The Effects of Orexin Antagonism on Fear Extinction in PTSD

PTSD affects approximately 22% of Veterans who have served in Iraq and Afghanistan. Symptoms of PTSD may include re-experiencing, avoidance of trauma reminders, negative thoughts or feelings, and hyperarousal, such as increased startle reactivity and disturbed sleep. Treatments for PTSD are based on fear extinction principles in which individuals are repeatedly exposed a feared cue in the absence of danger, resulting in diminishing physiological reactions, a process believed to underlie recovery from PTSD. Studies suggest that orexin, a wake-promoting neuropeptide, may enhance fear extinction. This study will examine whether suvorexant, a selective orexin-receptor antagonist, will enhance fear extinction in Veterans with PTSD and insomnia. Finding a role for orexins in fear extinction will support the rationale for its further evaluation in the treatment of PTSD. Suvorexant is an accessible, safe medication that has been well-established in treating insomnia. It has outstanding promise for treating common and distressing symptoms in Veterans with PTSD.

Study Overview

• Status: Not yet recruiting
• Conditions: PTSD; Insomnia
• Intervention / Treatment: Drug: Placebo; Drug: Suvorexant

Detailed Description

PTSD is a common consequence of combat manifested in part by trauma-related arousal and reactivity, seen in increased startle and impaired sleep that result from central and autonomic nervous system alterations. Impaired fear extinction may explain prolonged physiological alterations in PTSD. Preclinical evidence suggests that orexin, a wake-promoting neuropeptide, may be a shared mechanism underlying both sleep and fear extinction. While rodent studies have shown that pharmacological manipulations that block orexin in rodents facilitate fear extinction, no studies have tested this in humans with PTSD.

In line with the CSRD Combined Proof of Concept and Clinical Trial Merit Review Award mechanism, the investigators propose a proof-of-concept study leading to a clinical trial. During the initial phase, the investigators will develop and establish feasibility of the task and recruitment in 40 eligible participants with PTSD and insomnia. The task will involve a home-based multi-day remote fear conditioning experimental study, in which Veterans with PTSD and insomnia will receive nightly doses of suvorexant or placebo following extinction training over the subsequent 6 nights. Primary Aims of the proof of concept will be to: 1) establish remote fear conditioning procedures collaboratively with Veteran stakeholders; 2) evaluate enrollment, tolerability, adherence, and retention; 3) demonstrate fear conditioning and extinction learning using remote procedures; and 4) determine task feasibility of the home-based remote fear conditioning task. Go/No go milestones include: 1) the ability to enroll and randomize 40 participants by the end of month 23; 2) most participants (> 80%) will take medication as prescribed over 7 nights; 3) no SAEs during the course of treatment as determined by the data monitoring committee review (DMC); 4) < 10% of post-randomization participants will drop out (<4 participants), resulting in 36 individuals who complete all study procedures by month 23; 5) successful demonstration of measurement of fear conditioning (greater skin conductance (SC) responses to CS+ cues vs CS- cues) and fear extinction (differential SC responses to CS+ and CS- cues that diminish over trials) in the combined sample; 6) feasibility of the remote task demonstrated by <15% data loss due to recording issues (e.g., technical malfunction or UCS non-response in <6 participants).

If milestones are met, the investigators will advance to a clinical mechanistic trial to evaluate suvorexant in facilitating fear extinction using a double-blind randomized, placebo-controlled experimental design in Veterans with PTSD and insomnia. A total of 120 male and female Veterans with PTSD and insomnia will be randomized to either the suvorexant or placebo condition (n=60 in each condition). Participants will be trained in multi-day remote procedures involving fear conditioning (Day 1) and extinction 3 days later (Day 4), followed by 10 mg. suvorexant or placebo. A flexible dose titration of suvorexant (10-20 mg.) or matching placebo will be administered over the next 6 nights. Participants will then undergo extinction retention and fear reinstatement tests one week after extinction (Day 11). Primary outcome measures will be differential skin conductance responses to CS+ and CS- cues during extinction retention and reinstatement phases.

Primary Aims of the Clinical Trial will be: 1) To examine whether suvorexant facilitates fear extinction, seen as greater extinction retention compared to placebo. 2) To examine whether the facilitative effects of suvorexant are more resistant to reinstatement compared to placebo. Pending an effect of suvorexant on fear extinction retention and reinstatement, the investigators will evaluate whether improvement in insomnia mediates these effects. In-home sleep recording (including both sleep EEG and indices of sleep-disordered breathing) and sleep diary measures will be examined as secondary mediators. Greater improvement in sleep quality will partially account for greater extinction retention and less reinstatement. If successful, the proposed study will offer proof-of-concept data and meaningful guidance for future studies of suvorexant as an augmentation co-treatment in exposure therapy.

