The Neurophysiological Effects of Intravenous Alcohol as Potential Biomarkers of Ketamine's Rapid Antidepressant Effects in Major Depressive Disorder

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier:
NCT02122562
First received: April 23, 2014
Last updated: June 11, 2014
Last verified: March 2014
  Purpose

Objective:

Glutamate-based medications including the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine result in rapid, robust and sustained (up to one week) antidepressant effects in randomized controlled trials in treatment-refractory unipolar and bipolar depression. Previous work by our 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 with a subanesthetic dose of ketamine. Also, a family history of alcoholism alone predicts differential response to intravenous alcohol. Based on our prior post hoc results, we seek to prospectively demonstrate that a family history of alcohol dependence predicts a more robust antidepressant response to ketamine. We will also explore potential biomarkers of ketamine s antidepressant effects in treatment-refractory depressed patients at risk of alcohol dependence (using physiological and neurochemical responses to alcohol).

Study Population:

21-65 year old treatment-resistant major depressive disorder without psychotic features patients in a current major depressive episode of at least moderate severity will be recruited and enrolled in this protocol. All subjects must also be free of a lifetime substance use disorder diagnosis with the exception of a nicotine or caffeine use disorder) and will be psychotropic medication-free for at least two weeks prior to the first alcohol infusion. Our targeted number of completers will be 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 alcohol dependence on the Family Interview for Genetics Studies (FIGS) and Family Tree Questionnaire (FTQ)] and 25 FHN negative subjects.

Design:

This study is a single-site, open-label protocol in psychotropic medication-free depressed subjects admitted to the Clinical Research Center s Mood and Anxiety Disorder Inpatient Research Unit (7-SE). This protocol consists of two phases (Phase I and Phase II). The first phase consists of the medication taper and drug-free period. The second phase will have three subphases: Subphase IIA ( alcohol clamp infusion #1 with neurophysiological assessments), IIB ( alcohol clamp infusion #2 during 7 Tesla-Magnetic Resonance Spectroscopy/Imaging (7T-MRS/I)) and IIC (subanesthetic/antidepressant dose ketamine infusion during 7T-MRS/I).

Outcome Measures:

The primary hypothesis/outcome measure will be change in mean Montgomery-Asberg Depression Rating Scale (MADRS) total score from the pre-ketamine infusion baseline-to-7 days post-infusion between the FHP and FHN groups. Other exploratory measures include neurophysiological responses to intravenous alcohol infusion, brain neurochemical alterations during intravenous alcohol infusion, brain neurochemical alterations during intravenous ketamine infusion and resting state (task-free) functional magnetic resonance imaging as a function of family history of an alcohol use disorder.


Condition Intervention Phase
Magnetic Resonance Imaging
Major Depression
Alcoholism
Drug: Ketamine
Other: Alcohol Infusion
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Neurophysiological Effects of Intravenous Alcohol as Potential Biomarkers of Ketamine's Rapid Antidepressant Effects in Major Depressive Disorder

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Total MADRS score [ Time Frame: Change from baseline to seven days post infusion ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Neurophysiological measures during alcohol challenge, e.g. baseline grooved pegboard performance [ Time Frame: first alcohol infusion ] [ Designated as safety issue: No ]
  • AANts, e.g. baseline/intra-alcohol and ketamine infusion 1H-MRS detectable glutamate [ Time Frame: during second alcohol and detamine infusions ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: March 2014
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Ketamine
    Treatment
    Other: Alcohol Infusion
    Biomarker
Detailed Description:

Objective:

Glutamate-based medications including the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine result in rapid, robust and sustained (up to one week) antidepressant effects in randomized controlled trials in treatment-refractory unipolar and bipolar depression. Previous work by our 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 with a subanesthetic dose of ketamine. Also, a family history of alcoholism alone predicts differential response to intravenous alcohol. Based on our prior post hoc results, we seek to prospectively demonstrate that a family history of alcohol dependence predicts a more robust antidepressant response to ketamine. We will also explore potential biomarkers of ketamine s antidepressant effects in treatment-refractory depressed patients at risk of alcohol dependence (using physiological and neurochemical responses to alcohol).

Study Population:

21-65 year old treatment-resistant major depressive disorder without psychotic features patients in a current major depressive episode of at least moderate severity will be recruited and enrolled in this protocol. All subjects must also be free of a lifetime substance use disorder diagnosis with the exception of a nicotine or caffeine use disorder) and will be psychotropic medication-free for at least two weeks prior to the first alcohol infusion. Our targeted number of completers will be 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 alcohol dependence on the Family Interview for Genetics Studies (FIGS) and Family Tree Questionnaire (FTQ)] and 25 FHN negative subjects.

Design:

This study is a single-site, open-label protocol in psychotropic medication-free depressed subjects admitted to the Clinical Research Center s Mood and Anxiety Disorder Inpatient Research Unit (7-SE). This protocol consists of two phases (Phase I and Phase II). The first phase consists of the medication taper and drug-free period. The second phase will have three subphases: Subphase IIA ( alcohol clamp infusion #1 with neurophysiological assessments), IIB ( alcohol clamp infusion #2 during 7 Tesla-Magnetic Resonance Spectroscopy/Imaging (7T-MRS/I)) and IIC (subanesthetic/antidepressant dose ketamine infusion during 7T-MRS/I).

Outcome Measures:

The primary hypothesis/outcome measure will be change in mean Montgomery-Asberg Depression Rating Scale (MADRS) total score from the pre-ketamine infusion baseline-to-7 days post-infusion between the FHP and FHN groups. Other exploratory measures include neurophysiological responses to intravenous alcohol infusion, brain neurochemical alterations during intravenous alcohol infusion, brain neurochemical alterations during intravenous ketamine infusion and resting state (task-free) functional magnetic resonance imaging as a function of family history of an alcohol use disorder.

  Eligibility

Ages Eligible for Study:   21 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • 21 to 65 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.
  • DSM-IV-TR diagnosis of 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 two 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.

EXCLUSION CRITERIA:

  • 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).
  • Lifetime history of DSM-IV-TR drug or alcohol use disorder (except for caffeine or nicotine dependence), currently seeking or have a prior history of seeking help for alcohol problems, non-drinkers (no alcohol in the past year) and history of alcohol-induced flushing reactions.
  • Pregnant or nursing women or women of child bearing 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 4 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 > 4.

Additionally, the Investigators may exclude or terminate any patient for clinical reasons.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02122562

Contacts
Contact: Mark J Niciu, M.D. Not Listed niciumj@mail.nih.gov
Contact: Carlos A Zarate, M.D. (301) 451-0861 zaratec@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier: NCT02122562     History of Changes
Other Study ID Numbers: 140085, 14-M-0085
Study First Received: April 23, 2014
Last Updated: June 11, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Ketamine
Major Depression
Alcohol
Alcohol Clamp
NMDA Antagonist

Additional relevant MeSH terms:
Alcoholism
Depression
Depressive Disorder
Depressive Disorder, Major
Alcohol-Related Disorders
Behavioral Symptoms
Chemically-Induced Disorders
Mental Disorders
Mood Disorders
Substance-Related Disorders
Antidepressive Agents
Ethanol
Ketamine
Analgesics
Anesthetics
Anesthetics, Dissociative
Anesthetics, General
Anesthetics, Intravenous
Anti-Infective Agents
Anti-Infective Agents, Local
Central Nervous System Agents
Central Nervous System Depressants
Excitatory Amino Acid Agents
Excitatory Amino Acid Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs

ClinicalTrials.gov processed this record on October 28, 2014