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Epi-Genetic Modulators of Fear Extinction in Alcohol Dependence

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ClinicalTrials.gov Identifier: NCT02438969
Recruitment Status : Recruiting
First Posted : May 8, 2015
Last Update Posted : August 8, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Brief Summary:

Background:

- Researchers want to learn if people with alcohol dependence have more difficulty learning to feel calm, or learn to fear things more easily. They also want to study how early life stress (ELS) affects the ability to learn to feel calm.

Objective:

- To see if people with alcohol dependence and/or ELS have a harder time learning to feel calm than people without these. Also, to see if DNA is changed by ELS and if this change affects fear conditioning and extinction.

Eligibility:

  • Adults ages 21-65 with and without an alcohol use disorder (AUD) and with and without ELS.
  • Healthy volunteers.

Design:

  • Participants will be screened with:

    • Medical history
    • Physical exam
    • Blood and urine tests
    • Psychological tests
    • Treatment for symptoms of alcohol withdrawal, if needed
  • Healthy volunteers will have 1 overnight visit (2 days, 1 night). AUD participants will stay at the clinic for about 4 weeks.
  • Participants will:

    • Rate alcohol use/craving, depression, anxiety, and childhood trauma.
    • Have psychophysiological measures: electrodes and mild electric shock.
  • Have a functional magnetic resonance imaging (MRI) scan. Participants will lie on a table in a metal cylinder with a coil over their head. In the first scanning session, they will see pictures, do a simple task, and may get shocks. Participants will also do a second scanning session in which they will perform the aforementioned fear conditioning and extinction task, as well as a facial expression matching task, an affective word processing task, and a task measuring valuation of monetary rewards.

    • Answer questions about their emotions (some participants).
    • Have blood drawn from an arm vein or intravenous (IV) line.
    • AUD participants will get a dexamethasone pill. The next day, they will get a hormone injected in and have blood drawn from an IV line.
  • AUD participants will have 3 follow-up visits with questions and blood and lab tests.

Condition or disease
Fear Stress Alcohol Dependence

Detailed Description:

Objective:

The primary goal of this study is to evaluate the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction.

The central hypothesis is that participants with AUD and ELS will have disrupted fear extinction, and in addition, those with ELS will also have disrupted fear extinction. AUD with ELS will have the most severe disruption of fear extinction as observed clinically in alcoholics with severe trauma - often presenting with the most severe phenotypes and being most treatment resistant. A disruption in fear extinction or living in constant fear after stress/trauma could thus put the individual at risk for AUD.

Identification and characterization of the neurobiological correlates underlying this mechanism is thus essential and could provide new avenues for treatment of AUD; namely developing interventions that normalize abnormal fear extinctions. These interventions could be for example, cognitive-behavior based or molecular by targeting genetic/epigenetic pathways potentially identified.

Our proposal, if successful, will first establish a reliable measureable endophenotype of fear extinction in AUD/ELS, both behaviorally (skin conductance response) and neuronal (using an fMRI paradigm). Furthermore, we will carry out exploratory genetic and epigenetics studies that might influence these measures. This model can then be used in follow up studies for novel therapeutic interventions that could target treatment of these mechanisms in AUD.

Study Population:

The study sample includes two patient groups and two control groups:

  1. treatment-seeking or non-treatment-seeking individuals with AUD and ELS exposure;
  2. treatment-seeking or non-treatment-seeking individuals with AUD without ELS exposure;
  3. healthy volunteers with ELS exposure;
  4. healthy volunteers without ELS exposure.

Target accrual for each of these groups is 25.

Design:

Subjects will be evaluated for fear conditioning and extinction using shock conditioning (extinction procedure combined with fMRI imaging that utilizes galvanic skin response). All participants will undergo whole-genome methylome analyses to assess genome wide methylation patterns. Genotyping of variants in candidate genes implicated in the biology of fear conditioning/extinction will be carried out.

Outcome Parameters:

The primary outcome of interest is fear extinction, measured by fMRI paradigms. Secondary objectives include: (1) explore the role of genetic variants and epigenetic factors and their impact on fear extinction in AUD and healthy controls with or without ELS; (2) explore differences in reward processing and emotion processing, measured by fMRI as a function of AUD, ELS, and (epi)genetic modulators; and (3) examine the relationship between fear extinction and clinical outcomes in both AUD and ELS participants sample.


Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: (Epi)Genetic Modulators of Fear Extinction in Alcohol Dependence
Study Start Date : May 5, 2015
Estimated Primary Completion Date : December 30, 2019
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. The primary objective of the study is to evaluate the role and interaction of epigenetic/genetic factors, ELS exposure, and AUD on neuronal mechanisms of fear conditioning and extinction. [ Time Frame: Ongoing ]

Secondary Outcome Measures :
  1. Explore the genetic variants and epigenetic factors on fear extinction in AUD and non-AUD participants with or without ELS; examine the differences in reward and emotion processing, and neural response to alcohol; and examine the relationship be... [ Time Frame: Ongoing ]


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION AND EXCLUSION CRITERIA:

Inclusion and exclusion criteria will be evaluated following screening conducted under the NIAAA screening protocols (98-AA-009 and/or 14-AA-0181).

