorcid.org/0000-0002-7127-6990UNSPECIFIED
Ziegler, ChristianeUNSPECIFIEDorcid.org/0000-0001-8543-2010UNSPECIFIED
Schiele, Miriam A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mann, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geiger, Maximilian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schartner, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Homola, Gyorgy A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alpers, Geoerg W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buechel, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fehm, LydiaUNSPECIFIEDorcid.org/0000-0002-0825-8466UNSPECIFIED
Fydrich, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerlach, Alexander L.UNSPECIFIEDorcid.org/0000-0001-6794-5349UNSPECIFIED
Gloster, Andrew T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig-Lang, SylviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalisch, RaffaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kircher, TiloUNSPECIFIEDorcid.org/0000-0002-2514-2625UNSPECIFIED
Lang, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lonsdorf, Tina B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pane-Farre, Christiane A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroehle, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zwanzger, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arolt, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romanos, MarcelUNSPECIFIEDorcid.org/0000-0001-7628-8299UNSPECIFIED
Wittchen, Hans-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamm, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauli, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neufang, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoefler, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domschke, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-156969
DOI: 10.1038/s41398-019-0415-8
Journal or Publication Title: Transl. Psychiatr.
Volume: 9
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 2158-3188
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RANDOMIZED CONTROLLED-TRIAL; PREPRO-OREXIN; A LEVELS; DISORDER; RECEPTOR; AGORAPHOBIA; SYSTEM; METAANALYSIS; PERSPECTIVE; PREDICTORSMultiple languages
PsychiatryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15696

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