Characterization of [11C]Flumazenil to Image GABA Transmission in Healthy Adult Subjects and Subjects With Alcohol Dependence

Background:

- This study is being done to examine the role of a chemical GABA in the brain of alcohol dependent patients. GABA is the chief inhibitory neurotransmitter in the central nervous system. It helps induce relaxation and sleep and balances the brain by inhibiting over-excitation. Several studies have reported that anxiety disorders such as panic attacks, seizure disorders, and numerous other conditions including addiction, are all related to low GABA activity. Therefore, we will examine differences in GABA levels between healthy controls and subjects with alcohol addiction. Studies such as this are important to the understanding of the role of GABA in alcohol addiction.

Study Overview

• Status: Completed
• Conditions: Alcoholism
• Intervention / Treatment: Radiation: [11C]flumazenil; Drug: Tiagabine

Detailed Description

Objectives:

- By comparing the two PET scans (before and after tiagabine) done in the same day, we can understand more about how much GABA your brain makes and about the activity of your GABA receptors in the brain.

Eligibility:

- Individuals 18-45 years of age who are heavy drinkers or healthy controls.

Design:

• Procedures to determine if you are eligible to take part in a research study are called "screening procedures". This will require you to come to the investigators office for approximately ½ day. For this research study, the screening procedures include comprehensive psychiatric and medical evaluations. Participants be asked to abstain from drugs and alcohol for the duration of the study and will be required to make trips several times a week for two weeks to provide clean urine samples.
• During one of the visits prior to the PET scans, participants will have a magnetic resonance image (MRI) taken of their brain.
• We will be using a technology called Positron Emission Tomography (PET), which is a method used to take pictures of the body, in this case, the brain. We will be injecting you with a radiotracer called [11C]flumazenil. A radiotracer is a small amount of a drug with radioactivity attached. Because the radiotracer temporarily sticks to the GABA receptors in the brain, the PET scan can then measure the activity at GABA receptors by measuring the amount of the radiotracer. You will undergo two PET scans with [11C]flumazenil on one day for this study. After the first PET scan, you will be given an oral dose of tiagabine (Gabitril®), which is a medication approved for the treatment of seizure disorder. Tiagabine raises levels of GABA in the brain. It is used in this study so that we can measure the changes in GABA levels. Blood samples will be drawn during the PET scans.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Healthy Control Subjects:

1. Males or Females 18-45
2. Absence of present or past psychiatric conditions (including alcohol or drug dependence)
3. A negative urine drug screen
4. Medically Healthy

Subjects with alcohol dependence:

1. Males or Females 18-45
2. Fulfill DSM-IV Diagnosis for Alcohol Dependence
3. Negative Urine Drug Screen
4. Negative Urine ETG/ETS
5. Medically Healthy
6. Abstinent from alcohol for a minimum of 1 month prior to scanning procedures

Exclusion Criteria:

Healthy Control Subjects:

1. Pregnancy or lactation, lack of effective birth control during 15 days before the scans
2. Presence or positive history of serious medical or neurological illness, including low hemoglobin.
3. Any use (within recent past 6 weeks) of amphetamines, opiates, cocaine, ecstasy PCP.
4. Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan (but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant. Dental fillings do not present a risk for MRI), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists.
5. Currently employed as radiation worker; or participation in radioactive drug research protocols within the previous year such that the total cumulative annual radiation dose (i.e., from participation in the previous research studies and this study) would exceed the radiation dose limits specified in the FDA regulations at 21 CFR 361.1, Radioactive Drugs Considered Generally Safe and Effective (i.e. annual cumulative radiation dose limit = 5 rems to gonads, blood-forming organs, lens of eye, whole body; 15 rems to other organs).
6. Subjects with known hypersensitivity to flumazenil or benzodiazepines; subjects who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus or in patient who are showing signs of serious cyclic antidepressant overdose)

Subjects with alcohol dependence:

