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D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement (HFDEX)

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ClinicalTrials.gov Identifier: NCT02203786
Recruitment Status : Completed
First Posted : July 30, 2014
Results First Posted : April 25, 2016
Last Update Posted : April 25, 2016
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Daniela Lobo, Centre for Addiction and Mental Health

Tracking Information
First Submitted Date  ICMJE July 23, 2014
First Posted Date  ICMJE July 30, 2014
Results First Submitted Date  ICMJE January 20, 2016
Results First Posted Date  ICMJE April 25, 2016
Last Update Posted Date April 25, 2016
Study Start Date  ICMJE September 2009
Actual Primary Completion Date June 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2016)
Subjective Reinforcement Self-report Scales [ Time Frame: At key points in testing: immediately after the slot machine game, and at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration). ]
Self-reported Confidence to Refrain from Gambling (0 - 10) was assessed at test session baseline, before the slot machine and after the slot machine (Phase 1); and before amphetamine and at peak amphetamine (Phase 2). The maximum score (10) denotes complete confidence to refrain from gambling (i.e., NO urge or compulsion to gamble); the minimum score (0) denotes complete lack of confidence to refrain from gambling (i.e., overwhelming urge to gamble). Scores between 10 and 0 denote intermediate confidence to refrain from gambling with LOWER scores denoting less confidence to refrain from gambling -- i.e., GREATER urge or compulsive motivation to gamble. Scores shown are based on single item visual analogue ratings 0-10 from each participant at the specified time point. The mean (SD) of these single item ratings is presented for each sub-group.
Original Primary Outcome Measures  ICMJE
 (submitted: July 28, 2014)
Subjective Reinforcement self-report scales [ Time Frame: At key intervals, e.g., before/after slot machine, throughout each of 4 test sessions. Participants will be followed for the duration of the study: 4 weeks with 1 test session per week, from date of randomization until date of fourth test session. ]
Participants will complete self-report scales assessing motivation (e.g., desire to gamble), subjective effects of the drugs (Addiction Research Center Inventory), subjective effects of the slot machine (visual analogue scales), mood state (Profile of Mood States) at key intervals, e.g., before/after slot machine, throughout each session.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2016)
  • Diastolic Blood Pressure (DBP) [ Time Frame: At key points in testing: immediately after the slot machine game (change from session baseline), and at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration)(change from session baseline). ]
    Measure changes from baseline, especially physiologic reactivity to the slot machine and amphetamine.
  • Cognitive Task Performance [ Time Frame: At key points during testing: immediately after the slot machine, at expected peak subjective-behavioral effects for amphetamine (90-minutes post-capsule administration) ]
    Response time to words (gambling, alcohol, positive affect, negative affect) as a percentage of neutral categorized words (parts of a building). This provides an index of the relative salience of stimuli from these four categories against a baseline of reaction to words with no clinical relevance or emotional valence. Smaller scores indicate faster relative response time to the test stimuli vs. neutral stimuli (i.e., greater salience)
  • Betting Behaviour in Laboratory-based Slot Machine Game [ Time Frame: 1x per test session (total of 4 test sessions) for duration of the study: 4 weeks (1 session/week) ]
    Risk taking was operationally defined as credits wagered per spin (mean computed for total spins)
  • Speed of Play on Slot Machine Game [ Time Frame: 15-minutes ]
    Number of individual spins in a 15-minute slot machine game. Each spin corresponds to one wager.
  • Winnings on Slot Machine Upon Completion of Game [ Time Frame: 15-minutes ]
    Credits
Original Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2014)
  • HR/BP [ Time Frame: Approximately every 30 min during each test session. At key intervals, e.g., before/after slot machine on each test sessions, for duration of the study: 4 weeks (1 session/week) from date of randomization to date of test session 4. ]
    Measure changes from baseline, especially physiologic reactivity to the slot machine and amphetamine.
  • Cognitive Task Performance [ Time Frame: After cognitive tasks performed in each test session. At key intervals, e.g., before/after slot machine on each test sessions, for duration of the study: 4 weeks (1 session/week) from date of randomization to date of test session 4. ]
  • Betting Behaviour in Laboratory-based Slot Machine Game [ Time Frame: 1x per test session (total of 4 test sessions). At key intervals, e.g., before/after slot machine on each test sessions, for duration of the study: 4 weeks (1 session/week) from date of randomization to date of test session 4. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement
Official Title  ICMJE Comparative Effects of a D2 and Mixed D1-D2 Dopamine Antagonist on Gambling and Amphetamine Reinforcement in Pathological Gamblers and Healthy Controls
Brief Summary

