Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel Therapeutic Targets

NCT05046184 | Completed Phase 2 FDA Drug

• 1 other identifier: STU-2021-0667
• Study Type: interventional
• Target: 165
• Locations: 1 country
• Sites: 1

Brief Summary

The study is investigating dysfunctions in neurocircuitry in regards to irritability with healthy controls (HC) and individuals with Major Depressive Disorder (MDD) by performing MRIs. The MDD group will also be randomized to receive ketamine or midazolam to investigate changes post-treatment in neurocircuitry with regards to irritability.

Conditions

Major Depressive Disorder; Healthy Controls

Keywords

major depressive disorder; MDD; depression; depressive disorder; depression symptoms; healthy controls; irritability; ketamine

Outcome Measures

Primary Outcomes (4)

• Resting state functional connectivity.

  Resting-state functional connectivity between striatum and habenula will be measured by functional magnetic resonance imaging (fMRI) in healthy controls and in adults with major depressive disorder (MDD). Functional connectivity refers to the standardized correlation between resting state BOLD signal of the striatum and habenula regions of the brain.

  Baseline

• Striatal response to frustrative nonreward (FNR).

  Striatal response to frustrative nonreward (FNR) as measured by the BOLD (Blood Oxygen Level Dependent) signal within the striatum region of the brain on a functional MRI behavioral task of FNR in healthy controls and in adults with MDD. BOLD signal is the unit of measure of this outcome.

  Baseline

• Treatment-related change in striatum-habenula functional connectivity.

  Striatum-habenula functional connectivity is the standardized correlation between resting state BOLD signal of the striatum and habenula regions of the brain measured on a fMRI. Unit is the standardized correlation ranges from -1 to 1. MDD participants only.

  Baseline, at 14 days

• Treatment-related change in striatal response to FNR.

  Striatal response to FNR is the standardized correlation between resting state BOLD signal of the striatum and habenula regions of the brain measured on a fMRI. Unit is the standardized correlation ranges from -1 to 1. MDD participants only.

  Baseline, at 14 days

Secondary Outcomes (8)

• Change in symptoms of irritability after two weeks of twice-weekly infusions of ketamine versus midazolam.

  Baseline, at 14 days

• Change in symptoms of depression (including suicidal ideation) measured by MADR scale

  Baseline, at 14 days

• Change in symptoms of depression measured by QIDS report

  Baseline, at 14 days

• Change in symptoms including anxious arousal measured by MAS questionnaire

  Baseline, at 14 days

• Change in behavior (including anger attacks) measured by AAQ

  Baseline, at 14 days

Other Outcomes (1)

• To evaluate if changes in neurocircuit function with ketamine mediate treatment-related improvement in irritability.

  Up to 14 days

Study Arms (3)

Healthy Controls

NO INTERVENTION

Healthy controls will undergo clinician assessments and fMRI to compare to MDD group.

MDD - Ketamine

ACTIVE COMPARATOR

Participants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four ketamine infusions.

Drug: Ketamine Hydrochloride

MDD - Midazolam

PLACEBO COMPARATOR

Participants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four midazolam infusions.

Drug: Midazolam injection

Interventions

Ketamine Hydrochloride DRUG

Subjects with MDD will receive 2 weeks of twice-weekly 40-minutes long IV infusion of ketamine (0.5 mg/kg). Ketamine will be dissolved in 0.9% saline in a total volume of 100 mL and administered with an infusion pump at a constant rate.

MDD - Ketamine

Midazolam injection DRUG

Subjects with MDD will receive 2 weeks of twice-weekly 40-minutes long IV infusion of midazolam (0.02 mg/kg). Midazolam will be dissolved in 0.9% saline in a total volume of 100 mL and administered with an infusion pump at a constant rate.

MDD - Midazolam

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subjects, 18-65 years of age and body weight less than or equal to 120 kg on baseline visit.
• Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process.
• For Healthy Controls: Subjects must be free of any lifetime psychiatric condition based on the Mini-International Neuropsychiatric Interview (MINI). For MDD: Subjects must meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for current unipolar depression \[major depressive disorder (MDD) or persistent depressive disorder (PDD) in a current major depressive episode (MDE)\] based on MINI.
• A woman of childbearing potential who is sexually active with a male must agree to use an acceptable method of contraception \[defined as either one highly effective (permanent sterilization, intrauterine device or hormonal implant) or two other forms of contraception (such as oral contraceptive pill and condom)\] to avoid pregnancy throughout the study. Throughout the study and for 90 days (one spermatogenesis cycle) after receiving the last dose of study drug (ketamine/midazolam) man who is sexually active with a woman of childbearing potential must use an acceptable method of contraception (described above) with his female partner and must agree not to donate sperm.
• Subjects must either be free of psychotropic medications (including antidepressants, antipsychotics, benzodiazepines, mood stabilizers, sedative/hypnotics, dopamine agonists, stimulants, buspirone, and triptans) and certain anticonvulsants (topiramate and levetiracetam) or be stable on these medications for four weeks prior to the baseline visit \[first magnetic resonance imaging (MRI) scan\].
• Subjects with MDD should be willing to participate in neuroimaging scans before and after infusions, and be willing to undergo infusions with study drug.

You may not qualify if:

• Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder, pervasive developmental disorder or intellectual development disorder.
• Current diagnosis of obsessive-compulsive disorder, anorexia nervosa or bulimia. Comorbid anxiety, stress and trauma-related disorders are permitted as long as unipolar depression is the primary diagnosis.
• Diagnosis of a moderate or severe substance use disorder within the past 6 months per MINI; all subjects must have a negative urine toxicology test on the day of the MRI, prior to the scan.
• Female subjects who are pregnant, nursing, for may become pregnant. Women of childbearing potential must have a negative urine pregnancy test on the day of the fMRI, prior to scan, and on days of study drug infusion, prior to infusion.
• Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, immunologic, or hematologic disease.
• Inadequately treated obstructive sleep apnea (STOP-Bang score of 5-8 if untreated, if using positive airway pressure device then past-month apnea hypopnea index ≥ 15 per hour representing moderate or higher severity).
• Presence of a significant neurological disease such as Parkinson's disease, primary or secondary seizure disorders, intracranial tumors, or severe head trauma.
• Presence of neurocognitive or dementing disorders.
• Clinically significant abnormalities of laboratories, physical examination (including unstable hypertension - systolic blood pressure \>170, diastolic blood pressure \>100), or electrocardiogram at screening visit.
• Subjects judged to be at serious and imminent suicidal or homicidal risk by the PI or another study-affiliated psychiatrist.
• Any contraindications to MRI, including pacemakers or metallic objects in the body.
• Any claustrophobia or other conditions which may result in inability to lie still in the MRI scanner for 1 hour or more.
• Allergy to ketamine or midazolam in subjects with MDD.
• Must not be on any prohibited concomitant medication.

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

MeSH Terms

Conditions

Depressive Disorder, Major; Depression; Depressive Disorder

Interventions

Ketamine; Midazolam

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Subjects and study team members, including the PI, study-affiliated physicians, coordinator, nursing staff, and data analysts will be blinded to the drug assignment until the completion of the proposed project. Only the research pharmacist and study members involved in safety monitoring (medical monitor, independent safety monitor, and data analyst responsible for generating safety reports) will know the identity of the drug.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: All subjects (Healthy Controls and MDD) will undergo resting-state and task-based fMRI and cerebral prefusion to characterize the (i) patterns of functional connectivity and (ii) neural responses to a behavioral task eliciting frustrative nonreward (FNR) that are associated with irritability \[quantified with the 5-item irritability domain of Concise Associated Symptom Tracking scale (CAST-IRR)\]. The MDD cohort (n=60) will then be randomized to four 40-minute intravenous infusions over two weeks of either ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) in a double-blind, parallel-arm fashion. Clinical assessments and 3T MRI scans will be repeated after the last infusion to evaluate (i) pre-to-post treatment changes in neurocircuit function using resting-state and FNR task-based fMRI with ketamine versus midazolam and (ii) the association between changes in neurocircuit function and irritability.

Study Record Dates

• First Submitted: August 23, 2021
• First Posted: September 16, 2021
• Study Start: May 5, 2022
• Primary Completion: April 30, 2025
• Study Completion: April 30, 2025
• Last Updated: May 8, 2025

Record last verified: 2025-05

Locations

US (1)