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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.

SUBMITTER: Gottschalk MG

PROVIDER: S-EPMC6361931 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Project description:BackgroundTransdiagnostic Cognitive Behavior Therapy (TCBT) manuals delivered in individual format have been reported to be just as effective as traditional diagnosis specific CBT manuals. We have translated and modified the "The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders" (UP-CBT) for group delivery in Mental Health Service (MHS), and shown effects comparable to traditional CBT in a naturalistic study. As the use of one manual instead of several diagnosis-specific manuals could simplify logistics, reduce waiting time, and increase therapist expertise compared to diagnosis specific CBT, we aim to test the relative efficacy of group UP-CBT and diagnosis specific group CBT.Methods/designThe study is a partially blinded, pragmatic, non-inferiority, parallel, multi-center randomized controlled trial (RCT) of UP-CBT vs diagnosis specific CBT for Unipolar Depression, Social Anxiety Disorder and Agoraphobia/Panic Disorder. In total, 248 patients are recruited from three regional MHS centers across Denmark and included in two intervention arms. The primary outcome is patient-ratings of well-being (WHO Well-being Index, WHO-5), secondary outcomes include level of depressive and anxious symptoms, personality variables, emotion regulation, reflective functioning, and social adjustment. Assessments are conducted before and after therapy and at 6 months follow-up. Weekly patient-rated outcomes and group evaluations are collected for every session. Outcome assessors, blind to treatment allocation, will perform the observer-based symptom ratings, and fidelity assessors will monitor manual adherence.DiscussionThe current study will be the first RCT investigating the dissemination of the UP in a MHS setting, the UP delivered in groups, and with depressive patients included. Hence the results are expected to add substantially to the evidence base for rational group psychotherapy in MHS. The planned moderator and mediator analyses could spur new hypotheses about mechanisms of change in psychotherapy and the association between patient characteristics and treatment effect.Trial registrationClinicaltrials.gov NCT02954731 . Registered 25 October 2016.

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

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