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

Information source: University of California, San Francisco
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Impulsive Behavior

Intervention: Tolcapone (Drug); Placebo (Other); Entacapone (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: University of California, San Francisco

Official(s) and/or principal investigator(s):
Howard Fields, MD, PhD, Principal Investigator, Affiliation: UCSF: Ernest Gallo Clinic and Research Center
Jennifer Mitchell, PhD, Study Director, Affiliation: UCSF: Ernest Gallo Clinic and Research

Overall contact:
Jennifer Mitchell, PhD, Phone: 510-985-3921, Email: jmitchell@gallo.ucsf.edu

Summary

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.

Clinical Details

Official title: A Randomized, Double-Blind Study of Neural Circuit Responses to COMT Inhibitors

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Primary outcome: 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.

Secondary outcome: 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.

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

Minimum age: 18 Years. Maximum age: 50 Years. Gender(s): Both.

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.

Locations and Contacts

Jennifer Mitchell, PhD, Phone: 510-985-3921, Email: jmitchell@gallo.ucsf.edu

University of California, Berkeley, Berkeley, California 94704, United States; Recruiting
Jennifer Mitchell, PhD, Phone: 510-985-3921, Email: jmitchell@gallo.ucsf.edu
Dawn Weinstein, MS, NP, Phone: 510-985-3522, Email: dweinstein@gallo.ucsf.edu

UCSF: Ernest Gallo Clinic and Research Center, Emeryville, California 94591, United States; Recruiting
Jennifer Mitchell, PhD, Phone: 510-985-3921, Email: jmitchell@gallo.ucsf.edu
Dawn Weinstein, MS, NP, Phone: 510-985-3522, Email: dweinstein@gallo.ucsf.edu

Additional Information

Starting date: March 2010
Last updated: August 15, 2014

Page last updated: August 23, 2015

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