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.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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
Are there results?: Yes, posted in the registrySummary in the doctors' view

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.

United States1 site

UT Southwestern Medical Center
Dallas, Texas, 75235

Other trials in United States

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 groups in NCT05046184
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.

5 May 202230 Apr 2025

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.
More trials run by University of Texas Southwestern Medical CenterThe sponsor's other registered studies.
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)

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

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 8 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Elucidating the Neurocircuitry of Irritability With High-Field Neuroimaging to Identify Novel
ClinicalTrials.gov ID: NCT05046184
Acronym / sponsor ID: UNIKET / STU-2021-0667
Conditions: Major Depressive Disorder, Healthy Controls
Keywords: major depressive disorder, MDD, depression, depressive disorder, depression symptoms, healthy controls, irritability, ketamine
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 104 participants (actual)
Lead sponsor: University of Texas Southwestern Medical CenterUniversity, hospital or other
Study start: 5 May 2022 (actual)
Primary completion: 30 Apr 2025 (actual)
Study completion: 30 Apr 2025 (actual)
First posted: 16 Sep 2021 (actual)
Results: Posted 8 Oct 2026

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Other
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3
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.

Arm	Type	Receives
Healthy Controls	No intervention	–Healthy controls will undergo clinician assessments and fMRI to compare to MDD group.
MDD - Ketamine	Active comparator	Drug: Ketamine HydrochlorideParticipants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four ketamine infusions.
MDD - Midazolam	Placebo comparator	Drug: Midazolam injectionParticipants with MDD who have completed all baseline assessments including pre-treatment fMRI scan randomly allocated to receive four midazolam infusions.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

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].

Key exclusion criteria (14 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Ketamine HydrochlorideSubjects 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.	Drug	MDD - Ketamine
Midazolam injectionSubjects 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.	Drug	MDD - Midazolam

Primary outcome

Resting State Functional Connectivity.
Time frame: Baseline
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.
Striatal Response to Frustrative Nonreward (FNR).
Time frame: Baseline
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.
Treatment-related Change in Striatum-habenula Functional Connectivity.
Time frame: Assessed at baseline and end of treatment. See outcome measure 1 for baseline visit reporting
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.
Treatment-related Change in Striatal Response to FNR.
Time frame: Baseline, at 14 days. See outcome measure 2 for baseline timepoint data
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.

8 secondary outcomes

Change in Symptoms of Irritability After Two Weeks of Twice-weekly Infusions of Ketamine Versus Midazolam.
Time frame: 14 days (end of treatment)
Change in Symptoms of Depression (Including Suicidal Ideation) Measured by MADR Scale
Time frame: 14 days (end of treatment)
Change in Symptoms of Depression Measured by QIDS Report
Time frame: 14 days (end of treatment)
Change in Symptoms of Anxious Arousal Measured by MAS Questionnaire
Time frame: 14 days (end of treatment)
Number of Participants That Met Criteria for Experiencing an Anger Attack on Massachusetts General Hospital Anger Attack Questionnaire (AAQ)
Time frame: Baseline, at 14 days
Change in Brief Psychiatric Rating Scale Positive Domain
Time frame: 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
Time frame: 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)
Time frame: Pre-infusion, Immediately post-infusion, and 1 hour post infusion at each infusion visit (approximately every 3 days), and study exit (approximately 14 days)

Results and safety

Results posted to the registry on 8 Oct 2026, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Healthy Control	42	42
MDD - Midazolam	31	30
MDD - Ketamine	31	29

Primary outcome: Resting State Functional Connectivity.

Time frame: Baseline. Mean (Standard Deviation). Unit: Fisher z correlation coefficient

Measure	Healthy Control n = 36	MDD - Ketamine n = 25	MDD - Midazolam n = 27
Striatal network 1 - Habenula functional connectivity	-0.002355 (0.09229)	0.02525 (0.07618)	0.04504 (0.09565)
Striatal network 2 - Habenula functional connectivity	-0.005570 (0.01205)	-0.0006422 (0.009798)	-0.003755 (0.008074)
Striatal network 3 - Habenula functional connectivity	-0.003135 (0.04240)	0.007026 (0.04591)	0.005655 (0.042714)
Striatal network 4 - Habenula functional connectivity	-0.002556 (0.008471)	0.0003311 (0.008567)	-0.001633 (0.007936)
Striatal network 5 - Habenula functional connectivity	-0.0006443 (0.01734)	0.002509 (0.01250)	0.0008957 (0.01424)
Striatal network 6 - Habenula functional connectivity	0.0002023 (0.007428)	0.001734 (0.008458)	0.0018644074 (0.007666)
Striatal network 7 - Habenula functional connectivity	0.0005949 (0.008584)	0.001678 (0.009290)	0.0007463 (0.008234)

Population analysed: The number of participants in each arm who had usable fMRI resting state data at the baseline visit. Reasons scans were excluded include technical issues with the scanner, too many censored TRs due to motion, and structural abnormality.

Primary outcome: Striatal Response to Frustrative Nonreward (FNR).

