Brain imaging and a single lorazepam dose to find veterans with high‑arousal PTSD who respond to GABA‑targeting drugs

Individualized Computational Assessment of the Effects of GABA Receptor Modulation in Posttraumatic Stress Disorder

This project will test whether a single low dose of lorazepam combined with brain imaging and a computer task can identify veterans with PTSD and high anxious arousal who might benefit from GABA‑targeting medications.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 150 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: VA Office of Research and Development (Federal)
• Locations: 1 site (San Diego, California)
• Trial ID: NCT06852469 on ClinicalTrials.gov

What this trial studies

In this Phase 4 interventional project, Veterans with PTSD receive a single 1 mg dose of lorazepam or placebo while completing the rapid assessment of motor processing (RAMP) computational task during functional neuroimaging. The RAMP task models goal-directed control to produce a precise estimate of a dynamic inhibition parameter thought to reflect GABAergic signaling, and investigators will compare how lorazepam shifts that parameter versus placebo. The goal is to validate this computational and imaging marker as an objective phenotypic test to identify a high‑arousal PTSD subgroup for targeted GABA‑modulating treatments. Participants are Veterans aged 18–65 with current PTSD (CAPS‑5), must abstain from alcohol around testing, and are excluded for uncontrolled medical/psychiatric conditions, pregnancy, or contraindications to benzodiazepines or MRI.

Who should consider this trial

Good fit: Veterans aged 18–65 with a current CAPS‑5 diagnosis of PTSD who can undergo MRI, tolerate a single low dose of lorazepam, and follow study restrictions are ideal candidates.

Not a fit: Those without the high‑anxious‑arousal PTSD subtype, or with uncontrolled medical/psychiatric illness, pregnancy, seizure disorder, or contraindications to benzodiazepines or MRI are unlikely to receive benefit from this protocol.

Why it matters

Potential benefit: If successful, the test could let clinicians match veterans with high‑arousal PTSD to GABA‑targeting medications and improve symptom response.

How similar studies have performed: Prior work suggests GABAergic drugs can reduce anxious arousal in PTSD, but using a computational RAMP paradigm with lorazepam and fMRI for phenotypic validation is a novel approach.

Eligibility criteria

Inclusion Criteria:

Inclusion Criteria:

1. Veteran;
2. 18-65 years of age, inclusive;
3. Participants must be willing to abstain from alcohol 24 hours prior to and 24 hours after the testing session;
4. Participants must be able to participate and willing to give written informed consent and to comply with the study restrictions;

Additional Inclusion Criteria for PTSD Group:

(a) Current diagnosis of PTSD based on CAPS-5.

Exclusion Criteria:

Exclusion Criteria:

1. Has uncontrolled, clinically significant neurologic (including seizure disorders), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the subject to participate or potentially confound the study results;
2. Pregnancy (assessed by urine test at time of screening and prior to administration of study medication) or lactation;
3. Lifetime history of a chronic psychotic disorder or bipolar disorder type I as assessed by MINI;
4. Current moderate or severe substance use disorder as assessed by MINI;
5. Positive urine toxicology (drugs of abuse as determined by a positive urine test) at screening and before drug administration. Subjects who screen positive for THC will be given an opportunity to be included in the event of a negative urine test 2 weeks later. THC is not infrequently used for medicinal purposes and, in California, is legal for recreational use. Subjects who are positive for THC will therefore not be excluded, but will be retested to ensure that THC is unlikely to be influencing results;
6. Self-report or observable signs of drug or alcohol intoxication or withdrawal;
7. Current benzodiazepine or opioid use; other psychotropic medications are allowed as long as they are at a stable dose for at least 2 weeks and do not exhibit an unsafe interaction with the study medication;
8. Current or recent use of any medication deemed by the study physician (Dr. Howlett) to exhibit an unsafe interaction with lorazepam;
9. Past intolerance (including allergic) to lorazepam or another benzodiazepine;
10. Active suicidal ideation or otherwise considered at high suicidal risk by trained study staff using the C-SSRS;
11. History of a traumatic brain injury (TBI) resulting in loss of consciousness for more than 30 minutes;
12. Volunteers who do not have sufficient command of the English language, or who have any other impairment that would prevent them from reading and understanding the informed consent form(s) and completing the study procedures including clinical testing;
13. Any other reason why, per study physician, the subject should not participate in this study, including concomitant disease or condition that could interfere with, or for which the study drug might interfere with, the conduct of the study, or that would, in the opinion of the study physician, pose an unacceptable risk to the subject in this study.

Additional Exclusion Criteria for HC Group:

(a) Axis I disorder as assessed by MINI.

Additional Exclusion Criteria for fMRI Participants:

1. Contraindication to magnetic resonance imaging.
2. Not right-handed as assessed by Edinburgh Handedness Inventory.

Where this trial is running

San Diego, California

• VA San Diego Healthcare System, San Diego, CA — San Diego, California, United States (Recruiting)

Study contacts

• Principal investigator: Jonathan R Howlett, MD — VA San Diego Healthcare System, San Diego, CA
• Study coordinator: Vitaliana R Vasquez, BA

Conditions Stress Disorders, Post-Traumatic; Arousal; gamma-Aminobutyric Acid; Lorazepam; Neuroimaging