Ketamine Alcohol (in Treatment-Resistant Depression)

NCT02122562 | Recruiting Phase 2 FDA Drug

• 3 other identifiers: 20190672614-M-00854R00AA024142-02
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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). 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.

Conditions

Magnetic Resonance Imaging; Major Depression; Alcoholism

Keywords

Ketamine; Major Depression; NMDA Antagonist

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (18)

• Concentration of Glutamate and Other Neurometabolites

  Prior to and during ketamine infusions

• Resting State Functional Connectivity

  Prior to and during ketamine infusions

• Hamilton Depression Rating Scale (HDRS)

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

• Beck Depression Inventory (BDI)

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

• Hamilton Psychiatric Rating Scale for Anxiety (HAM-A)

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

Study Arms (1)

Ketamine

EXPERIMENTAL

Ketamine 0.5 mg/mL IV (infused over 40 minutes)

Drug: Ketamine

Interventions

Ketamine DRUG

Treatment

Ketamine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator
• Mark Niciu: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of Iowa Health Care

Iowa City, Iowa, 52242, United States

RECRUITING

Related Publications (3)

• 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.

  PMID: 10686270 BACKGROUND

• 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.

  PMID: 16894061 BACKGROUND

• 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.

  PMID: 21232924 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Alcoholism

Interventions

Ketamine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• Mark J Niciu, M.D. Ph.D.

  University of Iowa Health Care (UIHC)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 23, 2014
• First Posted: April 24, 2014
• Study Start: April 23, 2014
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)