Clinical trial NCT03921151: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
Official title: 5-HT2AR: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cocaine Dependence
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: The University of Texas Medical Branch, Galveston
name: National Institute on Drug Abuse (NIDA)
First posted: 2019-04-19
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: 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.
timeFrame: Baseline to 1 week
Secondary outcomes:
measure: Change in Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR Antagonist on the Functional Circuitry Underlying Cue Reactivity
timeFrame: Baseline to 1 week
Other outcomes:
measure: Change in Effective Connectivity Involved in the 5-HT2AR:5-HT2CR Homeostasis Impulsive Action
timeFrame: Baseline to 1 week
measure: Change in Effective Connectivity Involved in the 5-HT2AR:5-HT2CR Homeostasis Cue Reactivity
timeFrame: Baseline to 1 week
measure: Change in Explore Interactions Between Other 5-HT2CR SNPs and Brain Activation During Attentional Bias Task After a 5- HT2AR Antagonist
timeFrame: Baseline to 1 week
measure: Change in Explore Interactions Between Other 5-HT2CR SNPs and Brain Activation During Go/NoGo (Impulsivity) Task After a 5- HT2AR Antagonist
timeFrame: Baseline to 1 week
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Virginia Commonwealth University
name: Frederick Moeller, M.D.
role: PRINCIPAL_INVESTIGATOR
References: