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Magnetic Resonance ImagingPhase 2NCT02122562

Ketamine Alcohol (in Treatment-Resistant Depression)

A Phase 2 study testing Ketamine in people with Magnetic Resonance Imaging and Major Depression, run by Mark Niciu at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

A single subanesthetic dose infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and robust antidepressant effects in patients with treatment-refractory major depressive disorder (TRD). Read more about this study

Who is it for?
Ages 18 to 55 years
What is being tested?
Ketamine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
1 siteUnited States
Study dates
23 Apr 2014to Sep 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

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 55 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 18 to 55 years of age.
  • A level of understanding sufficient to agree to all required tests and examinations, sign an informed consent document and verify understanding by a score greater than or equal to 90% on the consent quiz.
  • Diagnostic and Statistical Manual-4th Edition-Text Revision (DSM-IV-TR)) diagnosis of major depressive disorder (MDD), single-episode (296.30) or recurrent (296.20) without psychotic features based on clinical assessment and confirmed by a Structured Clinical Interview for the DSM-IV- Patient Version (SCID-P). Subjects must be experiencing a current major depressive episode of at least 2 weeks duration.
  • Past failure of greater than or equal to one standard antidepressant trial based on the Antidepressant Treatment History Form (ATHF).
  • MADRS score greater than or equal to 20 at baseline and the day of ketamine infusion.

Who cannot join

  • Inadequate knowledge of family mental and substance use history, e.g. adoption.
  • Current psychotic features or prior diagnosis of a DSM-IV-TR psychotic spectrum disorder, e.g. schizophrenia, schizoaffective disorder, bipolar I disorder with psychotic features, MDD with psychotic features, or bipolar disorder, e.g. bipolar I disorder without psychotic features, bipolar II disorder and bipolar disorder not otherwise specified (NOS).
  • Current/active DSM-IV-TR substance use disorder (except for caffeine or nicotine dependence).
  • Pregnant or nursing women or women of childbearing potential not using at least one medically accepted means of contraception (to include oral, injectable, or implant birth control, condom or diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or partner with vasectomy).
  • Serious, unstable medical conditions/problems including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease, e.g. uncontrolled asthma, uncontrolled hyper/hypothyroidism or active cancer.
  • Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
Show all 20Show fewer
  • Clinically significant abnormal laboratory tests.
  • Subjects with one or more seizures without clear and resolved etiology and head injury with loss of consciousness for > 5 minutes or requiring hospitalization.
  • Treatment with psychiatric medications, e.g. selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, benzodiazepines and antipsychotics, at least two weeks of study phase II.
  • Treatment with fluoxetine within 5 weeks of study phase II.
  • Treatment with device-based treatment for depression, e.g. electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and vagal nerve stimulation (VNS), within 4 weeks of study phase II.
  • Lifetime history of deep brain stimulation.
  • Treatment with any disallowed concomitant medications.
  • Positive HIV test
  • Presence of ferromagnetic implants, e.g, heart pacemaker or aneurysm clip, or other contraindications to magnetic resonance imaging (MRI), e.g. claustrophobia or hearing loss.
  • Clinically-significant anatomical brain abnormalities detected on routine brain MRI.
  • Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of greater than or equal to 4.
  • A current NIMH employee/staff or their immediate family member (N.B. former exclusion criteria likely to be no longer relevant at the University of Iowa Health Care).
  • Currently engaged in an evidence-based structured psychotherapy for mood and/or anxiety disorders, e.g. cognitive-behavioral therapy (CBT) or interpersonal psychotherapy (IPT).
  • Additionally, the investigators may exclude or terminate any patient for clinical reasons.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Osura R Amarajeewa, M.B.B.S. contact

(319)-353-8536

osura-amarajeewa@uiowa.edu

Mark J Niciu, M.D. Ph.D. contact

(319)-594-8687

mark-niciu@uiowa.edu

United States1 site, 1 recruiting
  • University of Iowa Health Care

    Iowa City, Iowa, 52242

    Osura R Amarajeewa, M.B.B.S., 319-353-8536, emerson-buse@uiowa.edu

    Mark J Niciu, M.D. Ph.D., 319-356-1549, mark-niciu@uiowa.edu

    Recruiting

Other trials in United States

About this study

Official title: Functional Neuroimaging of the Enhanced Antidepressant Efficacy of Ketamine in a Biologically-Enriched Subgroup

A single subanesthetic dose infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and robust antidepressant effects in patients with treatment-refractory major depressive disorder (TRD). A family history of an alcohol use disorder (Family History Positive, FHP) is one of the strongest identified predictors of an improved antidepressant response to ketamine. Like ketamine, alcohol is a functional NMDA receptor antagonist. FHP is associated with differential response to ketamine, e.g. blunted psychotomimetic side effects. One of the primary mechanistic hypotheses for ketamine's antidepressant action is the acute intrasynaptic release of glutamate from major output neurons, e.g. cortical pyramidal cells. Preliminary clinical studies have demonstrated this acute glutamate "surge" in response to subanesthetic dose ketamine. Based on these findings, the investigators hypothesize that ketamine's enhanced antidepressant efficacy in FHP TRD subjects is, at least in part, attributable to increased glutamate release relative to TRD subjects without a family history of alcohol use disorder (Family History Negative, FHN). To test this hypothesis, the investigators have designed a now two-site, open-label study of 18-55-year-old medically and neurologically healthy, currently moderately-to-severely depressed TRD patients. In total, the investigators plan to recruit 25 FHP and 25 FHN TRD subjects. All subjects must not have a current substance use disorder (except nicotine or caffeine). The experimental portion consists of two phases. The preliminary first phase is a medication taper (if needed) and psychotropic medication-free period. The experimental second phase comprises one subanesthetic dose (0.5mg/kg x 40 minute) ketamine infusion. The ketamine infusion will occur during 7T-magnetic resonance imaging (MRI), both resting-state functional MRI (rs-fMRI) and magnetic resonance spectroscopy (MRS) to detect glutamate in the ventromedial prefrontal cortex/ventral anterior cingulate cortex (vmPFC/vACC). The primary outcome measure is group mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from pre-ketamine infusion (baseline) to one-week post-infusion, where the investigators observed ketamine's greatest antidepressant effect in FHP TRD. Additional outcome measures are vmPFC/vACC glutamate change in response to ketamine based on family history status. In summary, this study will provide key mechanistic information on ketamine's improved antidepressant efficacy in a biologically-enriched subgroup. This will contribute to the systematic development of more efficacious, personalized treatments for major depression in an effort to reduce its enormous public health burden.

Read the detailed description

Objective:

Glutamate-based medications including the glutamate modulator ketamine result in rapid, robust and sustained (typically up to one week) antidepressant effects in randomized controlled trials in treatment-refractory unipolar and bipolar depression. Previous work by the investigators' group has demonstrated that a family history of alcohol dependence predicts a more robust antidepressant response to ketamine in both treatment-resistant unipolar and bipolar depression.

Recently-detoxified alcoholics and affected first-degree relatives display blunted psychotomimetic, cognitive and other neuropsychiatric effects when administered a subanesthetic dose of ketamine. Based on the prior post hoc results, the investigators seek to prospectively demonstrate that a family history of an alcohol use disorder predicts a more robust antidepressant response to ketamine.

Study Population:

18-55 year old TRD without psychotic features patients in a current major depressive episode of at least moderate severity will be recruited and enrolled in this study. All subjects must not have a current substance use disorder (except nicotine or caffeine). All subjects must be psychotropic medication-free for at least two weeks prior to the ketamine infusion. The targeted number of completers is 50 depressed subjects (60 signing consent to account for attrition): 25 FHP subjects [as defined by either one first degree relative or two second-degree relatives with an alcohol user disorder on the Family Interview for Genetics Studies (FIGS) and Family Tree Questionnaire (FTQ)] and 25 FHN negative subjects.

Design:

This study is currently a single site, open-label protocol in psychotropic medication-free depressed subjects. This protocol consists of two phases. Phase I consists of a medication taper (if needed) and at least two week drug-free period. Phase II includes a subanesthetic/antidepressant dose ketamine infusion during 7T-MRI.

Outcome Measures:

The primary hypothesis/outcome measure will be mean change in MADRS total score from the pre-ketamine infusion (baseline) to 7 days post-infusion between the FHP and FHN groups. Other exploratory measures include glutamate alterations during intravenous ketamine infusions and rs-fMRI as a function of family history status.

Being tested
Ketamine
Keywords
Ketamine, Major Depression, NMDA Antagonist
Medical subject headings
Depressive Disorder, Major, Alcoholism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02122562
Study groupRoleWhat they receive
KetamineExperimentalKetamine 0.5 mg/mL IV (infused over 40 minutes)
Receives: Drug: Ketamine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Montgomery-Åsberg Depression Rating Scale (MADRS)

    The MADRS contains 10 items, and each item is scored 0-6. These item scores are summed to create a scale score; thus, scale scores range from 0 to 60. A scale score of 0 indicates the absence of depressive symptoms, while a score of 60 indicates severe depression. The primary outcome is the mean change in total MADRS score. A decrease in the mean MADRS score indicates a decrease (or improvement) in depressive symptoms, whereas an increase in the mean MADRS score indicates an increase (or worsening) in depressive symptoms.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

Secondary outcomes (18)
  1. Concentration of Glutamate and Other Neurometabolites

