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

Medientyp: E-Artikel
Titel: Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
Beteiligte: 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; [...]
Erschienen: Springer Science and Business Media LLC, 2019
Erschienen in: Translational Psychiatry
Sprache: Englisch
DOI: 10.1038/s41398-019-0415-8
ISSN: 2158-3188
Schlagwörter: Biological Psychiatry ; Cellular and Molecular Neuroscience ; Psychiatry and Mental health
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>Preclinical studies point to a pivotal role of the orexin 1 (OX<jats:sub>1</jats:sub>) receptor in arousal and fear learning and therefore suggest the <jats:italic>HCRTR1</jats:italic> 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 <jats:italic>HCRTR1</jats:italic> C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total <jats:italic>n</jats:italic> = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (<jats:italic>n</jats:italic> = 189), as well as with respect to agoraphobic cognitions (ACQ) (<jats:italic>n</jats:italic> = 483 patients, <jats:italic>n</jats:italic> = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (<jats:italic>n</jats:italic> = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (<jats:italic>n</jats:italic> = 271). The <jats:italic>HCRTR1</jats:italic> rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (<jats:italic>p</jats:italic> = 4.2 × 10<jats:sup>−7</jats:sup>), particularly in the female subsample (<jats:italic>p</jats:italic> = 9.8 × 10<jats:sup>−9</jats:sup>). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: <jats:italic>p</jats:italic> = 7.5 × 10<jats:sup>−4</jats:sup>). 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 <jats:italic>HCRTR1</jats:italic> 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.</jats:p>
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