INCLUSION CRITERIA:

INCLUSION CRITERIA FOR AUD GROUP:

  • Between 21 and 65 years of age
  • Ability to provide written informed consent as determined by successful completion of consent quiz prior to signing consent
  • Females: Negative urine pregnancy test, not currently breastfeeding, agree to abstain or use accepted form of contraception
  • Diagnosed with current alcohol dependence according to Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM IV)
  • Alcohol consumption within the past month provided by self-report
  • Specify alcohol as their preferred drug in a clinical interview
  • 98-AA-0009 and/or 14-AA-0181 screening consents signed
  • Cleared venous access assessment
  • Additional inclusion criteria for non-treatment seeking AUD: Able and willing to abstain from consuming alcohol 1 day prior to each study visit

INCLUSION CRITERIA FOR NON-AUD (HEALTHY VOLUNTEER) GROUP:

  • Between 21 and 65 years of age
  • Ability to provide written informed consent as determined by successful completion of consent quiz prior to signing consent
  • Females: Negative urine pregnancy test, not currently breastfeeding, agree to abstain or use accepted form of contraception
  • 98-AA-0009 and/or 14-AA-0181 screening consents signed
  • Cleared venous access assessment

EXCLUSION CRITERIA:

EXCLUSION CRITERIA FOR AUD GROUP:

  • Neurological symptoms of the wrist or arm, e.g., carpal tunnel syndrome, as determined by history and physical exam
  • Chronic use of psychotropic medications within four weeks of the study, with the exception of fluoxetine, for which the exclusionary time period is six weeks. Incidental use of psychotropic medications is allowed, but any use must be discontinued prior to the study for a time period exceeding 5 half-lives of the medication in question.
  • Presence of any current or past DSM IV diagnosis of bipolar disorder, or psychotic disorder (e.g, schizophrenia, schizoaffective disorder), or current substance dependence other than alcohol, nicotine, or caffeine.
  • Major medical problems (e.g., central nervous system (CNS), cardiovascular, respiratory, gastrointestinal (GI), hepatic, renal, endocrine, HIV, reproductive) that in the judgment of the PI, in consultation with relevant Clinical Center consult services, cannot be adequately managed at the Clinical Center.
  • Presence of ferromagnetic objects in the body, fear of enclosed spaces, or other standard contraindication to MRI, as determined by self-report
  • Left-handedness
  • Use of intrauterine device (IUD)
  • Excluded from the optional DEX-CRH test if:

    • Allergy to dexamethasone or CRH
    • Use of medications that can affect the results of the test, including certain antibiotics, anti-seizure drugs, corticosteroids, and hormonal contraception
  • Additional exclusionary criteria for non-treatment seeking AUD:

    • Presence of significant alcohol withdrawal symptoms, defined as a CIWA-Ar > 8.
    • History of epilepsy or alcohol-related seizures.
    • Are currently seeking treatment for alcohol problems

EXCLUSION CRITERIA FOR NON-AUD (HEALTHY VOLUNTEER) GROUP:

  • Neurological symptoms of the wrist or arm, e.g., carpal tunnel syndrome, as determined by history and physical exam.
  • Chronic use of psychotropic medications within four weeks of the study, with the exception of fluoxetine, for which the exclusionary time period is six weeks. Incidental use of psychotropic medications is allowed, but any use must be discontinued prior to the study for a time period exceeding 5 half-lives of the medication in question.
  • Presence of any current or past DSM IV diagnosis of bipolar disorder, or psychotic disorder (e.g, schizophrenia, schizoaffective disorder), or substance dependence other than nicotine, or caffeine.
  • Major medical problems (e.g., CNS, cardiovascular, respiratory, GI, hepatic, renal, endocrine, HIV, reproductive) that in the judgment of the PI, in consultation with relevant Clinical Center consult services, cannot be adequately managed at the Clinical Center
  • Presence of ferromagnetic objects in the body, fear of enclosed spaces, or other standard contraindication to MRI, as determined by self-report
  • Current or past DSM IV diagnosis of alcohol dependence or abuse
  • Currently seeking treatment for alcohol problems as assessed by self-report
  • Positive urine drug test at screening (for opiates, cannabinoids, amphetamines, cocaine, benzodiazepines)
  • Positive breathalyzer test at screening
  • Alcohol abstainer (never consumed alcohol in entire life)
  • Left-handedness
  • Use of intrauterine device (IUD)

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): NCT02438969


Contacts
Contact: Falk W Lohoff, M.D. (301) 827-1542 falk.lohoff@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 Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
Principal Investigator: Falk W Lohoff, M.D. National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Additional Information:
Publications:
Responsible Party: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ClinicalTrials.gov Identifier: NCT02438969     History of Changes
Other Study ID Numbers: 150127
15-AA-0127
First Posted: May 8, 2015    Key Record Dates
Last Update Posted: August 8, 2018
Last Verified: April 27, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) ):
Alcohol
Alcohol Dependence
Stress
Fear Conditioning

Additional relevant MeSH terms:
Alcoholism
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Ethanol
Anti-Infective Agents, Local
Anti-Infective Agents
Central Nervous System Depressants
Physiological Effects of Drugs