D1 and D2 Dopamine Receptors in Gambling and Amphetamine Reinforcement

Pathological Gambling Clinical Trial

— HFDEX  

Official title:

Comparative Effects of a D2 and Mixed D1-D2 Dopamine Antagonist on Gambling and Amphetamine Reinforcement in Pathological Gamblers and Healthy Controls

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02203786
• Other study ID #: 232-2009
• Status: Completed
• Phase: Phase 2
• First received: July 23, 2014
• Last updated: November 25, 2015
• Start date: September 2009
• Est. completion date: September 2015

Study information

• Verified date: November 2015
• Source: Centre for Addiction and Mental Health
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: September 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 19 Years to 65 Years

Eligibility

Inclusion Criteria:

• PATHOLOGICAL GAMBLERS

• otherwise healthy, non-treatment seeking, non-abstinent

• male or female

• ages 19-65

• DSM-IV PG symptom scale (Beaudoin and Cox, 1999) score > 5

• SOGS 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 > 13 (more than low dependence)

• BDI short form > 10 (more than low depression)

• DAST > 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Gambling
• Pathological Gambling

Intervention

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.
• 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.
• 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.
• 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.

Behavioral:
• Slot Machine
15 minute play of a commercial slot machine game in bar-simulated laboratory setting.

Locations

Country	Name	City	State
Canada	Centre for Addiction and Mental Health	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Centre for Addiction and Mental Health	Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada, 

References & Publications (7)

APA (2000) Diagnostic and Statistical Manual of Mental Disorders. IV-TR ed. American Psychiatric Association: Washington, DC.

Enggasser JL, de Wit H. Haloperidol reduces stimulant and reinforcing effects of ethanol in social drinkers. Alcohol Clin Exp Res. 2001 Oct;25(10):1448-56. — View Citation

Holley FO, Magliozzi JR, Stanski DR, Lombrozo L, Hollister LE. Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol Ther. 1983 Apr;33(4):477-84. — View Citation

Lesieur HR, Blume SB. The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers. Am J Psychiatry. 1987 Sep;144(9):1184-8. — View Citation

Midha KK, McKay G, Edom R, Korchinski ED, Hawes EM, Hall K. Kinetics of oral fluphenazine disposition in humans by GC-MS. Eur J Clin Pharmacol. 1983;25(5):709-11. — View Citation

Wachtel SR, Ortengren A, de Wit H. The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers. Drug Alcohol Depend. 2002 Sep 1;68(1):23-33. — View Citation

Wong YN, Wang L, Hartman L, Simcoe D, Chen Y, Laughton W, Eldon R, Markland C, Grebow P. Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers. J Clin Pharmacol. 1998 Oct;38(10):971-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Subjective Reinforcement self-report scales	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.	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.	No
Secondary	HR/BP	Measure changes from baseline, especially physiologic reactivity to the slot machine and amphetamine.	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.	Yes
Secondary	Cognitive Task Performance		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.	No
Secondary	Betting behaviour in laboratory-based slot machine game		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.	No

External Links

•   The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.