Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression

NCT06004115 | Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: 2022-009R01MH132565
• Study Type: interventional
• Target: 165
• Locations: 1 country
• Sites: 1

Brief Summary

This mechanistic study uses an anti anxiety drug and brain imaging to study the threat processing system and associated brain circuits in people with depression, anxiety disorders and comorbid depression and anxiety disorders. In a double blind, placebo controlled crossover design, up to 65 individuals will be recruited who will have a diagnosis of major depressive disorder (MDD) and at least one anxiety disorder (AD) (AD-MDD group), up to 65 participants will have a diagnosis of MDD and no diagnosis of an AD and up to 65 participants will have no diagnosis of MDD and a diagnosis of at least one AD will be enrolled to participate in an two session study to obtain 150 completers (50 per group). All participants will receive a single dose of Lorazepam and placebo (order randomized) taken orally. After the \~2.5 hr screening session, participants will complete two identical \~5 hr experimental sessions, each of which include a 30 min eyeblink startle session and a 1.5 hr functional magnetic resonance imaging (MRI) brain scan session. The total time involved in the study is approximately 10.5 hours. The main questions the study seeks to answer are:

• are people with comorbid depression and anxiety different than those with depression alone in terms of their eyeblink startle response to threat?
• are people with comorbid depression and anxiety different than those with depression alone in terms of their brain activation in response to threat?
• are people with comorbid depression and anxiety different than those with depression alone in terms of their responses to anxiety drugs?

Conditions

Depression, Anxiety; Fear; Depression; Anxiety and Fear; Anxiety Disorders; Anxious Depression

Keywords

depression; anxiety; fMRI; threat sensitivity; flight initiation distance; startle reflex; benzodiazepine

Outcome Measures

Primary Outcomes (1)

• Eyeblink startle magnitude under threat in AD-MDD compared to MDD.

  Difference in magnitude of eyeblink startle response under threat of predictable and unpredictable shock conditions compared to neutral condition in the Neutral, Predictable, Unpredictable (NPU) Threat Task measured with electromyography. Comparing the AD-MDD group to the MDD group.

  1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2)

Secondary Outcomes (2)

• Magnitude of blood oxygenated level dependent (BOLD) response to threat in AD-MDD compared to MDD.

  1-2 hours after single session placebo administration, an average of 1-5 weeks after enrollment (placebo could be session 1 or session 2)

• The effect of Lorazepam on eyeblink startle magnitude and BOLD response to threat in AD-MDD compared to MDD

  1-2 hours after single session drug administration, after both Lorazepam and sessions have been completed, an average of 5 weeks after enrollment

Study Arms (2)

Lorazepam

EXPERIMENTAL

Participants will receive a single 1mg dose of Lorazepam, to be taken orally under registered nurse (RN) supervision

Drug: Lorazepam

Placebo

PLACEBO COMPARATOR

Participants will receive a single dose of placebo, to be taken orally under RN supervision

Other: Placebo

Interventions

Lorazepam DRUG

1mg of Lorazepam will be prepared by pharmacy (Barnes, Tulsa) in capsule form

Also known as: Lorazepam Intensol, Ativan

Lorazepam

Placebo OTHER

placebo will be prepared by pharmacy (Barnes, Tulsa) in capsule form

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects:
• Female or male sex assigned at birth;
• Age 18-65;
• Normal or corrected to normal vision/hearing, as protocol elements may not be valid otherwise;
• Fluent English speaker, capable of providing written informed consent
• MDD and AD-MDD subjects:
• Current major depressive episode assessed by clinician with guidance from the MINI;
• Minimum score of 55 on PROMIS Depression scale
• AD and AD-MDD subjects:
• Current anxiety disorder (generalized anxiety disorder, panic disorder, agoraphobia and social phobia) assessed by clinician with guidance from the MINI;
• Minimum score of 55 on PROMIS Anxiety Scale

You may not qualify if:

• All subjects:
• 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;
• Reported body mass index (BMI) \> 40;
• History of moderate or severe traumatic brain injury, as assessed by a TBI questionnaire;
• History of eating disorder or obsessive-compulsive disorder, schizophrenia, schizo-affective disorder, bipolar disorder or any sign of psychosis;
• Current post-traumatic stress disorder (PTSD) diagnosis (although history of trauma is allowed);
• Current use of medications with major effects on brain function or the fMRI hemodynamic response (e.g., methylphenidate, acetazolamide, excessive caffeine intake \> 1000 mg/day) following an initial list compiled by LIBR but also assessed on a case-by-case basis. Individuals who are currently on medication (antidepressants such as SSRIs, TCAs, SNRIs, and Bupropion) and who have not undergone dose or medication changes over the past 6 weeks will be allowed to participate;
• Current benzodiazepine or opiate use;
• Moderate to severe current substance use disorder, defined as 5 or more symptoms of the criteria for Substance Use Disorder according to DSM 5;
• Drug or alcohol intoxication (based on positive UTOX or breathalyzer test at screening or study session) or reported alcohol/drug withdrawal, last cannabis use must be \>48 hours prior to study session;
• Has a risk of suicide according to the Investigator's clinical judgement or per Columbia-Suicide Severity Rating Scale (C-SSRS) or equivalent PhenX instrument, the subject scores "yes" on items 4 or 5 in the Suicidal Ideation section with referent to a 30-day period prior to Screening/Baseline or the subject has had one or more suicidal attempts with reference to a 2-year period prior to Screening;
• MRI contraindications;
• Is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during this time-period;
• Any subject judged by the Investigator to be inappropriate for the study.
• MDD subjects:

Sponsors & Collaborators

• Laureate Institute for Brain Research, Inc.: lead
• National Institute of Mental Health (NIMH): collaborator
• California Institute of Technology: collaborator

Study Sites (1)

Laureate Institute for Brain Research

Tulsa, Oklahoma, 74136, United States

RECRUITING

MeSH Terms

Conditions

Depression; Anxiety Disorders

Interventions

Lorazepam

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Maria Ironside, DPhil

  Laureate Institute for Brain Research

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Ironside, DPhil

CONTACT

16174175065; mironside@laureateinstitute.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: placebo preparation by the pharmacy
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: double blind crossover design

Study Record Dates

• First Submitted: July 7, 2023
• First Posted: August 22, 2023
• Study Start: November 8, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: October 31, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)