Ketamine Alcohol (in Treatment-Resistant Depression)

Study Overview
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Brief Summary
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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 both alcohol, e.g. decreased body sway and plasma cortisol, and 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). The investigators also hypothesize that alcohol similarly augments glutamate release in this bio- logically-enriched subgroup, which may be a more objective biomarker than family history status. To test these hypotheses, the investigators have designed a now two-site, open-label study of 21-65 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 lifetime substance use disorder (except nicotine or caffeine), no lifetime history of an alcohol use disorder and socially drink. 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 two pharmacokinetically-defined basal-bolus alcohol and one subanesthetic dose (0.5mg/kg x 40 minute) ketamine infusions. The first alcohol infusion will establish the pharmacokinetic profile for a subsequent alcohol infusion occurring 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 ketamine infusion will also occur during 7T-MRI. 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 and alcohol challenge 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.

Detailed Description
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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. A family history of alcoholism also predicts differential response to intravenous alcohol. 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. The research team will also explore potential biomarkers of ketamine's antidepressant effects in treatment-refractory depressed patients at greater risk of developing an alcohol use disorder, using physiological and neurochemical responses to alcohol. Study Population: 21-65 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 lifetime substance use disorder (except nicotine or caffeine), no lifetime history of an alcohol use disorder and socially drink. All subjects must be psychotropic medication-free for at least two weeks prior to the first alcohol 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 a now two-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 has three subphases: Subphase IIA (alcohol clamp infusion #1 with neurophysiological assessments), Subphase IIB (alcohol clamp infusion #2 during 7T-MRI) and Subphase IIC (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 neurophysiological responses to intravenous alcohol, glutamate) alterations during intravenous alcohol infusion and ketamine infusions, and rs-fMRI as a function of family history status.

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

Conditions
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Magnetic Resonance Imaging, Major Depression, Alcoholism

Intervention / Treatment
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* Drug: Ketamine
* Other: Alcohol Infusion


Participation Criteria
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Eligibility Criteria
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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. 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. 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). Current/active DSM-IV-TR drug or alcohol use disorder (except for caffeine or nicotine dependence), currently seeking help for alcohol problems, abstinent with a history of an alcohol use disorder, non-drinkers (no alcohol in the past year), or a 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 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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Ketamine|Treatment|
|Other: Alcohol Infusion|Biomarker|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biphasic Alcohol Effects Scale (BAES) | The BAES is a self-reported rating scale that consists of 14 items that comprise two subscales: stimulant and sedative effects. The items from each subscale are summed to create the subscale score. Subscale scores range from 0 to 70, with 0 indicating a sober state and 70 indicating a state of severe intoxication. | Prior to and during first alcohol infusion | 
| Drug Effects Questionnaire (DEQ) | DEQ is a measure of alcohol's effects and the desire to consume more alcohol. The DEQ consists of 4 subscales: Feel (the effects), Like (the effects), High (from drug), and Want More (of drug), all of which are on a 0 to 100 scale, where 0 = not at all, 50 = neutral, and 100 = very much/a lot. | Prior to and during first alcohol infusion | 
| Profile of Mood States (POMS) | POMS assesses transitory changes in mood. It consists of 65 adjectives, rating of 6 domains (tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, vigor-activity and confusion-bewilderment) on an escalating 5-point scale (0=not at all; 1=a little; 2=moderately; 3-quite a bit; 4=extremely). Item scores are summed to create a scale score, and subscale scores are added to create a measure of total mood disturbance. A score of 0 indicates absence of mood disturbance while higher scores indicate greater mood disturbances. | Prior to and during first alcohol infusion | 
| Number of Drinks Questionnaire (NODQ) | NODQ is a single-item questionnaire that asks the subject how many drinks it feels like they have consumed at a given time point. | Prior to and during first alcohol infusion | 
| Self Rating of the Effects of Alcohol (SRE) scale | SRE is 12-item instrument used to retrospectively assess the number of drinks it takes to experience physiological effects from alcohol. This is recorded for 3 periods in the individual's lifetime, i.e. the first 5 times that the individual drank, during a regular drinking period and during the period of heaviest drinking. | Prior to and during first alcohol infusion | 
| Heart Rate Variability | This will be recorded using a heart rate monitor placed on the chest at the start of the study session. | Prior to and during first alcohol infusion | 
| Grooved Pegboard (GPB) | GPB performance has been to assess fine motor and manipulative dexterity. The device consists of 25 holes with randomly positioned slots. The pegs (which have a key along one side) must be rotated to match the hole before insertion. The participant will be asked to insert the pegs into each hole with being timed to completion and number of drops measured. | Prior to and during first alcohol infusion | 
| Body Sway | Two minutes eyes-open and two minutes eyes-closed body weight distribution will be measured using a Wii balance board. | Prior to and during first alcohol infusion | 
| Balloon Analogue Risk Task (BART) | BART is a computer-based task that measures behavioral disinhibition and risk-taking. Subjects will click a mouse to pump up a virtual balloon on the computer screen. The bigger the subject pumps up the balloon, the more points he or she could win; however, if the balloon pops before the subject stops pumping the balloon and collects his or her winnings, they will lose the virtual money earned. There are 20 trials in each task run. A greater number of pumps indicates increased behavioral disinhibition. Greater pumps during the alcohol clamp in comparison to before alcohol infusion indicates increasing disinhibition in response to alcohol. | Prior to and during first alcohol infusion | 
| Risk Taking Task | The Risk Taking Task is computer-based task in which subjects have the option of pressing a button to choose a safe but small reward or a greater reward that may result in either a win or a loss. Increased incidence of selecting the riskier reward at baseline indicates greater impulsivity. Greater selection of riskier rewards during the alcohol clamp in comparison to baseline indicates increasing disinhibition in response to alcohol. | Prior to and during first alcohol infusion | 
| 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 | Prior to and during second alcohol and ketamine infusions | 
| Resting State Functional Connectivity | Task-free (resting state) functional magnetic resonance imaging (rs-FMRI) to detect changes in blood oxygen-level dependent (BOLD) signal | Prior to and during second alcohol and ketamine infusions | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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). | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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. | Pre-ketamine (baseline) to one week post-ketamine infusion | 
| 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). | Pre-ketamine (baseline) to one week post-ketamine infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketamine, Major Depression, Alcohol, Alcohol Clamp, NMDA Antagonist