Orexin Receptor Antagonists as Modulators of Threat Sensitivity in individuals with Alcohol Use Disorder

ABSTRACT Alcohol use disorder affects millions and is one of the leading causes of preventable death worldwide. In the US, pharmacotherapy for AUD is under-utilized; related to the fact that there are only three FDA-approved drugs to treat patients with AUD. These medications work well for some but have small to moderate effect sizes on

drinking outcomes. The development of more efficacious pharmacotherapies for AUD is a top public health priority. A recent emphasis in psychiatric medication development is the use of reliable human laboratory measures of AUD dysfunction to test promising compounds to directly inform and power large-scale mechanistic

clinical trials. PI Gorka and Co-I Phan have developed an assay of stress reactivity that is robustly related to drinking behavior and AUD. This assay reflects a negative reinforcement model of AUD and is reliably captured in the lab using complimentary objective psychophysiological (i.e., startle eyeblink potentiation) and

functional neuroimaging measures. Using this model, we have uncovered that suvorexant (SUV) – a dual receptor antagonist of the orexin system, FDA-approved for insomnia – acutely modifies our AUD target in healthy adults, while sparing changes in other markers of stress reactivity. Compelling animal and human

evidence together suggests that the orexin system is critically involved in stress-related alcohol use. The overarching goal of this R21 proposal is to systematically advance this line of work to uncover if, how, and for whom orexin antagonism modifies brain-behavior stress targets of AUD to inform and power future large scale

clinical trials. The study is a targeted double-blind, between-subjects, randomized clinical trial design with repeat lab assessment. A total of eighty subjects with AUD will complete our psychophysiological stress paradigm at baseline. They will return to the lab days later to repeat the protocol following administration of a single dose of

either 10mg SUV or placebo (40 subjects/arm). Participants are then instructed to take daily 10mg capsules of SUV or placebo for the next 4-weeks before returning for a post-treatment lab assessment. Daily reports of medication adherence, side-effects, sleep, alcohol use, and mood will be collected via smartphones. This study

is high-risk, high-reward, and to match the scope of the R21 mechanism we will focus on startle eyeblink potentiation as the primary outcome; although a subset of 20 subjects per arm (40 total) will also complete our stress task during simultaneous startle and functional magnetic resonance imaging (fMRI), pre- and post-

treatment. This innovative multimodal design allows for a well-controlled test of whether an acute dose of SUV (Aim 1) and/or daily use of SUV (Aim 2) modifies brain-behavior targets of AUD dysfunction, particularly within individuals with high objective baseline stress reactivity. We will also examine whether daily SUV changes

alcohol behavior, and whether this change in behavior is linked to brain-behavior change (Aim 3). Findings from this study will provide critical new knowledge regarding if and how orexin antagonism can be leveraged to treat AUD. The findings will also be used to inform and power a large-scale mechanistic clinical trial of SUV for AUD.