Impulsive Behavior
Conditions
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.
Interventions
DRUGTolcapone
Drug: Tolcapone 200mg (single dose) administered at study visit
OTHERPlacebo
Placebo (200mg) administered at study visit
Sponsors
University of California, Berkeley
United States Department of Defense
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between the Impulsive Choice Ratio and Baseline Impulsivity, as Measured With the Barratt Impulsiveness Scale | 120 minutes after drug ingestion | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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) | 120 minutes after drug ingestion | 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). |
Countries
United States
Participant flow
Pre-assignment details
Subjects were screened for inclusion / exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All study participants receiving either Tolcapone 200mg (single dose) or Placebo (single dose) administered at study visit, followed by crossover to other drug at next visit - all participants were randomized to receive all interventions. | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 1st Intervention (1 Day) | Physician Decision | 1 | 2 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 26.1 years STANDARD_DEVIATION 6.3 |
| Barratt Impulsiveness Scale | 58.6 units on a scale STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 0 / 26 | 0 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
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.
Time frame: 120 minutes after drug ingestion
Population: The outcome for this study was the correlation between the baseline BIS score and the difference in ICR (tolcapone minus placebo). As such, one Arm/Group is presented below.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Functional MRI Arm (Tolcapone and Placebo) | Correlation Between the Impulsive Choice Ratio and Baseline Impulsivity, as Measured With the Barratt Impulsiveness Scale | -0.45 Correlation coefficient |
Comparison: The comparison group represents the difference in ICR and the baseline impulsiveness scale.p-value: 0.032Fisher transformation
Other Pre-specified
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).
Time frame: 120 minutes after drug ingestion
Population: The outcome for this study was the correlation between the difference in the ICR and the difference in BOLD activity (tolcapone minus placebo). As such, one Arm / Group is presented below.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Functional MRI Arm (Tolcapone and Placebo) | 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) | -0.50 Correlation coefficient |
p-value: <0.05Fisher transformation