Orexin Receptor Antagonists as Modulators of Threat Sensitivity in Individuals With Alcohol Use Disorder

Early Phase 1

Completed

Conditions: Alcohol Use Disorder

Interventions: Drug: Suvorexant
Other: Placebo

Registration Number: NCT05656534

Lead Sponsor: Ohio State University

Brief Summary: The goal of this double-blind clinical trial is to further explore if, how, and for whom orexin antagonism modifies brain-behavior stress targets in moderate to severe alcohol use disorder (AUD). The main questions it aims to answer are:

* Does an acute dose of suvorexant (SUV) and/or daily use of SUV modify brain-behavior targets of AUD dysfunction?

* Does daily SUV use change alcohol behavior and if so, is this change in behavior linked to brain-behavior change?

Participants will be randomized to a treatment group (SUV or placebo) and protocol arm, electromyography (EMG) only or EMG+functional magnetic resonance imaging (fMRI). Participants will be asked to complete the following:

* Baseline lab visit(s) that include the psychophysiological stress paradigm (EMG only or EMG+fMRI, dependent upon randomization).

* Acute drug challenge where the participant will return to the lab to repeat the stress paradigm following administration of a single dose of either 10mg SUV or placebo.

* Medication trial where participants will be instructed to take 10mg capsules of SUV or placebo orally each night before bedtime for 4-weeks.

* Daily reports of medication adherence, side-effects, sleep, alcohol use, and mood will be collected via smartphones during the 4-week medication trial.

* Post-treatment lab visit(s) where participants will return to the lab at the end of the medication trial and complete the same stress paradigm from baseline (EMG only or EMG+fMRI, dependent upon randomization).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 81

Inclusion Criteria

Age 18-65.
Participant is able to give informed consent.
Generally medically and physically healthy as confirmed by medical history.
Meet DSM-5 diagnostic criteria for current moderate or severe AUD.
Engage in heavy alcohol use defined as drinking equal or greater than 14 standard drinks per week if male and equal or greater than 7 standard drinks per week if female.

Exclusion Criteria

Clinically significant medical or neurological condition (e.g., liver disease, narcolepsy, complex sleep behaviors, severe hepatic impairment, COPD, severe obstructive sleep apnea).
Current cognitive dysfunction (traumatic brain injury, mental retardation, organic mental syndrome, pervasive developmental disorder, or dementia).
Current use of antihistamines, strong or moderate inhibitors of CYP3A liver enzymes, strong CYP3A inducers, or digoxin.
Current or past DSM-5 diagnosis of mania, schizophrenia, psychosis, suicidality, major depressive disorder, or obsessive compulsive disorder.
Current substance use disorder other than alcohol or mild cannabis use disorder.
Treatment seeking for AUD.
Recent psychotropic medication use in the past 2 months.
Currently smokes 5 or more cigarettes (or electronic equivalent) per day.
BMI equal or greater than 35.
Engage in night-shift work.
Lack of fluency in English.
Presence of ferrous-containing metal in the body.
Inability to tolerate small, enclosed spaces.
Deafness in one or both ears.
Currently pregnant (positive pregnancy test), lactating, or not agreeing to use birth control methods during the duration of the trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Suvorexant Treatment	Suvorexant	Individuals will take 10mg of suvorexant (Merck \& Co Inc.) during the Acute Drug Challenge and daily for 28 days.
Control	Placebo	Individuals will take a placebo pill during the Acute Drug Challenge and daily for 28 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Heavy Drinking Days During Daily Use of Suvorexant.	Change from baseline to post-treatment, over the course of 4 weeks.	Percentage of heavy drinking days (PHDD) was calculated each week for all four weeks of the trial. A heavy drinking day was defined using NIH criteria: 5+ drinks for males and 4+ drinks for females in a single day. We conducted a multilevel mixed model with PHDD from week 1 to 4 as the within-subjects variable and treatment arm as the between subjects variable.
Startle Eyeblink Electromyographic (EMG) Response to Stress With an Acute Dose of Suvorexant	Change from baseline to 2 hours post-ingestion of an acute dose of suvorexant.	Startle EMG responses were collected during the well-validated No-Predictable-Unpredictable threat paradigm. The task includes within-subjects conditions and raw EMG responses were averaged for each condition. To quantify the difference between threat and no-threat periods, we calculated a standardized residual score for unpredictable threat (U-threat) by saving the variance leftover (i.e., the amount of variability in a dependent variable \[DV\] that is not explained by an independent variable \[IV\]) in a simple linear regression, where the no-threat EMG startle average (IV) was entered to predict the U-threat EMG startle average (DV). The U-threat residual score was used as the primary variable. It has a mean of zero and higher scores reflect greater startle reactivity to U-threat. U-threat residual scores were calculated for the baseline session and the acute challenge.
Startle Eyeblink Electromyographic (EMG) Response to Stress With Daily Use of Suvorexant.	Change from baseline to post-treatment, up to 2 months.	Startle EMG responses were collected during the well-validated No-Predictable-Unpredictable threat paradigm. The task includes within-subjects conditions and raw EMG responses were averaged for each condition. To quantify the difference between threat and no-threat periods, we calculated a standardized residual score for unpredictable threat (U-threat) by saving the variance leftover (i.e., the amount of variability in a dependent variable \[DV\] that is not explained by an independent variable \[IV\]) in a simple linear regression, where the no-threat EMG startle average (IV) was entered to predict the U-threat EMG startle average (DV). The U-threat residual score was used as the primary variable. It has a mean of zero and higher scores reflect greater startle reactivity to U-threat.

Secondary Outcome Measures

Name	Time	Method
Changes in Neural Activation During Unpredictable Stress Anticipation Following Daily Use of Suvorexant.	Change from baseline to post-treatment, up to 2 months.	Activation parameter estimates (arbitrary units) were extracted from anatomical bilateral aINS masks for each individual, pre and post treatment. Specifically, activation parameter estimates were extracted from anticipation of unpredictable threat \> anticipation of no-threat individual contrast maps for each scanning session. Greater values reflect greater activation in the bilateral insula during the anticipation of unpredictable threat. A repeated measures analysis of variance was used to test the session (time 1 vs. time 2) by treatment arm interaction on bilateral aINS activation during unpredictable threat. Significance was set at p \<.05