A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 12/20/2018 |
| Start Date: | March 2010 |
| End Date: | December 2018 |
A Randomized, Double-Blind Study of Neural Circuit Responses to COMT Inhibitors
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.
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.
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.
(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.
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.
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