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5HT2CR Balance in Brain Connectivity in Cocaine Dependence

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ClinicalTrials.gov Identifier: NCT03921151
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : April 19, 2019
Sponsor:
Collaborators:
The University of Texas Medical Branch, Galveston
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Virginia Commonwealth University

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
Cocaine Dependence Drug: Mirtazapine 15 MG (administered at Scan 1) and Placebo oral capsule (administered at Scan 2) Drug: Placebo oral capsule (administered at Scan 1) and Mirtazapine 15 MG (administered at Scan 2) 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, we 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, we 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover 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
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : September 30, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Mirtazapine

Arm Intervention/treatment
Experimental: Mirtazapine at Scan 1
Single 15mg dose of mirtazapine prior to the scan
Drug: Mirtazapine 15 MG (administered at Scan 1) and Placebo oral capsule (administered at Scan 2)
15mg of mirtazapine prior to scan
Other Names:
  • Remeron
  • Dextrose placebo in gelatin capsule

Placebo Comparator: Placebo at Scan 1
Dextrose placebo in gelatin capsule
Drug: Placebo oral capsule (administered at Scan 1) and Mirtazapine 15 MG (administered at Scan 2)
Oral placebo consisting of dextrose in gelatin capsule
Other Names:
  • Dextrose placebo in gelatin capsule
  • Remeron




Primary Outcome Measures :
  1. 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. [ Time Frame: 1 day ]
    fMRI activation during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose


Secondary Outcome Measures :
  1. Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR antagonist on the functional circuitry underlying cue reactivity [ Time Frame: 1 day ]
    fMRI activation during Attentional bias task with placebo dose vs Mirtazapine dose


Other Outcome Measures:
  1. Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis impulsive action [ Time Frame: 1 day ]
    Impulsivity as measured by Go/NoGo task with placebo dose vs Mirtazapine dose

  2. Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis cue reactivity [ Time Frame: 1 day ]
    Cue reactivity as measured by Attentional bias task with placebo dose vs Mirtazapine dose

  3. Explore interactions between other 5-HT2CR SNPs and brain activation during attentional bias task after a 5- HT2AR antagonist [ Time Frame: 1 day ]
    fMRI activation with other 5-HT2CR SNPs during Attentional bias task with placebo dose vs Mirtazapine dose

  4. Explore interactions between other 5-HT2CR SNPs and brain activation during Go/NoGo (impulsivity) task after a 5- HT2AR antagonist [ Time Frame: 1 day ]
    fMRI activation with other 5-HT2CR SNPs during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose



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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03921151


Contacts
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Contact: Lori KeyserMarcus, PhD 804-828-4164 lori.keysermarcus@vcuhealth.org

Locations
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United States, Virginia
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23298
Contact: Eddie Zuniga    804-828-3686    study4u@vcu.edu   
Sponsors and Collaborators
Virginia Commonwealth University
The University of Texas Medical Branch, Galveston
National Institute on Drug Abuse (NIDA)
Investigators
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Principal Investigator: Frederick Moeller, M.D. Virginia Commonwealth University

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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT03921151     History of Changes
Other Study ID Numbers: HM15289
P20DA024157-04S1 ( U.S. NIH Grant/Contract )
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Cocaine-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Cocaine
Mirtazapine
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Antidepressive Agents
Psychotropic Drugs
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Anti-Anxiety Agents
Tranquilizing Agents
Adrenergic alpha-2 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents