5HT2CR Balance in Brain Connectivity in Cocaine Dependence

Sponsor
Virginia Commonwealth University (Other)
Overall Status
Completed
CT.gov ID
NCT03921151
Collaborator
The University of Texas Medical Branch, Galveston (Other), National Institute on Drug Abuse (NIDA) (NIH)
90
1
2
56.4
1.6

Study Details

Study Description

Brief Summary

This project will evaluate the role of the 5-HT2CR:5-HT2AR balance in impulsive action and cue reactivity in cocaine-dependent subjects as compared to non-drug using controls.

Condition or Disease Intervention/Treatment Phase
  • Drug: Mirtazapine 15 MG Oral Tablet
Phase 1/Phase 2

Detailed Description

The overall goal of this project is to evaluate the role of molecular interactions between 5-HT2AR and 5-HT2CR in behavioral phenotypes that confer risk for cocaine dependence and relapse. Specifically, this project will evaluate the role of the 5-HT2CR:5-HT2AR balance in impulsive action and cue reactivity in cocaine-dependent subjects as compared to non-drug using controls. Brain and behavioral responses to the 5-HT2AR blocking medication mirtazapine will be compared between subjects who have high and low functioning of the 5-HT2CR based on presence of a specific, functionally-relevant single nucleotide polymorphism (SNP) of the 5-HT2CR (Cys23Ser). The 5-HT2CR Cys23Ser SNP is thought to decrease the function of the protein and a preliminary observation indicates cocaine-dependent subjects carrying the CC genotype (Ser23 protein variant) display significantly higher cue reactivity. For Aims 1 and 2, two fMRI analysis methods will be used: 1) a voxelwise whole brain analysis; 2) a region of interest analysis based on proposed integrative circuitry shown in the model below. Because neuroimaging studies have shown that performance of impulsive action tasks and exposure to cocaine-associated cues (cue reactivity paradigms) activate brain regions in brain circuits in humans, impulsive action and cue reactivity may be engendered in related pathways. To explore this hypothesis, researchers will employ functional magnetic resonance imaging (fMRI)-based dynamic causal modeling (DCM) to ascertain the causal influences of one brain region over another. Employing DCM, researchers will uncover the effective connectivity within nodes of the neurocircuitry involved in impulsive action and cue reactivity. This project will parallel preclinical work studying the relationship between 5-HT2AR and 5-HT2CR on impulsive action and cue reactivity.

Study Design

Study Type:
Interventional
Actual Enrollment :
90 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Basic Science
Official Title:
5-HT2AR: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
Actual Study Start Date :
May 13, 2014
Actual Primary Completion Date :
Jan 24, 2019
Actual Study Completion Date :
Jan 24, 2019

Arms and Interventions

Arm Intervention/Treatment
Other: Cocaine-dependent

Participants who use and are dependent on cocaine

Drug: Mirtazapine 15 MG Oral Tablet
The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment.
Other Names:
  • Remeron
  • Other: Non-drug using Healthy Controls

    Participants who are not drug users

    Drug: Mirtazapine 15 MG Oral Tablet
    The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment.
    Other Names:
  • Remeron
  • Outcome Measures

    Primary Outcome Measures

    1. Change in Interaction of the Serotonin Receptor (5-HTR) Type-2C Cys23Ser Single Nucleotide Polymorphism (SNP) and a 5-HT2AR Antagonist on the Functional Circuitry Underlying Impulsive Action. [Baseline to 1 week]

      Change in fMRI activation during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose. Brain activation measured using blood-oxygen-level dependent (BOLD) contrast

    Secondary Outcome Measures

    1. Change in Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR Antagonist on the Functional Circuitry Underlying Cue Reactivity [Baseline to 1 week]

      Change in fMRI activation during Attentional bias task with placebo dose vs Mirtazapine dose measured using whole brain blood oxygenation level dependent (BOLD) signal

    Other Outcome Measures

    1. Change in Effective Connectivity Involved in the 5-HT2AR:5-HT2CR Homeostasis Impulsive Action [Baseline to 1 week]

      Change in Impulsivity as measured by Go/NoGo task with placebo dose vs Mirtazapine dose

    2. Change in Effective Connectivity Involved in the 5-HT2AR:5-HT2CR Homeostasis Cue Reactivity [Baseline to 1 week]

      Change in Cue reactivity as measured by Attentional bias task with placebo dose vs Mirtazapine dose

    3. Change in Explore Interactions Between Other 5-HT2CR SNPs and Brain Activation During Attentional Bias Task After a 5- HT2AR Antagonist [Baseline to 1 week]

      Change in fMRI activation with other 5-HT2CR SNPs during Attentional bias task with placebo dose vs Mirtazapine dose

    4. Change in Explore Interactions Between Other 5-HT2CR SNPs and Brain Activation During Go/NoGo (Impulsivity) Task After a 5- HT2AR Antagonist [Baseline to 1 week]

      Change in fMRI activation with other 5-HT2CR SNPs during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    Cocaine Dependent Subjects

    1. Be English-speaking volunteers

    2. Be aged between 18 and 60 years

    3. Meet DSM-5 criteria for cocaine dependence

    4. Have a self-reported history of using cocaine

    5. Have hematology and chemistry laboratory tests that are within reference limits ( 10%) with the following exceptions: hemoglobin and hematocrit within normal limits (for fMRI).

    6. Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant abnormalities

    7. Have a medical history and physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the principal investigator.

    8. Have no metal fragments or other bodily metal (e.g., pacemaker) or significant claustrophobia that would put the subjects at risk for MRI scanning.

    Non-Drug Using Controls

    1. Be English-speaking volunteers

    2. Be aged between 18 and 60 years

    3. Have no past history of Psychiatric or non-Psychiatric medical disorders which could affect the central nervous system as assessed by SCID and physical examination.

    4. Have hematology and chemistry laboratory tests that are within reference limits ( 10%), with the following exceptions: hemoglobin and hematocrit within normal limits (for fMRI)

    5. Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant abnormalities

    6. Have a medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the Principal investigator.

    7. Have no metal fragments or other bodily metal (pacemaker) or significant claustrophobia that would put the subjects at risk for MRI scanning

    Exclusion Criteria:

    Cocaine Dependent Subjects

    1. Have any history or evidence suggestive of seizure disorder or brain injury.

    2. Have any previous medically adverse reaction to mirtazapine or other antidepressants.

    3. Have neurological or psychiatric disorders, such as (a) psychosis, bipolar illness or major depression as assessed by SCID; (b) organic brain disease or dementia assessed by clinical interview; (c) history of any psychiatric disorder that would require ongoing treatment or that would make study compliance difficult; and (d) history of suicide attempts within the past 3 months and/or current suicidal ideation/plan.

    4. Have evidence of uncontrolled clinically significant heart disease or hypertension, as determined by the PI.

    5. Have evidence of non-psychiatric medical illness including neuroendocrine, autoimmune, renal, hepatic, or active infectious disease.

    6. Use of any medications or drugs that can affect the central nervous system other than cocaine, marijuana, alcohol caffeine and nicotine.

    7. Have a positive HIV test.

    8. Be pregnant or nursing. Other females must either be unable to conceive (i.e., surgically sterilized, sterile, or postmenopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, weekly during the study, and at the end of study participation.

    9. Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study.

    Non-Drug Using Controls

    1. Meet DSM-5 criteria for any current or past Axis I disorder.

    2. Meet DSM-5 criteria for an Axis II diagnosis of Borderline or Antisocial Personality Disorder.

    3. Have any history or evidence suggestive of seizure disorder or brain injury.

    4. Have any previous medically adverse reaction to mirtazapine or other antidepressants.

    5. Have evidence of uncontrolled clinically significant heart disease or hypertension, as determined by the PI.

    6. Have evidence of medical illness including neuroendocrine, autoimmune, renal, hepatic, or active infectious disease.

    7. Use of any medications or drugs that can affect the central nervous system other than caffeine or nicotine.

    8. Have a positive HIV test.

    9. Be pregnant or nursing. Other females must either be unable to conceive (i.e., surgically sterilized, sterile, or postmenopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, weekly during the study, and at the end of study participation.

    10. Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Virginia Commonwealth University Richmond Virginia United States 23298

    Sponsors and Collaborators

    • Virginia Commonwealth University
    • The University of Texas Medical Branch, Galveston
    • National Institute on Drug Abuse (NIDA)

    Investigators

    • Principal Investigator: Frederick Moeller, M.D., Virginia Commonwealth University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Virginia Commonwealth University
    ClinicalTrials.gov Identifier:
    NCT03921151
    Other Study ID Numbers:
    • HM15289
    • P20DA024157-04S1
    First Posted:
    Apr 19, 2019
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Cocaine-dependent Non-drug Using Healthy Controls
    Arm/Group Description Participants who use and are dependent on cocaine Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment. Participants who are not drug users Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment.
    Period Title: Overall Study
    STARTED 46 44
    COMPLETED 35 28
    NOT COMPLETED 11 16

    Baseline Characteristics

    Arm/Group Title Cocaine-dependent Non-drug Using Healthy Controls Total
    Arm/Group Description Participants who use and are dependent on cocaine Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment. Participants who are not drug users Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment. Total of all reporting groups
    Overall Participants 35 28 63
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    44.6
    (8.62)
    34.29
    (12.5)
    40.02
    (11.64)
    Sex: Female, Male (Count of Participants)
    Female
    9
    25.7%
    14
    50%
    23
    36.5%
    Male
    26
    74.3%
    14
    50%
    40
    63.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    35
    100%
    28
    100%
    63
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    34
    97.1%
    24
    85.7%
    58
    92.1%
    White
    1
    2.9%
    4
    14.3%
    5
    7.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    35
    100%
    28
    100%
    63
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change in Interaction of the Serotonin Receptor (5-HTR) Type-2C Cys23Ser Single Nucleotide Polymorphism (SNP) and a 5-HT2AR Antagonist on the Functional Circuitry Underlying Impulsive Action.
    Description Change in fMRI activation during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose. Brain activation measured using blood-oxygen-level dependent (BOLD) contrast
    Time Frame Baseline to 1 week

    Outcome Measure Data

    Analysis Population Description
    Change scores could not be calculated for 17 cocaine-dependent participants and 14 non-drug using participants due to a missing or unusable fMRI scan.
    Arm/Group Title Cocaine-dependent Non-drug Using Healthy Controls
    Arm/Group Description Participants who use and are dependent on cocaine Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment. Participants who are not drug users Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment.
    Measure Participants 18 14
    Mean (90% Confidence Interval) [percent of whole brain BOLD signal]
    0.6889
    -1.1091
    2. Secondary Outcome
    Title Change in Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR Antagonist on the Functional Circuitry Underlying Cue Reactivity
    Description Change in fMRI activation during Attentional bias task with placebo dose vs Mirtazapine dose measured using whole brain blood oxygenation level dependent (BOLD) signal
    Time Frame Baseline to 1 week

    Outcome Measure Data

    Analysis Population Description
    Change scores could not be calculated for 12 cocaine-dependent participants and 9 non-drug using participants due to a missing or unusable fMRI scan.
    Arm/Group Title Cocaine-dependent Non-drug Using Healthy Controls
    Arm/Group Description Participants who use and are dependent on cocaine Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment. Participants who are not drug users Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment.
    Measure Participants 23 19
    Mean (90% Confidence Interval) [percent of BOLD signal]
    -0.135
    0.2225
    3. Other Pre-specified Outcome
    Title Change in Effective Connectivity Involved in the 5-HT2AR:5-HT2CR Homeostasis Impulsive Action
    Description Change in Impulsivity as measured by Go/NoGo task with placebo dose vs Mirtazapine dose
    Time Frame Baseline to 1 week

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Other Pre-specified Outcome
    Title Change in Effective Connectivity Involved in the 5-HT2AR:5-HT2CR Homeostasis Cue Reactivity
    Description Change in Cue reactivity as measured by Attentional bias task with placebo dose vs Mirtazapine dose
    Time Frame Baseline to 1 week

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Other Pre-specified Outcome
    Title Change in Explore Interactions Between Other 5-HT2CR SNPs and Brain Activation During Attentional Bias Task After a 5- HT2AR Antagonist
    Description Change in fMRI activation with other 5-HT2CR SNPs during Attentional bias task with placebo dose vs Mirtazapine dose
    Time Frame Baseline to 1 week

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Other Pre-specified Outcome
    Title Change in Explore Interactions Between Other 5-HT2CR SNPs and Brain Activation During Go/NoGo (Impulsivity) Task After a 5- HT2AR Antagonist
    Description Change in fMRI activation with other 5-HT2CR SNPs during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose
    Time Frame Baseline to 1 week

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Adverse events were monitored during the first study visit (practice MRI) through the last study visit (Dose 2 MRI) approximately 1 week.
    Adverse Event Reporting Description During the practice MRI visit, adverse events (AEs) were recorded using the 24 hour questionnaire. During the Dose 1 and Dose 2 MRI visits, AEs were recorded using the 24 questionnaire (pre dose), Drug Effects Questionnaire (pre dose, 1.25 hr post dose, 3.75 hr post dose, 4.5 hr post dose), and neurological exam (5 hr post dose completed by physician). All AEs were entered into a secure REDCap database.
    Arm/Group Title Cocaine-dependent Non-drug Using Healthy Controls
    Arm/Group Description Participants who use and are dependent on cocaine Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment. Participants who are not drug users Mirtazapine 15 MG Oral Tablet: The intervention will be a 15mg of mirtazapine oral tablet given to participants prior to their treatment scan and assessments. In order to ensure that biases or social desirability do not contaminate baseline assessments, all participants will also be given a tablet consisting of dextrose in gelatin prior to their baseline scan and assessment.
    All Cause Mortality
    Cocaine-dependent Non-drug Using Healthy Controls
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/35 (0%) 0/28 (0%)
    Serious Adverse Events
    Cocaine-dependent Non-drug Using Healthy Controls
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/35 (0%) 0/28 (0%)
    Other (Not Including Serious) Adverse Events
    Cocaine-dependent Non-drug Using Healthy Controls
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/35 (0%) 1/28 (3.6%)
    Gastrointestinal disorders
    Nausea and dizziness 0/35 (0%) 0 1/28 (3.6%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Liangsuo Ma, PhD
    Organization Virginia Commonwealth University
    Phone (804) 828-2871
    Email liangsuo.ma@vcuhealth.org
    Responsible Party:
    Virginia Commonwealth University
    ClinicalTrials.gov Identifier:
    NCT03921151
    Other Study ID Numbers:
    • HM15289
    • P20DA024157-04S1
    First Posted:
    Apr 19, 2019
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Nov 1, 2021