Ketamine Alcohol (in Treatment-Resistant Depression)
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|ClinicalTrials.gov Identifier: NCT02122562|
Recruitment Status : Recruiting
First Posted : April 24, 2014
Last Update Posted : July 7, 2020
|Condition or disease||Intervention/treatment||Phase|
|Magnetic Resonance Imaging Major Depression Alcoholism||Drug: Ketamine Other: Alcohol Infusion||Phase 2|
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.
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.
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).
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||The Neurophysiological Effects of Intravenous Alcohol as Potential Biomarkers of Ketamine's Rapid Antidepressant Effects in Major Depressive Disorder|
|Study Start Date :||April 23, 2014|
|Estimated Primary Completion Date :||September 2021|
|Estimated Study Completion Date :||September 2021|
- Drug: Ketamine
- Other: Alcohol Infusion
- Montgomery-Åsberg Depression Rating Scale (MADRS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Biphasic Alcohol Effects Scale (BAES) [ Time Frame: Prior to and during first alcohol infusion ]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.
- Drug Effects Questionnaire (DEQ) [ Time Frame: Prior to and during first alcohol infusion ]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.
- Profile of Mood States (POMS) [ Time Frame: Prior to and during first alcohol infusion ]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.
- Number of Drinks Questionnaire (NODQ) [ Time Frame: Prior to and during first alcohol infusion ]NODQ is a single-item questionnaire that asks the subject how many drinks it feels like they have consumed at a given time point.
- Self Rating of the Effects of Alcohol (SRE) scale [ Time Frame: Prior to and during first alcohol infusion ]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.
- Heart Rate Variability [ Time Frame: Prior to and during first alcohol infusion ]This will be recorded using a heart rate monitor placed on the chest at the start of the study session.
- Grooved Pegboard (GPB) [ Time Frame: Prior to and during first alcohol infusion ]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.
- Body Sway [ Time Frame: Prior to and during first alcohol infusion ]Two minutes eyes-open and two minutes eyes-closed body weight distribution will be measured using a Wii balance board.
- Balloon Analogue Risk Task (BART) [ Time Frame: Prior to and during first alcohol infusion ]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.
- Risk Taking Task [ Time Frame: Prior to and during first alcohol infusion ]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.
- Concentration of Glutamate and Other Neurometabolites [ Time Frame: Prior to and during second alcohol and ketamine infusions ]High-magnetic field strength (7T) proton magnetic resonance spectroscopy (1H-MRS) detectable glutamate and other neurometabolites, e.g. N-acetylaspartate and creatine
- Resting State Functional Connectivity [ Time Frame: Prior to and during second alcohol and ketamine infusions ]Task-free ("resting state") functional magnetic resonance imaging (rs-FMRI) to detect changes in blood oxygen-level dependent (BOLD) signal
- Hamilton Depression Rating Scale (HDRS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Beck Depression Inventory (BDI) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Young Mania Rating Scale (YMRS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Temporal Experience of Pleasure Scale (TEPS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Scale for Suicidal Ideation (SSI) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Alcohol Urge Questionnaire (AUQ) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Obsessive Compulsive Drinking Scale (OCDS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Brief Psychiatric Rating Scale (BPRS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Visual Analog Scale (VAS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- Clinical Global Impression/Severity (CGI) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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).
- Modified Version of the NIMH Data Safety Event Codes (NIMH-DSEC) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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.
- The Positive and Negative Affect Schedule (PANAS) [ Time Frame: Pre-ketamine (baseline) to one week post-ketamine infusion ]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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02122562
|Contact: Sage M Comstock, M.A.||(319)-firstname.lastname@example.org|
|Contact: Mark J Niciu, M.D. Ph.D.||(319)-email@example.com|
|Principal Investigator:||Mark J Niciu, M.D. Ph.D.||University of Iowa Health Care (UIHC)|