• Study Type: Interventional
• Enrollment (Estimated): 40120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sabra S Inslicht, PhD; Phone Number: 3341 (415) 221-4810; Email: sabra.inslicht@va.gov

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94121-1563
      • San Francisco VA Medical Center, San Francisco, CA
      • Contact: Sabra S Inslicht, PhD; Phone Number: 3341 (415) 221-4810; Email: sabra.inslicht@va.gov
      • Principal Investigator: Sabra S Inslicht, PhD
  • South Carolina
    • Charleston, South Carolina, United States, 29401-5703
      • Ralph H. Johnson VA Medical Center, Charleston, SC
      • Contact: Lisa McTeague, PhD; Email: McTeague@musc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• (same for Phase 1 and Phase 2):

  • men and women
  • a history of US military service
  • capable of reading and understanding English
  • able to provide written informed consent
• Criterion A event meets DSM-5 criteria and occurred during military service, including combat and military sexual trauma
• Chronic full PTSD diagnosis >3 months duration as indexed by CAPS-5 at screening, and CAPS-5 score > 30
• Insomnia indicated by insomnia severity index (ISI) score > 14

• Subjects on non-exclusionary medications, and must be on a stable dose for at least 4 weeks prior to randomization, including Selective Serotonin Reuptake Inhibitors (SSRIs, e.g.,):

  • sertraline
  • paroxetine
  • fluoxetine
  • fluvoxamine
  • citalopram
  • escitalopram

• Serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g.):

  • Desvenlafaxine
  • Duloxetine
  • Levomilnacipran
  • Venlafaxine
• For subjects who are in psychotherapy, treatment must be stable for 6 weeks
• Women of child-bearing potential must not be pregnant or have plans for pregnancy or breastfeeding during the study and must use a medically acceptable method of birth control

Exclusion Criteria:

• Moderate or severe DSM-5 alcohol or cannabis use disorder in the last 3 months

  • Mild alcohol use disorder with abstinence of 30 days will be allowed
  • Mild marijuana use disorder will be allowed with abstinence for one week prior to participation
  • Any other DSM-5 drug use disorder in the last 3 months will be excluded
• Lifetime bipolar disorder I or II, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, or major depressive disorder with psychotic features
• Exposure to trauma in the last 3 months
• Use of exclusionary antidepressant (trazodone, mirtazapine, doxepin, tricyclics), mood stabilizers (e.g., lithium), antipsychotic medication
• Prominent suicidal or homicidal ideation or any suicidal behavior in the past 3 months on the Columbia Suicide Severity Rating Scale (C-SSRS) or increased risk of suicide that necessitates additional therapy or inpatient treatment
• Pre-existing moderate sleep apnea or positive screen for sleep apnea by type III device (AHI>15) in the absence of adherence to effective treatment (such as CPAP or oral device)
• Night shift work or extreme morning or evening tendencies in order to avoid the impact of circadian factors on subjective and objective sleep measures
• Neurologic disorder or systemic illness affecting CNS function

• Chronic or unstable medical illness, including:

  • unstable angina
  • myocardial infarction within the past 6 months
  • congestive heart failure
  • preexisting hypotension or orthostatic hypotension
  • heart block or arrhythmia
  • chronic renal or hepatic failure
  • pancreatitis
  • severe chronic obstructive pulmonary disease
• History of severe traumatic brain injury as assessed by the Ohio State University Traumatic Brain Injury Identification Method (OSU-TBI ID)
• Uncorrected hearing impairment
• Mild cognitive impairment assessed by the Montreal Cognitive Assessment (MOCA)
• Pregnancy, breastfeeding and/or refusal to use effective birth control (for women)
• Previous adverse reaction to a hypnotic

• Current use of benzodiazepines, strong inhibitors of CYP3A, or Digoxin

  • The investigators will require that all participants do not consume heavy amounts of alcohol per week (>7 drinks for women, >14 drinks for men) or use illicit drugs for one week prior to participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Suvorexant; Suvorexant pills (10-20 mg)	Drug: Suvorexant; Suvorexant pills (10-20 mg)
Placebo Comparator: Placebo; Matching placebo pills	Drug: Placebo; Matching placebo pills

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
enrollment	Goal of enrolling 40 individuals to achieve a total of 30 completers by the end of month 23.	Month 4-23
Medication Adherence	Pill count and adherence to instructions over 7 study nights	Month 4-23
side effect reports	SAEs	Month 4-23
Post-randomization drop out	Post-randomization drop-out rates	Month 4-23
Fear conditioning and extinction	Fear conditioning (greater SC responses to CS+ cues vs CS- cues) and fear extinction (differential SC responses to CS+ and CS- cues that diminish over repeated trials) in the combined sample	Month 4-23
Rates of technical malfunction	Rates of technical malfunction (SC levels that are missing or <.02 microsiemens) and or non-responding to the UCS (e.g., SCR<.05 microsiemens)	Month 4-23
Electrodermal Activity	Differential SC responses to CS+ and CS- cues during extinction retention and 2) during reinstatement.	Years 2-7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insomnia Severity Index	Self-reported sleep	Years 2-7
Sleep EEG	Total sleep time, REM	Years 2-7

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Sabra S Inslicht, PhD, San Francisco VA Medical Center, San Francisco, CA

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): March 1, 2032
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: January 16, 2025
• First Submitted That Met QC Criteria: January 16, 2025
• First Posted (Actual): January 23, 2025

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: PTSD; Insomnia; Fear conditioning
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Stress Disorders, Traumatic; Sleep Initiation and Maintenance Disorders; Stress Disorders, Post-Traumatic; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Neurotransmitter Agents; Hypnotics and Sedatives; suvorexant
• Other Study ID Numbers: MHBP-006-24S

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes