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

Transl Psychiatry. 2019 Feb 4;9(1):75. doi: 10.1038/s41398-019-0415-8.


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.

Trial registration: ClinicalTrials.gov NCT01323556.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Agoraphobia* / genetics
  • Agoraphobia* / physiopathology
  • Agoraphobia* / therapy
  • Avoidance Learning / physiology*
  • Case-Control Studies
  • Cerebrum / diagnostic imaging
  • Cerebrum / physiopathology*
  • Cognitive Behavioral Therapy*
  • Fear / physiology*
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Orexin Receptors / genetics*
  • Outcome Assessment, Health Care*
  • Panic Disorder* / genetics
  • Panic Disorder* / physiopathology
  • Panic Disorder* / therapy
  • Phenotype
  • Young Adult


  • HCRTR1 protein, human
  • Orexin Receptors

Associated data

  • ClinicalTrials.gov/NCT01323556