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

Impulsive Behavior Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01158950
• Other study ID #: 2009-12-461
• Secondary ID: W81XWH-10-1-0231
• Status: Completed
• Phase: N/A
• Start date: March 2010
• Est. completion date: December 2018

Study information

• Verified date: November 2020
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Impulsive Behavior

Intervention

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

Other:
• Placebo
Placebo (200mg) administered at study visit

Locations

Country	Name	City	State
United States	University of California, Berkeley	Berkeley	California
United States	UCSF: Ernest Gallo Clinic and Research Center	Emeryville	California

Sponsors (3)

Lead Sponsor	Collaborator
University of California, San Francisco	United States Department of Defense, University of California, Berkeley

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)	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).	120 minutes after drug ingestion
Primary	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.	120 minutes after drug ingestion