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

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 × 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.

Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

“…Orexin neurons are activated in a rat model of panic disorder, and the orexin levels in cerebrospinal fluid (CSF) increase in humans with panic-related anxiety [94]. OX1R gene variations are associated with the development of panic disorder and the treatment response to cognitive behavioral therapy [95]. Systemic administration of the SORA1 SB-334867 and silencing the orexin gene in the hypothalamus block panic responses and anxiety-like behavior in a rat model of CO 2and sodium lactate-induced panic [94,96].…”

Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender

“…For example, the locus coeruleus received the densest extrahypothalamic projections from the orexin neurons (Peyron et al, 1998), and predominantly express the OX1 receptors. Of note, the HCRTR1 rs2271933 genotype was recently found to be associated with activation of the locus coeruleus, this being higher with the A-allele in an additive manner (Gottschalk et al, 2019).…”

“…The HCRTR1 genotype was also associated with re-occurrence of driving while impaired by alcohol and with involvement in traffic accidents (Harro et al, 2019). Another recent study has revealed that with each A-allele of the HCRTR1 rs2271933 there is less fMRI-measured activition in the inferior frontal cortex and more activation in the locus coeruleus (Gottschalk et al, 2019).…”

Experimental Drugs for Panic Disorder: An Updated Systematic Review

“…Notably, important concerning translational studies, conservation between human and rat forms of OX-A and OX1R is very high, namely 100 and 94%, respectively. 46 Finally, preliminary studies in humans found associations between orexin receptor genetic polymorphisms and PD with AG, 62 , 63 and increased OX in the cerebrospinal fluid (CSF) of individuals with panic symptoms. 59 Long-term therapy with the SSRI sertraline, a recommended anti-panic drug, reduced CSF OX levels in depressed patients, whereas treatment with bupropion, an antidepressant without anti-panic activity, did not.…”