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

Primary Purpose

Impulsive Behavior

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Tolcapone
Placebo
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Impulsive Behavior

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • University of California, Berkeley
  • UCSF: Ernest Gallo Clinic and Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tolcapone

Placebo

Arm Description

Drug: Tolcapone 200mg (single dose) administered at study visit

Drug: Placebo for tolcapone administered at study visit

Outcomes

Primary Outcome Measures

Correlation Between the Impulsive Choice Ratio and Baseline Impulsivity, as Measured With the Barratt Impulsiveness Scale
The presented value represents a correlation. Subjects completed a delay discounting task while functional MRI images were obtained. In this task, subjects made hypothetical choices between a smaller amount of money available sooner, and a larger amount of money available later. Performance on the delay discounting task, as assessed by the impulsive choice ratio, was determined for both the tolcapone and placebo sessions, and the difference between them (tolcapone minus placebo) was calculated. This difference value was then correlated with baseline scores on the Barratt Impulsiveness Scale.

Secondary Outcome Measures

Full Information

First Posted
July 7, 2010
Last Updated
November 18, 2020
Sponsor
University of California, San Francisco
Collaborators
University of California, Berkeley, United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT01158950
Brief Title
A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors
Official Title
A Randomized, Double-Blind Study of Neural Circuit Responses to COMT Inhibitors
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
March 2010 (Actual)
Primary Completion Date
December 2018 (Actual)
Study Completion Date
December 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
University of California, Berkeley, United States Department of Defense

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
In this study, we seek to understand the effects of tolcapone, an FDA-approved COMT inhibitor, 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Impulsive Behavior

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tolcapone
Arm Type
Experimental
Arm Description
Drug: Tolcapone 200mg (single dose) administered at study visit
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Drug: Placebo for tolcapone administered at study visit
Intervention Type
Drug
Intervention Name(s)
Tolcapone
Other Intervention Name(s)
Tasmar
Intervention Description
Drug: Tolcapone 200mg (single dose) administered at study visit
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo (200mg) administered at study visit
Primary Outcome Measure Information:
Title
Correlation Between the Impulsive Choice Ratio and Baseline Impulsivity, as Measured With the Barratt Impulsiveness Scale
Description
The presented value represents a correlation. Subjects completed a delay discounting task while functional MRI images were obtained. In this task, subjects made hypothetical choices between a smaller amount of money available sooner, and a larger amount of money available later. Performance on the delay discounting task, as assessed by the impulsive choice ratio, was determined for both the tolcapone and placebo sessions, and the difference between them (tolcapone minus placebo) was calculated. This difference value was then correlated with baseline scores on the Barratt Impulsiveness Scale.
Time Frame
120 minutes after drug ingestion
Other Pre-specified Outcome Measures:
Title
Correlation Between the Difference in ICR (Tolcapone Minus Placebo) and the Difference in Blood Oxygen Level Dependent (BOLD) Signal in the Brain (Tolcapone Minus Placebo)
Description
The presented value represents a correlation. The difference in performance on the delay discounting task was calculated as the change in ICR (tolcapone minus placebo). In addition, the difference in BOLD activity throughout the brain was determined (tolcapone minus placebo).
Time Frame
120 minutes after drug ingestion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Howard Fields, MD, PhD
Organizational Affiliation
UCSF: Ernest Gallo Clinic and Research Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jennifer Mitchell, PhD
Organizational Affiliation
UCSF: Ernest Gallo Clinic and Research
Official's Role
Study Director
Facility Information:
Facility Name
University of California, Berkeley
City
Berkeley
State/Province
California
ZIP/Postal Code
94704
Country
United States
Facility Name
UCSF: Ernest Gallo Clinic and Research Center
City
Emeryville
State/Province
California
ZIP/Postal Code
94591
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22764248
Citation
Kayser AS, Allen DC, Navarro-Cebrian A, Mitchell JM, Fields HL. Dopamine, corticostriatal connectivity, and intertemporal choice. J Neurosci. 2012 Jul 4;32(27):9402-9. doi: 10.1523/JNEUROSCI.1180-12.2012.
Results Reference
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A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors

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