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Functional Neuroimaging of Alcoholism Vulnerability (PIT) (CTNA)

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ClinicalTrials.gov Identifier: NCT01585168
Recruitment Status : Completed
First Posted : April 25, 2012
Results First Posted : May 25, 2018
Last Update Posted : May 25, 2018
Sponsor:
Information provided by (Responsible Party):
Yale University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Healthy Drug: Memantine Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: All subjects received both the study drug and placebo. Family history was the main variable of interest, and randomization was stratified by this variable.
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Functional Neuroimaging of Alcoholism Vulnerability: Glutamate, Reward, Impulsivity and Pavlovian-to-Instrumental Transfer (PIT)
Study Start Date : December 2011
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Family history positive, Memantine first, then placebo
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.
Drug: Memantine
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.

Drug: Placebo
Identically appearing sugar pill, given orally

Placebo Comparator: Family history positive, placebo first, then Memantine
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.
Drug: Memantine
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.

Drug: Placebo
Identically appearing sugar pill, given orally

Experimental: Family history negative, Memantine first, then placebo
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.
Drug: Memantine
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.

Drug: Placebo
Identically appearing sugar pill, given orally

Placebo Comparator: Family history negative, placebo first, then Memantine
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.
Drug: Memantine
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.

Drug: Placebo
Identically appearing sugar pill, given orally




Primary Outcome Measures :
  1. Change in Blood Oxygenation Level Dependent (BOLD) Activation in the Amygdala During "Win" Monetary Incentive Delay (MID) Task Between Placebo and Study Medication [ Time Frame: 4 hours post intervention on each study day, separated by 1 week to 1 month ]
    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.

  2. 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 [ Time Frame: 4 hours post intervention on each study day, separated by 1 week to 1 month ]
    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.


Secondary Outcome Measures :
  1. Change in Impulsive Behavior as Measured on the Balloon Analog Risk Task (BART) Computerized Task Between Placebo and Study Medication [ Time Frame: 3 hours post intervention on each study day, separated by 1 week to 1 month ]
    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.

  2. Change in Impulsive Behavior as Measured on the Experimental Discounting Delay (EDT) Computerized Task Between Placebo and Study Medication [ Time Frame: 3 hours post intervention on each study day, separated by 1 week to 1 month ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Biological father with a history of Alcoholism
  • A least 1 other first- or second-degree relative with a history of Alcoholism.

Exclusion Criteria:

  • Cannot be an only child
  • A diagnosis of DSM-IV-TR Axis I psychotic disorders screened with the Mini International Neuropsychiatric Interview (MINI), done in the BARCS study (with the exception of Alcohol Abuse)
  • Report of psychotic disorder in a 1º relative
  • Prenatal exposure to alcohol (mother reported to drink 3 or more drinks on an occasion or more than 3 times per month during pregnancy
  • Not speaking English fluently or being a non-native English speaker, or being educated in a primary language other than English >grade 1
  • Mental retardation (Full Scale IQ<70)
  • Traumatic brain injury with loss of consciousness > 30 minutes or concussion in last 30 days
  • Presence or history of any medical/neurologic illness that may affect brain physiology (e.g., epilepsy, Multiple Sclerosis), including focal brain lesion seen on structural MRI (all structural scans are read by a licensed radiologist)
  • Current pregnancy (all females will be tested with urine screens on the day of MRI)
  • Any positive alcohol screen will result in exclusion
  • Inability to comprehend the consent form appropriately
  • Other specific fMRI exclusions include metal devices, clips or fragments in body (orbital x-ray performed if needed)
  • Female participants under 125 pounds will be excluded from participating due to the strength and side effects in this segment of the population.

Information from the National Library of Medicine

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): NCT01585168


Locations
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United States, Connecticut
Olin Neuropsychiatry Research Center at the Institute of Living, Hartford Hospital
Hartford, Connecticut, United States, 06106
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Godfrey D Pearlson, MD Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT01585168     History of Changes
Other Study ID Numbers: 1106008650
First Posted: April 25, 2012    Key Record Dates
Results First Posted: May 25, 2018
Last Update Posted: May 25, 2018
Last Verified: April 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yale University:
Reward Circuitry
Impulsivity
Family History of Alcoholism
NMDA/DA Interactions

Additional relevant MeSH terms:
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Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Memantine
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents