5HT2CR Balance in Brain Connectivity in Cocaine Dependence

• ClinicalTrials.gov Identifier: NCT03921151
• Recruitment Status: Recruiting
• First Posted: April 19, 2019
• Last Update Posted: December 12, 2019
• Sponsor: Virginia Commonwealth University
• Collaborators: The University of Texas Medical Branch, Galveston; National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): Virginia Commonwealth University

Tracking Information

• First Submitted Date: April 10, 2019
• First Posted Date: April 19, 2019
• Last Update Posted Date: December 12, 2019
• Actual Study Start Date: May 13, 2014
• Estimated Primary Completion Date: February 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 5, 2019)

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. [ Time Frame: Baseline to 1 week ]

Change in fMRI activation during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose

Original Primary Outcome Measures (submitted: April 15, 2019)

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

• Change History: Complete list of historical versions of study NCT03921151 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: November 5, 2019)

Change in Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR antagonist on the functional circuitry underlying cue reactivity [ Time Frame: Baseline to 1 week ]

Change in fMRI activation during Attentional bias task with placebo dose vs Mirtazapine dose

Original Secondary Outcome Measures (submitted: April 15, 2019)

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

Current Other Pre-specified Outcome Measures (submitted: November 5, 2019)

• Change in Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis impulsive action [ Time Frame: Baseline to 1 week ]
  Change in Impulsivity as measured by Go/NoGo task with placebo dose vs Mirtazapine dose
• Change in Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis cue reactivity [ Time Frame: Baseline to 1 week ]
  Change in Cue reactivity as measured by Attentional bias task with placebo dose vs Mirtazapine dose
• Change in Explore interactions between other 5-HT2CR SNPs and brain activation during attentional bias task after a 5- HT2AR antagonist [ Time Frame: Baseline to 1 week ]
  Change in fMRI activation with other 5-HT2CR SNPs during Attentional bias task with placebo dose vs Mirtazapine dose
• Change in Explore interactions between other 5-HT2CR SNPs and brain activation during Go/NoGo (impulsivity) task after a 5- HT2AR antagonist [ Time Frame: Baseline to 1 week ]
  Change in fMRI activation with other 5-HT2CR SNPs during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose

Original Other Pre-specified Outcome Measures (submitted: April 15, 2019)

• 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
• 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
• 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
• 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

Descriptive Information

• Brief Title: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
• Official Title: 5-HT2AR: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
• 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.
• 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 Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Basic Science
• Condition: Cocaine Dependence

Intervention

• Drug: Mirtazapine 15 MG Oral Tablet
  15mg of mirtazapine oral table prior to scan
  Other Name: Remeron
• Other: Placebo oral capsule
  Oral placebo consisting of dextrose in gelatin capsule prior to scan
  Other Name: Dextrose placebo in gelatin capsule

Study Arms

• Cocaine-dependent
  Participants who use and are dependent on cocaine
  Interventions:

  • Drug: Mirtazapine 15 MG Oral Tablet
  • Other: Placebo oral capsule
• Non-drug
  Participants who are not drug users
  Interventions:

  • Drug: Mirtazapine 15 MG Oral Tablet
  • Other: Placebo oral capsule

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 15, 2019): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2020
• Estimated Primary Completion Date: February 2020 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03921151
• Other Study ID Numbers: HM15289; P20DA024157-04S1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Virginia Commonwealth University
• Study Sponsor: Virginia Commonwealth University

Collaborators

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

Investigators

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

• PRS Account: Virginia Commonwealth University
• Verification Date: December 2019