Time frame: Baseline. Mean (Standard Deviation). Unit: Estimated BOLD signal (beta estimate)

Measure	Healthy Control n = 39	MDD - Ketamine n = 29	MDD - Midazolam n = 28
Contrast of striatal network 1 activation following frustrating vs positive feedback	0.008095 (0.1880)	0.0299566552 (0.2375327599)	0.0575584643 (0.2340562227)
Contrast of striatal network 2 activation following frustrating vs positive feedback	0.02017 (0.1006)	-0.002985828 (0.1059210865)	0.0429733571 (0.0997051875)
Contrast of striatal network 3 activation following frustrating vs positive feedback	-0.015433282 (0.1624008534)	-0.012460897 (0.1447045331)	0.027166 (0.1874875272)
Contrast of striatal network 4 activation following frustrating vs positive feedback	0.009815 (0.1041)	0.0065397241 (0.1068566889)	0.0501653214 (0.1030575279)
Contrast of striatal network 5 activation following frustrating vs positive feedback	0.01036 (0.1346)	0.0424085517 (0.1015805136)	0.0648926429 (0.1293505982)
Contrast of striatal network 6 activation following frustrating vs positive feedback	0.006723 (0.1402)	0.0016498966 (0.1287143706)	0.0320963929 (0.1118624523)
Contrast of striatal network 7 activation following frustrating vs positive feedback	0.02340 (0.1237)	0.03740475 (0.1128758572)	0.03740475 (0.1110403024)

Population analysed: The number of participants in each arm who had usable fMRI task data at the baseline visit. Reasons scans were excluded include technical issues with the scanner, too many censored TRs due to motion, and structural abnormality.

Primary outcome: Treatment-related Change in Striatum-habenula Functional Connectivity.

Time frame: Assessed at baseline and end of treatment. See outcome measure 1 for baseline visit reporting. Mean (Standard Deviation). Unit: Fisher z correlation coefficient

Measure	MDD - Ketamine n = 23	MDD - Midazolam n = 23
Striatal network 1 - Habenula functional connectivity	-0.0009734 (0.05776)	-0.01185 (0.07534)
Striatal network 2 - Habenula functional connectivity	-0.002656739 (0.0160103506)	-0.000169 (0.0100583457)
Striatal network 3 - Habenula functional connectivity	-0.012500043 (0.037625987)	-0.000802696 (0.037625987)
Striatal network 4 - Habenula functional connectivity	-0.004466304 (0.0122943308)	0.0017146522 (0.0091285944)
Striatal network 5 - Habenula functional connectivity	0.003012087 (0.015576652)	0.0029876957 (0.0126743798)
Striatal network 6 - Habenula functional connectivity	-0.001122 (0.0092733779)	0.0013288696 (0.0109347196)
Striatal network 7 - Habenula functional connectivity	-0.001283609 (0.0121899456)	0.0000793913 (0.0108864131)

Population analysed: The number of participants in each arm who had usable fMRI resting state data at the end of treatment visit. Reasons scans were excluded include technical issues with the scanner, too many censored TRs due to motion, early withdrawal from the study, and structural abnormality. Only MDD participants. Healthy control participants did not receive any infusions, therefore they are not included in the end of treatment analyses.

Primary outcome: Treatment-related Change in Striatal Response to FNR.

Time frame: Baseline, at 14 days. See outcome measure 2 for baseline timepoint data. Mean (Standard Deviation). Unit: Estimated BOLD signal (beta estimate)

Measure	MDD - Ketamine n = 29	MDD - Midazolam n = 28
Contrast of striatal network 1 activation following frustrating vs positive feedback	-0.043221536 (0.2355486241)	-0.049248448 (0.2134111013)
Contrast of striatal network 2 activation following frustrating vs positive feedback	0.0277769643 (0.0785526745)	0.0244194138 (0.093963263)
Contrast of striatal network 3 activation following frustrating vs positive feedback	0.02633 (0.0982122041)	0.0057957931 (0.1500521724)
Contrast of striatal network 4 activation following frustrating vs positive feedback	0.034981931 (0.0916752534)	0.03323825 (0.0902350144)
Contrast of striatal network 5 activation following frustrating vs positive feedback	0.0333037857 (0.1005225603)	0.0322243103 (0.1231102155)
Contrast of striatal network 6 activation following frustrating vs positive feedback	0.0173799286 (0.0973618907)	0.0228358276 (0.0953103359)
Contrast of striatal network 7 activation following frustrating vs positive feedback	0.0299317857 (0.0685636315)	0.0282071034 (0.0950889413)

Population analysed: The number of participants in each arm who had usable fMRI task data at the end of treatment visit. Reasons scans were excluded include technical issues with the scanner, too many censored TRs due to motion, early withdrawal from the study, and structural abnormality. Only MDD participants. Healthy control participants did not receive any infusions, therefore they are not included in the end of treatment analyses. There is no change over time for healthy controls, because they only had 1 visit.

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: From date of informed consent until end of follow-up (maximum of 5 weeks). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
MDD: Ketamine	0 of 31 (0%)	11 of 31 (35.5%)	0 of 31
MDD: Midazolam	0 of 31 (0%)	5 of 31 (16.1%)	0 of 31
Healthy Control	0 of 42 (0%)	1 of 42 (2.4%)	0 of 42

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Undecided. IPD will be shared based on institutional approval

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Resting State Functional Connectivity. (time frame: Baseline). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05046184.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2026.