    High-magnetic field strength (7T) proton magnetic resonance spectroscopy (1H-MRS) detectable glutamate and other neurometabolites, e.g. N-acetylaspartate and creatine

    Measured: Prior to and during ketamine infusions

  2. Resting State Functional Connectivity

    Task-free ("resting state") functional magnetic resonance imaging (rs-FMRI) to detect changes in blood oxygen-level dependent (BOLD) signal

    Measured: Prior to and during ketamine infusions

  3. Hamilton Depression Rating Scale (HDRS)

    The HDRS is a clinician-administered depression rating scale that contains 21 items. The first 17 items are summed to create a total scale score. Score ranges indicate depression severity: 0-7 indicates the absence of depression, 8-13 indicates mild depression, 14-18 indicates moderate depression, 19-22 indicates severe depression, and >22 indicates very severe depression.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  4. Beck Depression Inventory (BDI)

    The BDI is a self-administered 21-item measure of depression severity. Each item is scored (in increasing severity) on a scale from 0-3. Total scores range from 0-63: 0-9 indicates no depression, 10-18 indicates mild depression, 19-29 indicates moderate depression, >29 indicates severe depression.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  5. Hamilton Psychiatric Rating Scale for Anxiety (HAM-A)

    The HAM-A is a clinician-administered scale of anxiety severity that comprises 14 items rated on a scale of 0-4. The HAM-A total score is the sum of 14 items with a score range from 0-56, with lower scores indicating low levels of anxiety and higher scores indicating greater anxiety severity.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  6. Young Mania Rating Scale (YMRS)

    The YMRS scale is an 11-item clinician-administered rating scale to assess hypo/manic symptoms. Items 5, 6, 8, and 9 (irritability, speech, content and disruptive-aggressive behavior) are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). Items 5, 6, 8, and 9 are given twice the weight of the remaining 7 items. The YMRS total score ranges from 0 to 60. Lower scores indicate absence of manic-like symptoms while higher scores indicate increasingly severe manic-like symptoms.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  7. Snaith-Hamilton Pleasure Scale (SHAPS)

    The SHAPS scale is a 14-item self-reported instrument to measure anhedonia. Scale scores are created by summing each item. Higher scale scores indicate more anhedonia, and lower scale scores indicate increased hedonic value.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  8. Temporal Experience of Pleasure Scale (TEPS)

    The TEPS scale is an 18-item self-reported questionnaire that measures pleasure associated with the consumption and anticipation of rewards. Lower scores indicate less pleasure while higher scores indicate greater hedonic value.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  9. Scale for Suicidal Ideation (SSI)

    The SSI is a 19-item clinician-administered instrument designed to quantify the intensity of current conscious suicidal ideation in various dimensions of self-destructive thoughts or wishes: the extent of the wish to die, the desire to make an actual suicide attempt, and details of any plans; also, internal deterrents to an active attempt, and subjective feelings of control and/or courage regarding a proposed attempt. We will administer both the full and a short (5-item) version to assess rapid change in suicidal thinking. Scale scores are calculated by summing item scores and range from 0-38. Lower scores indicate less suicidal ideation and higher scores indicate escalating severity of suicidal thinking.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  10. Columbia-Suicide Severity Rating Scale (C-SSRS)

    The C-SSRS is a clinician-administered instrument designed to measures suicidal ideation/behaviors with both "Lifetime/Recent" and "Since Last Visit" versions. There are four subscales. Severity of ideation subscale is measured on a 5-point ordinal scale in which 1=wish to be dead, 2=nonspecific active suicidal thoughts, 3=suicidal thoughts with methods, 4=suicidal intent, and 5=suicidal intent with plan. The intensity of ideation subscale has 5 items: frequency, duration, controllability, deterrents, and reason for ideation, which is rated on a 5 point scale. The suicidal behavior subscale is rated on attempts, preparatory behavior, and nonsuicidal self-injury. The lethality subscale measures lethalities of actual attempts, which is rated on a 6 point scale.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  11. Alcohol Urge Questionnaire (AUQ)

    The AUQ is an 8-item self-report scale to assess acute alcohol cravings. It utilizes a 7 point Likert scale, and items are summed for a total scale score, where higher scores indicate greater cravings/urges to drink alcohol. This measure will be used to assess alcohol-related expectancies with both alcohol and ketamine.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  12. Obsessive Compulsive Drinking Scale (OCDS)

    The OCDS is a self-administered instrument that consists of 14 items that has been shown to be sensitive and specific for the obsessive and compulsive characteristics of alcohol misuse: drinking-related preoccupations, urges to drink, and the ability to desist these thoughts/urges. This measure will also be used to assess alcohol-related expectancies related to both alcohol and ketamine infusions. Items are rated on a 5 point Likert scale. Higher scores indicate more preoccupation, urges, or difficulty controlling urges to drink/consume alcohol.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  13. Brief Psychiatric Rating Scale (BPRS)

