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

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