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A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors

This study is currently recruiting participants.
Verified January 2013 by University of California, San Francisco
Sponsor:
Collaborators:
University of California, Berkeley
Department of Defense
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01158950
First received: July 7, 2010
Last updated: January 2, 2013
Last verified: January 2013
History of Changes
  Purpose

In this study, we seek to understand the effects of tolcapone and entacapone, FDA-approved COMT inhibitors, on reward choice and response inhibition, two measures we have previously shown to be altered in subjects with alcoholism. We now plan to test the hypothesis that COMT regulation of cortical dopamine levels is critical for regulation financial choices. Specifically, we propose that the lower levels of cortical dopamine present in individuals with the val158val COMT genotype reduces the inhibitory effect of frontal cortical areas on impulsive choice; an idea that extends previous hypotheses about the negative consequences of decreased prefrontal dopamine levels on inhibitory control. Moreover, this hypothesis suggests that inhibiting COMT may slow the degradation of dopamine and thereby decrease impulsivity.


Condition Intervention
Impulsive Behavior
 Drug: Tolcapone
Other: Placebo
Drug: Entacapone

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: A Randomized, Double-Blind Study of Neural Circuit Responses to COMT Inhibitors

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Behavioral tasks such as the delay discounting task, primary data, including the identity of each response and the associated reaction time will be stored and analyzed. [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Resting-state and task active fMRI data will be processed off-line using SPM2 and SPM5 software according to standard procedures for image slice-timing correction, realignment, normalization and smoothing. The functional data will be analyzed. [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: March 2010
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tolcapone
Drug: Tolcapone 200mg (single dose) administered at study visit
 Drug: Tolcapone
Drug: Tolcapone 200mg (single dose) administered at study visit
Other Name: Tasmar
Placebo Comparator: Placebo
Drug: Placebo for tolcapone administered at study visit
 Other: Placebo
Placebo (200mg) administered at study visit
Other Name: Placebo
Experimental: Entacapone
Drug: Entacapone 200mg (single dose) administered at study visit
 Drug: Entacapone
Entacapone 200mg (single dose) administered at study visit
Other Name: Comtan

Detailed Description:

Drug consumption despite adverse consequences is a defining feature of human addiction (DSM-IV-TR, 2004). Impulsivity, a tendency to choose an immediate action despite delayed adverse consequences, is a major risk factor for tobacco, psychostimulant, opioid and alcohol abuse. In humans, impulsivity can be quantified by presenting subjects with a choice between a small immediate monetary reward or a larger but delayed reward. We recently found that the val158val allele for the enzyme catechol-O-methyltransferase (COMT), which is associated with more rapid cortical dopamine catabolism and thus lower cortical dopamine levels correlates with greater impulsivity and greater fMRI blood oxygen level dependent (BOLD) signal in dorsolateral prefrontal and posterior parietal cortices.

The first phase of the study will involve healthy controls. The second phase of the study will involve abstinent alcoholics matched for age, education, and gender. Subjects will range in age between 18 and 50 years old.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age between 18 and 50 years.
  • Subject is right-handed.
  • If female, subject is non-lactating, not pregnant, and using a reliable contraception method (i.e. abstinence, intrauterine device (IUD), hormonal birth control or barrier method).
  • Subject is able to read and speak English.
  • Subject is a high school graduate.
  • Subject is able and willing to provide written and informed consent.
  • Subject is able to understand and follow the instructions of the investigator, and understand all ratings scales.
  • Subject is in good health.

Exclusion Criteria:

  • Using cocaine, stimulants (other than THC, nicotine, & caffeine)amphetamines, hallucinogens, "ecstasy", opiates, sedatives, pain pills, sleeping pills or other psychoactive drugs within two weeks of the start of the study OR more than 10 times in the last year.
  • Has a current dependence on, or addiction to any psychoactive drug (except nicotine or caffeine) including alcohol.
  • Clinically significant medical or psychiatric illness requiring treatment as determined by screening blood tests, medical history, and physical exam performed or reviewed by the study physician.
  • Subject has a history of major alcohol related complications within the proceeding 2 years (liver failure/cirrhosis, pancreatitis, esophageal varices, etc.)
  • Liver function test ≥ 3 times normal upper limit.
  • BAC level > 0.05% at the beginning of screening visit (within margin of error of detection).
  • Has a neurological dysfunction or psychiatric disorder.
  • Has severe low blood pressure.
  • Has uncontrolled high blood pressure.
  • Regular use of any of the drugs on the tolcapone or entacapone contraindications list OR within 2 weeks of drug administration.
  • Regular use of SSRIs.
  • Has an allergy or intolerance to tolcapone or entacapone.
  • Subject has received an investigational drug within 30 days of screening visit.
  • Subject is considered unsuitable for the study in the opinion of the investigator or study physician for any other reason.

MRI Exclusion Criteria:

  • The subject has metal (metal plates, pins, wires or screws, artificial limb, joint replacement or anything that might have been inserted during an operation) in his/her body.
  • Subject has a pacemaker, defibrillator, stent, or any metal implants related to heart/blood flow problems.
  • Subject has worked with metals (ie. metallurgy, metal shaving, welding, soldering, etc).
  • Subject has been wounded with anything metal (bullet, shrapnel or metal filling).
  • Has ever gotten a piece of metal in the eye.
  • Has tattoos done with ink containing metal or permanent eyeliner.
  • Wears color contact lenses.
  • Has a hearing problem or hearing aid, cochlear implant or past ear surgery.
  • Has any irremovable dental bridges, dental plates, metal caps or any other non-removable metal in the mouth.
  • The subject is claustrophobic.
  • The subject is pregnant. (women only)
  • Has a IUD. (women only)
  • Significantly overweight.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01158950

Contacts
Contact: Jennifer Mitchell, PhD 510-985-3921 jmitchell@gallo.ucsf.edu
Contact: Dawn Weinstein, MS, NP 510-985-3522 dweinstein@gallo.ucsf.edu

Locations
United States, California
University of California, Berkeley Recruiting
Berkeley, California, United States, 94704
Contact: Jennifer Mitchell, PhD     510-985-3921     jmitchell@gallo.ucsf.edu    
Contact: Dawn Weinstein, MS, NP     510-985-3522     dweinstein@gallo.ucsf.edu    
UCSF: Ernest Gallo Clinic and Research Center Recruiting
Emeryville, California, United States, 94591
Contact: Jennifer Mitchell, PhD     510-985-3921     jmitchell@gallo.ucsf.edu    
Contact: Dawn Weinstein, MS, NP     510-985-3522     dweinstein@gallo.ucsf.edu    
Sponsors and Collaborators
University of California, San Francisco
University of California, Berkeley
Department of Defense
Investigators
Principal Investigator: Howard Fields, MD, PhD UCSF: Ernest Gallo Clinic and Research Center
Study Director: Jennifer Mitchell, PhD UCSF: Ernest Gallo Clinic and Research
  More Information

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01158950     History of Changes
Other Study ID Numbers: 2009-12-461, W81XWH-10-1-0231
Study First Received: July 7, 2010
Last Updated: January 2, 2013
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Impulsive Behavior
Tolcapone
Entacapone
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
 Pharmacologic Actions
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 19, 2013