    The BPRS is a clinician-administered instrument with 4 key items will be used as an index of positive symptoms of schizophrenia. These 4 key positive domains are conceptual disorganization, hallucinatory behavior, suspiciousness and unusual thought content. 3 additional BPRS items - blunted affect, emotional withdrawal and motor retardation - are selected as a measure of negative schizophrenia symptoms. Each item is scored on a 7 point Likert scale, with 1 indicating absence of a given symptom and 7 indicating highest measured severity. Individual item are added to form a total scale score.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  14. Visual Analog Scale (VAS)

    The VAS is a 7-item self-administered Likert-type measure with individual items scored between 0-10. This instrument rates 7 domains: happy/euphoric, restless, sad, anxious, irritated/angry, drowsy and alert. A score of 0 is described as "none", 1-3 is "mild", 4-6 is "moderate", 7-9 is "marked" and 10 is "extreme" for each given item.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  15. Clinician-Administered Dissociative States Scale (CADSS)

    The CADSS is a measure of perceptual, behavioral and attentional changes occurring during dissociative experiences that has been tested in healthy subjects and post-traumatic stress disorder (PTSD). This scale involves 19 self-reported questions and 8 observer ratings scored from 0 (not at all) - 4 (extremely). Greater scores indicate greater ketamine-induced dissociation.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  16. Clinical Global Impression/Severity (CGI)

    The CGI is a clinician-measured scale of 3 items: Severity of Illness (item 1), Global Improvement (item 2), and Efficacy Index (item 3). Items 1 and 2 are rated on a 7-point Likert scale (1=normal, 7=among the most extremely ill patients) with a possible response of "not assessed." Item 3 is rated on a 4-point Likert scale from "none" to "outweighs therapeutic effect." Items 1 and 3 are assessed in relation to last clinical encounter (if possible).

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  17. Modified Version of the NIMH Data Safety Event Codes (NIMH-DSEC)

    This clinician-collected form collects information over 100 symptoms/signs across multiple organ systems. The "Specific" form is for tracking side effects that are often seen during the infusion at multiple time points. The "Regular" form is for the baseline (-60 minutes), +230 minute post-ketamine infusion (final time point on the day of ketamine infusion) and other daily time points post-ketamine infusion.

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

  18. The Positive and Negative Affect Schedule (PANAS)

    The PANAS is a self-report questionnaire comprised of 2 mood scales, one that measures positive affect and one that measures negative affect. Used as a psychometric scale, the PANAS can show relations between positive and negative affect with personality states and traits. 10 descriptors are used for each positive and negative affect scale to define their meanings. Participants are asked to respond to a 20-item test, and each individual item is scored on a a 5-point Likert scale that ranges from very slightly or not at all (1) to extremely (5).

    Measured: Pre-ketamine (baseline) to one week post-ketamine infusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Apr 2014 (estimated)
  2. Study start23 Apr 2014
  3. Primary completionSep 2028 (estimated)
  4. Study completionSep 2028 (estimated)

Resources

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
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02122562
Sponsor's protocol ID
201906726
Other IDs
14-M-0085, 4R00AA024142-02
Status last verified
Apr 2026
First submitted
23 Apr 2014
Last updated
1 May 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4. doi: 10.1016/s0006-3223(99)00230-9.

    PubMed 10686270
  • Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64. doi: 10.1001/archpsyc.63.8.856.

    PubMed 16894061
  • Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, Krystal JH, Sanacora G. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011 Feb 28;191(2):122-7. doi: 10.1016/j.pscychresns.2010.10.009. Epub 2011 Jan 12.

    PubMed 21232924
  • Gorka A, Evans J, Kvarta M, Ballard E, Zarate C. Major depressive disorder is associated with reduced intrinsic connectivity between the bed nucleus of the stria terminalis and ventral striatum. J Psychiatry Neurosci. 2026 Jan 1;51:1-7. doi: 10.1139/jpn-2025-0160.

    PubMed 42171126

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ketamine in people with Magnetic Resonance Imaging and Major Depression, run by Mark Niciu at 1 site in United States.

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 5 inclusion and 20 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: looking for participants now, as of the sponsor's last update on 1 May 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. 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?

This study is still under way. Results are not available in the source record yet.

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

Contact Osura R Amarajeewa, M.B.B.S. ((319)-353-8536, osura-amarajeewa@uiowa.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Montgomery-Åsberg Depression Rating Scale (MADRS) (time frame: Pre-ketamine (baseline) to one week post-ketamine infusion). 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 NCT02122562, which also lists 4 linked publications.

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 1 May 2026.

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