5HT2CR Balance in Brain Connectivity in Cocaine Dependence

5-HT2AR: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03921151

Enrollment

Registered

2019-04-19

Start date

2014-05-13

Completion date

2019-01-24

Last updated

2021-11-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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.

Interventions

DRUGMirtazapine 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.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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

Measure	Time frame	Description
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
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
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
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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cocaine-dependent 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.	35
Non-drug Using Healthy Controls 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.	28
Total	63

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	11	16

Baseline characteristics

Characteristic	Cocaine-dependent	Total	Non-drug Using Healthy Controls
Age, Continuous	44.6 years STANDARD_DEVIATION 8.62	40.02 years STANDARD_DEVIATION 11.64	34.29 years STANDARD_DEVIATION 12.5
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	35 Participants	63 Participants	28 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	34 Participants	58 Participants	24 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	1 Participants	5 Participants	4 Participants
Region of Enrollment United States	35 participants	63 participants	28 participants
Sex: Female, Male Female	9 Participants	23 Participants	14 Participants
Sex: Female, Male Male	26 Participants	40 Participants	14 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 35	0 / 28
other Total, other adverse events	0 / 35	1 / 28
serious Total, serious adverse events	0 / 35	0 / 28

Outcome results

Primary

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.

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