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This project compares Family History Positive (FHP) for alcoholism subjects to matched Family History Negative (FHN) subjects derived from the project Principal Investigator's National Institute on Alcohol Abuse and Alcoholism-funded longitudinal study of drinking behavior in a 2000 college freshman population (known as the Brain and Alcohol Research in College Students study (BARCS)). The age of these subjects is a valuable one at which to capture the transition from harmful use to abuse/dependence. This project explores the effects of memantine in a double-blind, randomized, counterbalanced manner on alcoholism risk-relevant tasks. More specifically, this project studies functional MRI tasks related to different aspects of reward and/or impulsivity-related behavior in different contexts, compares the underlying neural circuitry across tasks, and uses a pharmacologic probe of the glutamatergic system to examine NMDA/DA interactions. The combined measures provide the opportunity to advance our understanding of specific aspects of brain function related to familial alcoholism vulnerability in an already well-characterized population as some members evolve into alcohol abuse. In addition to conventional within-task analyses, functional network connectivity and allied approaches will be used to examine brain networks across tasks.
The investigators will study adult male and female subjects in equal numbers who are either offspring of an alcoholic parent or are FHN matched controls. The investigators will recruit and assess a total of 84 (42 FHP and 42 matched FHN) subjects between the ages of 18-21 years on initial BARCS contact. The investigators will use 4 cognitive tasks during the functional MRI (fMRI) which include: 1) a Monetary Incentive Delay Task that distinguishes networks engaged in motivational (anticipation) and consummatory (outcome) components of reward processing; 2) a Go/No-Go Task that measures the ability to inhibit response to a pre-potent stimulus; 3) an Alcohol Cue Reactivity Task that examines Nucleus Accumbens response to alcohol-related versus matched soft drink stimuli; and 4) a Pavlovian-to-Instrumental Transfer (PIT) Task that dissects a component of the Monetary Incentive Delay (MID) Task, and provides an imaging assay of a transfer-like process that can be related to real-world drinking behavior, thus informing upon and extending the key findings from CTNA-2.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Family history positive, Memantine first, then placebo | Experimental | Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered. |
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| Family history positive, placebo first, then Memantine | Placebo Comparator | Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered. |
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| Family history negative, Memantine first, then placebo | Experimental | Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered. |
|
| Family history negative, placebo first, then Memantine | Placebo Comparator | Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Memantine | Drug | Memantine is a low-side-effect NMDA receptor antagonist usually administered therapeutically to elderly persons with moderately severe Alzheimer's disease in typical doses of 10-20 mg daily. In this study, single doses of 40 mg are administered. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During "Win" Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner. | 4 hours post intervention on each study day, separated by 1 week to 1 month |
| Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During "Loss" Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner. | 4 hours post intervention on each study day, separated by 1 week to 1 month |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | All participants completed the BART task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. BART is a computer decision-making task that measures risk taking. Participants are presented with a series of "balloons." The object is to earn as much money as possible by pumping the balloon without popping it. The point of explosion varies from trial to trial and costs participants the money they have earned in that trial. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Godfrey D Pearlson, MD | Yale University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Olin Neuropsychiatry Research Center at the Institute of Living, Hartford Hospital | Hartford | Connecticut | 06106 | United States |
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82 participants were screened for eligibility and then were consented at the Olin Research Center. However, after consent and prior to group randomization, 11 participants were excluded from the study due to follow-up eligibility paperwork (i.e. psychiatric interview, family history review, etc.) for a total of 71 randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | Family History Negative (FHN): Memantine, Then Placebo | Participants received 2-20mg tablets of Memantine on the morning of the first study visit, then received 2 matching placebo tablets on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Negative (FHN): People who have no affected first- or second-degree relatives. |
| FG001 | Family History Negative (FHN): Placebo, Then Memantine | Participants received 2 matching placebo tablets on the morning of the first study visit, then received 2-20mg tablets of Memantine on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Negative (FHN): People who have no affected first- or second-degree relatives. |
| FG002 | Family History Positive (FHP): Memantine, Then Placebo | Participants received 2-20mg tablets of Memantine on the morning of the first study visit, then received 2 matching placebo tablets on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. |
| FG003 | Family History Positive (FHP): Placebo, Then Memantine | Participants received 2 matching placebo tablets on the morning of the first study visit, then received 2-20mg tablets of Memantine on the morning of the second study visit. Visits were approximately 1 week to 1 month a part on average. Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Family History Positive (FHP) | People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. |
| BG001 | Family History Negative (FHN) |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During "Win" Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner. | The number of subjects analyzed differs from the overall number of subjects because analyses for this measure occurred about 48 months into recruitment. | Posted | Mean | Standard Deviation | voxel wise BOLD signal | 4 hours post intervention on each study day, separated by 1 week to 1 month |
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AE data were collected over the duration of the study (4 years).
All AE information that were collected were expected side effects of the study medication.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Family History Positive (FHP) | People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Godfrey Pearlson | Yale University | (860) 545-7757 | Godfrey.Pearlson@hhchealth.org |
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| ID | Term |
|---|---|
| D007175 | Impulsive Behavior |
| ID | Term |
|---|---|
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D008559 | Memantine |
| ID | Term |
|---|---|
| D000547 | Amantadine |
| D000218 | Adamantane |
| D001952 | Bridged-Ring Compounds |
| D006844 | Hydrocarbons, Cyclic |
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All subjects received both the study drug and placebo. Family history was the main variable of interest, and randomization was stratified by this variable.
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| Placebo | Drug | Identically appearing sugar pill, given orally |
|
| 3 hours post intervention on each study day, separated by 1 week to 1 month |
| Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | All participants completed the EDT task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. EDT is a delay-discounting task that exposes participants to choice consequences during test administration. The EDT involves multiple blocks of choices, one for each delay. Choices are made between a standard amount that is delivered immediately and is certain and a probable amount that is delayed and uncertain. | 3 hours post intervention on each study day, separated by 1 week to 1 month |
People who have no affected first- or second-degree relatives.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | The number of participants analyzed is different from the overall baseline participants because a total of 6 participants (2 FHP, 4 FHN) did not complete both of the interventions (memantine, placebo) due to lost to follow-up. | Mean | Full Range | years |
|
| Sex: Female, Male | The number of participants analyzed is different from the overall baseline participants because a total of 6 participants (2 FHP, 4 FHN) did not complete both of the interventions (memantine, placebo) due to lost to follow-up. | Count of Participants | Participants |
|
| Region of Enrollment | The number of participants analyzed is different from the overall baseline participants because a total of 6 participants (2 FHP, 4 FHN) did not complete both of the interventions (memantine, placebo) due to lost to follow-up. | Number | participants |
|
Family History Negative (FHN): People who have no affected first- or second-degree relatives. |
| OG001 | FHN - Placebo | Family History Negative (FHN): People who have no affected first- or second-degree relatives. |
| OG002 | FHP - Memantine | Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. |
| OG003 | FHP - Placebo | Family History Positive (FHP): People who have a biological father with alcoholism and at least one other first- or second-degree relative with alcoholism. |
|
|
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| Secondary | Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication | All participants completed the BART task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. BART is a computer decision-making task that measures risk taking. Participants are presented with a series of "balloons." The object is to earn as much money as possible by pumping the balloon without popping it. The point of explosion varies from trial to trial and costs participants the money they have earned in that trial. | Participants with a family history of alcoholism (family history positive) and without a history of alcoholism (family history negative) who completed BART task. | Posted | Mean | Standard Deviation | total pumps | 3 hours post intervention on each study day, separated by 1 week to 1 month |
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| Secondary | Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication | All participants completed the EDT task approximately 3 hours post drug administration on both study visits. Study days were approximately 1 week to 1 month a part. EDT is a delay-discounting task that exposes participants to choice consequences during test administration. The EDT involves multiple blocks of choices, one for each delay. Choices are made between a standard amount that is delivered immediately and is certain and a probable amount that is delayed and uncertain. | Posted | Mean | Standard Deviation | responses | 3 hours post intervention on each study day, separated by 1 week to 1 month |
|
|
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| Primary | Change in Blood Oxygenation Level Dependent (BOLD) Activation in Anterior Cingulate Cortex During "Loss" Condition of Monetary Incentive Delay (MID) Task Between Placebo and Study Medication | All participants completed the fMRI Monetary Incentive Delay task on each study day. During the task, participants needed to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI. Participant's BOLD activation response (A measurement of oxygen level that is released to neurons since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen to perform the tasks.) was measured while they performed the task in MRI scanner. | The number of subjects analyzed differs from the overall number of subjects because analyses for this measure occurred about 48 months into recruitment. | Posted | Mean | Standard Deviation | voxel wise BOLD signal | 4 hours post intervention on each study day, separated by 1 week to 1 month |
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| 0 |
| 35 |
| 0 |
| 35 |
| 24 |
| 35 |
| EG001 | Family History Negative (FHN) | People who have no affected first- or second-degree relatives. | 0 | 36 | 0 | 36 | 26 | 36 |
| Lightheaded | General disorders | Systematic Assessment |
|
| "Drunk" or "Tipsy" | General disorders | Systematic Assessment | Study intervention did not involve use of alcohol, however one common side effect of the study medication includes feeling "drunk." |
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| Nausea | General disorders | Systematic Assessment |
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| Vomit | General disorders | Systematic Assessment |
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| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| # of times "immediate" pressed in Delay Condition |
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| # of times "delayed" pressed in Immediate Cond. |
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| # of times "immediate" pressed in Immediate Cond. |
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| t-test, 2 sided |
| 0.009 |
| Median Difference (Net) |
| 1.8348 |
| 2-Sided |
| Other |