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Preclinical studies point to a pivotal role of the orexin 1 (OX 1 ) 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.

translational psychiatry

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