1. Pregnancy or lactation, lack of effective birth control during 15 days before the scans
2. Presence or positive history of serious medical or neurological illness or any cardiovascular disease, low hemoglobin
3. Any other current major axis I psychiatric diagnosis except alcohol dependence (subjects with nicotine dependence will not be excluded)
4. Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan (but not limited to, those with a pacemaker, presence of metallic fragments near the eyes or spinal cord, or cochlear implant. Dental fillings do not present a risk for MRI), as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists.
5. Currently employed as radiation worker; or participation in radioactive drug research protocols within the previous year such that the total cumulative annual radiation dose (i.e., from participation in the previous research studies and this study) would exceed the radiation dose limits specified in the FDA regulations at 21 CFR 361.1, Radioactive Drugs Considered Generally Safe and Effective (i.e. annual cumulative radiation dose limit = 5 rems to gonads, blood-forming organs, lens of eye, whole body; 15 rems to other organs).
6. Subjects with known hypersensitivity to flumazenil or benzodiazepines; subjects who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus or in patient who are showing signs of serious cyclic antidepressant overdose)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PET scans; Both alcoholics and healthy controls will undergo two [11C]flumazenil PET scans: one at baseline and one post administration of 0.2 mg/kg Tiagabine.	Radiation: [11C]flumazenil; [11C]flumazenil is a radiotracer used to measure levels of the neurotransmitter GABA in the human brain.; Drug: Tiagabine; Tiagabine raises levels of GABA in the brain. It is used in this study so that we can measure the changes in GABA levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To measure changes in [11C]flumazenil binding in the brain using PET scans		Day 1: baseline PET scan and a follow-up PET scan 0.5 hours post administration of Tiagabine
Tiagabine induced change in [C-11]flumazenil distribution volume (VT)	Refer to for consensus nomenclature J Cereb Blood Flow Metab. 2007 Sep;27(9):1533-9. Epub 2007 May 9.	1 hour

Collaborators and Investigators

• Sponsor: Rajesh Narendran
• Investigators: Principal Investigator: Rajesh Narendran, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Lingford-Hughes AR, Wilson SJ, Cunningham VJ, Feeney A, Stevenson B, Brooks DJ, Nutt DJ. GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology (Berl). 2005 Aug;180(4):595-606. doi: 10.1007/s00213-005-2271-x. Epub 2005 Apr 28.
• Gilman S, Adams KM, Johnson-Greene D, Koeppe RA, Junck L, Kluin KJ, Martorello S, Heumann M, Hill E. Effects of disulfiram on positron emission tomography and neuropsychological studies in severe chronic alcoholism. Alcohol Clin Exp Res. 1996 Nov;20(8):1456-61. doi: 10.1111/j.1530-0277.1996.tb01149.x.
• Farde L, Pauli S, Litton JE, Halldin C, Neiman J, Sedvall G. PET-determination of benzodiazepine receptor binding in studies on alcoholism. EXS. 1994;71:143-53. doi: 10.1007/978-3-0348-7330-7_15.
• Litton JE, Neiman J, Pauli S, Farde L, Hindmarsh T, Halldin C, Sedvall G. PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls. Psychiatry Res. 1993 Apr;50(1):1-13. doi: 10.1016/0925-4927(93)90019-e.

Helpful Links

• Psychiatric Molecular Imaging Program Addiction Website

Study record dates

Study Major Dates

• Study Start: April 19, 2011
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: July 16, 2013
• First Submitted That Met QC Criteria: July 17, 2013
• First Posted (Estimate): July 22, 2013

Study Record Updates

• Last Update Posted (Actual): August 29, 2017
• Last Update Submitted That Met QC Criteria: August 25, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; GABA Modulators; GABA Agents; Anticonvulsants; Antidotes; GABA Uptake Inhibitors; Flumazenil; Tiagabine
• Other Study ID Numbers: PRO#10100519

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No