To determine if:

  1. pathological gambling is similar to psychostimulant addiction as reflected by parallel roles for D1 and D2 receptors in gambling and stimulant reinforcement.
  2. these parallel roles are linked with gambling pathology or if they are evident in both gamblers and controls.
Detailed Description

BACKGROUND: No previous research appears to have investigated the role of dopamine (DA) D1 or D2 receptors in psychostimulant reinforcement in pathological gamblers. Effects of haloperidol vs. placebo will reveal the role of D2 and the effects of fluphenazine vs. haloperidol will reveal the role of D1 in this process.

OBJECTIVE: This study will begin to define the neurochemistry of Pathological Gambling by examining the roles of dopamine D1 and D2 receptors in gambling reinforcement and psychostimulant reinforcement, and exploring genetic predictors of response to DA probes in Pathological Gambling subjects (subjects) and healthy controls.

METHODS: A double-blind, placebo controlled, counterbalanced between-within design will be employed. Each participant will attend 4 sessions with a minimum of 1 week between sessions to ensure drug washout. Responses to the slot machine will be assessed in sessions 1 and 2 (Phase I), and responses to amphetamine will be assessed in sessions 3 and 4 (Phase II). A second capsule (dummy) will be administered at expected peak levels for each antagonist on sessions 1 and 2 to standardize the procedure across sessions.

Subjective reinforcement self-report scales will be administered at key intervals throughout the study.

HYPOTHESIS: It is hypothesized that haloperidol (3-mg) will increase priming (Desire to Gamble, Gambling word salience) and pleasurable effects (e.g., Enjoyment/Liking) induced by playing a slot machine in Pathological Gambling subjects (N = 40). If gambling and stimulant reinforcement are mediated by common mechanisms, haloperidol will also increase priming and pleasurable effects of amphetamine (20-mg) in Pathological Gambling subjects.

If D1 mediates effects of haloperidol, the mixed D1-D2 antagonist, fluphenazine (fluphenazine; 3-mg) will decrease or not alter responses to the slot machine and amphetamine in Pathological Gambling subjects. If D2 deficits are linked with gambling pathology, haloperidol will not affect slot machine or amphetamine reinforcement in controls (N= 40).

If D1 deficits are linked with gambling pathology, fluphenazine will increase gambling and amphetamine reinforcement in controls, by mitigating undue D1 activation in subjects with high baseline D1 function. If D1 or D2 genes contribute to gambling or amphetamine reinforcement, genotype will predict responses to the manipulations.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Condition  ICMJE Pathological Gambling
Intervention  ICMJE
  • Drug: Haloperidol

    Dose/maximum dose = 3-mg; route = oral. Participants assigned to the haloperidol antagonist group will receive 2 doses (@ 3 mg) on alternate sessions (with minimum of 2 weeks between individual doses).

    Dose 1: 3 visually identical capsules, each containing 1 mg haloperidol.

    Other Names:
    • Teva-Haloperidol
    • DIN: 00396818
    • Haldol
  • Drug: Fluphenazine

    Dose/maximum dose = 3-mg; route = oral. Participants assigned to the fluphenazine antagonist group will receive 2 doses (@ 3 mg) on alternate sessions (with minimum of 2 weeks between individual doses).

    Dose 1: 3 visually identical capsules, each containing 1 mg fluphenazine.

    Other Names:
    • APO-Fluphenazine
    • DIN: 00405345
    • Prolixin
    • Permitil
  • Drug: Dexedrine

    Dose/maximum dose = 20-mg; route = oral. All participants will receive 2 doses (@ 20 mg) during Phase II - sessions 3, 4, with minimum 1 week between individual doses.

    Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg D-amphetamine.

    Other Names:
    • Dextro-amphetamine sulphate
    • DIN: 01924516
    • D-amphetamine
  • Drug: Placebo

    Dose 1: On alternate sessions (1 and 3 or 2 and 4, depending on counterbalancing) participants will receive 3 visually identical placebo (lactose) capsules.

    Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1.

    Other Name: lactose capsule
  • Behavioral: Slot Machine
    15 minute play of a commercial slot machine game in bar-simulated laboratory setting.
    Other Name: reward cue
Study Arms  ICMJE
  • Active Comparator: Haloperidol

    Subjects randomized to pre-treatment drug sequence 1 (haloperidol on day 1 of each phase), or drug sequence 2 (haloperidol on day 2 of each phase).

    Dose 1: 3 visually identical capsules, each containing 1 mg haloperidol OR 3 visually identical placebo (lactose) capsules

    Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg dexedrine.

    Response measured to 15 min session of a commercial slot machine game.

    Interventions:
    • Drug: Haloperidol
    • Drug: Dexedrine
    • Drug: Placebo
    • Behavioral: Slot Machine
  • Active Comparator: Fluphenazine

    Subjects randomized to pre-treatment drug sequence 1 (fluphenazine on day 1 of each phase), or drug sequence 2 (fluphenazine on day 2 of each phase).

    Dose 1: 3 visually identical capsules, each containing 1 mg fluphenazine OR 3 visually identical placebo (lactose) capsules

    Dose 2: when participants reach expected peak blood levels for dose 1, they will receive their second dose. On sessions 1 and 2 (Phase I), this will consist of 2 dummy capsules, visually identical to those administered for dose 1. On sessions 3 and 4 (Phase II), the dose will consist of 2 visually identical capsules each containing 10 mg dexedrine.

    Response measured to 15 min session of a commercial slot machine game.

    Interventions:
    • Drug: Fluphenazine
    • Drug: Dexedrine
    • Drug: Placebo
    • Behavioral: Slot Machine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 25, 2015)
60
Original Estimated Enrollment  ICMJE
 (submitted: July 28, 2014)
80
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date June 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • PATHOLOGICAL GAMBLERS
  • otherwise healthy, non-treatment seeking, non-abstinent
  • male or female
  • ages 19-65
  • DSM-IV PG symptom scale score > 5
  • SOGS (South Oaks Gambling Screen) score > 5
  • nicotine dependence acceptable
  • CONTROLS
  • healthy
  • male or female
  • ages 19-65
  • DSM-IV PG symptom scale score = 0
  • SOGS score = 0
  • nicotine dependence acceptable
  • must have played slot machine > 5 times

Exclusion Criteria:

  • both Pathological Gamblers and Controls
  • Axis I psychopathology aside from nicotine dependence (or PG) based on SCID
  • Schizotypal or Borderline Personality Disorder based on psychiatric interview
  • Family history of schizophrenia or bipolar disorder
  • English comprehension below grade 7 level.
  • ADS (Alcohol Dependence Scale) > 13 (more than low dependence)
  • BDI (Beck Depression Inventory) short form > 10 (more than low depression)
  • DAST (Drug Abuse Screening Test) > 4 (possible drug abuse)
  • Consumption of > 20/15 (men/women) standard alcoholic drinks/ week (hazardous drinking)
  • Smoking > 20 cigarettes/day to help minimize withdrawal symptoms during test phase
  • Any prior use of psychostimulant drugs
  • Current use of medication that could interact with any of the study medications
  • Women who are pregnant or breastfeeding
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02203786
Other Study ID Numbers  ICMJE 232-2009
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Daniela Lobo, Centre for Addiction and Mental Health
Study Sponsor  ICMJE Centre for Addiction and Mental Health
Collaborators  ICMJE Canadian Institutes of Health Research (CIHR)
Investigators  ICMJE
Principal Investigator: Daniela Lobo, MD, Ph.D. Centre for Addiction and Mental Health
PRS Account Centre for Addiction and Mental Health
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP