Major Depressive DisorderPhase 2UNIKETNCT05046184
Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel Therapeutic Targets
A Phase 2 study testing Ketamine Hydrochloride and Midazolam injection in people with Major Depressive Disorder and Healthy Controls, run by University of Texas Southwestern Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Major Depressive Disorder, Healthy Controls
- What is being tested?
- Ketamine Hydrochloride and Midazolam injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 104 participants
- Where
- 1 siteUnited States
- Study dates
- 5 May 2022to 30 Apr 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel
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.
Read the detailed description
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
- Major Depressive Disorder, Healthy Controls
- Being tested
- Ketamine Hydrochloride, Midazolam injection
- Keywords
- major depressive disorder, MDD, depression, depressive disorder, depression symptoms, healthy controls, irritability, ketamine
- Medical subject headings
- Depressive Disorder, Major, Depression, Depressive Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketamine HydrochlorideDrug
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.
Midazolam injectionDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Midazolam injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Resting State Functional Connectivity.
Functional connectivity refers to the standardized correlation between resting state BOLD signal measured by fMRI of 7 striatal regions and habenula region of the brain (higher correlation means higher connectivity). Parcels from the striatal regions of the Schaefer atlas (2018) were assigned to the 7 resting state networks outlined by Yeo (2011) (i.e. Schaefer-Yeo atlas was used). Correlation coefficient represents a Fisher Z-transformed coefficient.
Measured: Baseline
Striatal Response to Frustrative Nonreward (FNR).
Difference between striatal response to frustrative nonreward (FNR) vs striatal response to positive feedback on the Affective Posner 3 task, as measured by the estimated difference in BOLD (Blood Oxygen Level Dependent) signal within the striatum regions of the brain (beta estimate from general linear test; from gltsym in AFNI's afniproc command). 7 regions correspond to those outlined by Schaefer-Yeo atlas 7-network version.
Measured: Baseline
Treatment-related Change in Striatum-habenula Functional Connectivity.
Functional connectivity refers to the standardized correlation between resting state BOLD signal measured by fMRI of 7 striatal regions and habenula region of the brain (higher correlation means higher connectivity). Parcels from the striatal regions of the Schaefer atlas (2018) were assigned to the 7 resting state networks outlined by Yeo (2011) (i.e. Schaefer-Yeo atlas was used). MDD participants only. Correlation coefficient represents a Fisher Z-transformed coefficient.
Measured: Assessed at baseline and end of treatment. See outcome measure 1 for baseline visit reporting
Treatment-related Change in Striatal Response to FNR.
Difference between striatal response to frustrative nonreward (FNR) vs striatal response to positive feedback on the Affective Posner 3 task, as measured by the estimated difference in BOLD (Blood Oxygen Level Dependent) signal within the striatum regions of the brain (beta estimate from general linear test; from gltsym in AFNI's afniproc command). 7 regions correspond to those outlined by Schaefer-Yeo atlas 7-network version.
Measured: Baseline, at 14 days. See outcome measure 2 for baseline timepoint data
Secondary outcomes (8)
Change in Symptoms of Irritability After Two Weeks of Twice-weekly Infusions of Ketamine Versus Midazolam.
Symptoms of irritability will be measured Concise Associated Symptom Tracking scale (CAST-IRR) where possible scores range from 5-25 and higher scores indicate greater severity of irritability. Reported scores represent change in scale units from baseline.
Measured: 14 days (end of treatment)
Change in Symptoms of Depression (Including Suicidal Ideation) Measured by MADR Scale
Possible scores range from 0 to 60 where higher scores indicate worse outcome. Reported scores represent change in scale units from baseline
Measured: 14 days (end of treatment)
Change in Symptoms of Depression Measured by QIDS Report
Possible scores range from 0 to 27 where higher scores indicate worse outcome. Reported scores represent change in scale units from baseline
Measured: 14 days (end of treatment)
Change in Symptoms of Anxious Arousal Measured by MAS Questionnaire
Possible scores range from 10-50 where higher scores indicate worse outcome. Reported scores represent change in scale units from baseline
Measured: 14 days (end of treatment)
Number of Participants That Met Criteria for Experiencing an Anger Attack on Massachusetts General Hospital Anger Attack Questionnaire (AAQ)
Anger attacks were assessed for using the Massachusetts General Hospital Anger Attack Questionnaire (AAQ), which asks about symptoms of anger attacks. If certain criteria on the AAQ are met, the individual is counted as having experienced an anger attack.
Measured: Baseline, at 14 days
Change in Brief Psychiatric Rating Scale Positive Domain
The Brief Psychiatric Rating Scale (BPRS) is a clinician-administered assessment used to capture acute behavioral changes throughout treatment. We used only the 4 items assessing positive symptoms of psychosis such as conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content for this study. Each item is rated on a 7-point scale, ranging from 1 (not observed) to 7 (very severe), with a total score range from 4-28, where higher scores indicate psychiatric symptoms. MDD participants only.
Measured: Pre-infusion, Immediately post-infusion, and 1 hour post infusion at each infusion visit (approximately every 3 days), and study exit (approximately 14 days)
Change in Clinician-Administered Dissociative Symptom Scale
The Clinician-Administered Dissociative States Scale (CADSS) was used before and after each infusion to assess the severity of dissociative symptoms associated with study drug administration. Possible scores range from 0-5 where higher scores indicate worse outcome/more severe symptoms. MDD participants only
Measured: Pre-infusion, Immediately post-infusion, and 1 hour post infusion at each infusion visit (approximately every 3 days), and study exit (approximately 14 days)
Number of Participants Reporting Symptoms From the Patient Rated Inventory of Side Effects (PRISE)
The Patient Rated Inventory of Side Effects (PRISE) is a clinician administered questionnaire used to qualify side effects by identifying and evaluating the tolerability of each symptom. Symptoms are grouped into domains by organ class. Numbers reported here reflect number of participants who reported at least one symptom in a given class over the total study duration, from baseline to study exit. Please note that many "other" side effects are symptoms of depression, and many were present at baseline since this was an MDD population. Here, we report the number of participants who endorsed symptoms from each organ class of symptoms.
Measured: Pre-infusion, Immediately post-infusion, and 1 hour post infusion at each infusion visit (approximately every 3 days), and study exit (approximately 14 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Sep 2021
- Study start5 May 2022
- Primary completion30 Apr 2025
- Study completion30 Apr 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 104 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Manish Jha, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05046184
- Sponsor's protocol ID
- STU-2021-0667
- Acronym
- UNIKET
- Status last verified
- Sep 2026
- First submitted
- 23 Aug 2021
- Last updated
- 8 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided: IPD will be shared based on institutional approval