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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

165 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-05-05

Study Completion Date

2025-04-30

Brief Summary

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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.

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Detailed Description

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The proposed study aims to 1 (Aim 1) identify dysfunctions in neurocircuitry that engender irritability, and (Aim 2) determine how changes in neurocircuit function related to change in irritability. We will accomplish Aim 1 with resting-state and frustrative nonreward (FNR) task-based fMRI data from n=30 HCs and n=60 subjects with MDD ((Fig 3). For Aim 2, we will randomize the MDD cohort (n=60; same as Aim 1) to 2 weeks of twice-weekly 40-minutes long intravenous infusion of either ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) in a double-blind parallel-arm fashion, and by repeating clinical assessments and fMRI scans after the last infusion. The central hypothesis of the proposed study is that striatum is a key hub in the neurocircuitry of irritability, and that treatment-related improvement in irritability is associated with normalization of these neurocircuit functioning.

Conditions

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Major Depressive Disorder Healthy Controls

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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.

Primary Study Purpose

OTHER

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

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.

Study Groups

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Healthy Controls

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

Group Type NO_INTERVENTION

No interventions assigned to this group

MDD - Ketamine

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

Group Type ACTIVE_COMPARATOR

Ketamine Hydrochloride

Intervention Type 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 - Midazolam

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

Group Type PLACEBO_COMPARATOR

Midazolam injection

Intervention Type 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.

Interventions

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Ketamine Hydrochloride

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.

Intervention Type DRUG

Midazolam injection

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.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Male or female subjects, 18-65 years of age and body weight less than or equal to 120 kg on baseline visit.
2. 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.
3. 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.
4. 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.
5. 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 \[first magnetic resonance imaging (MRI) scan\].
6. Subjects with MDD should be willing to participate in neuroimaging scans before and after infusions, and be willing to undergo infusions with study drug.

Exclusion Criteria

1. Lifetime diagnosis of schizophrenia or any psychotic disorder, bipolar disorder, pervasive developmental disorder or intellectual development disorder.
2. 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.
3. 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.
4. 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.
5. Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, immunologic, or hematologic disease.
6. 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).
7. Presence of a significant neurological disease such as Parkinson's disease, primary or secondary seizure disorders, intracranial tumors, or severe head trauma.
8. Presence of neurocognitive or dementing disorders.
9. Clinically significant abnormalities of laboratories, physical examination (including unstable hypertension - systolic blood pressure \>170, diastolic blood pressure \>100), or electrocardiogram at screening visit.
10. Subjects judged to be at serious and imminent suicidal or homicidal risk by the PI or another study-affiliated psychiatrist.
11. Any contraindications to MRI, including pacemakers or metallic objects in the body.
12. Any claustrophobia or other conditions which may result in inability to lie still in the MRI scanner for 1 hour or more.
13. Allergy to ketamine or midazolam in subjects with MDD.
14. Must not be on any prohibited concomitant medication.

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes