Brain Networks and Addiction Susceptibility

NCT01924468 | Completed Phase 1 FDA Drug

• 2 other identifiers: 99991348313-DA-N483
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- The risk for becoming addicted to drugs varies from person to person, even among those using similar drugs in a similar way. Researchers do not fully understand why some people become addicted to drugs and others do not. Studies suggest that under certain life circumstances, some genes may increase the risk for addiction. This study will use genetic information, computer tasks, magnetic resonance imaging (MRI), and other tests to see what brain networks may be related to drug addiction. Objectives: \- To better understand brain networks that may be related to susceptibility to drug addiction. Eligibility: \- Healthy non-smoking volunteers between 18 and 55 years of age. Design:

• This study will have one screening visit and four all-day study visits. For male participants, the visits will be about 7 days apart over 5 to 7 weeks. Female participants will have the visits scheduled to coordinate with their menstrual cycle.
• This study involves small doses of three approved drugs: two oral dopamine drugs and a nicotine patch. For each scanning session, participants will have three study drugs. However, only one pill or patch will be the real drug; the other two will be placebos. Some participants may have only placebos during a visit.
• Participants will be screened with a physical exam and medical history. Blood and urine samples will be taken. Other tests will be given to ensure that participants are not smoking or using drugs while they are in the study.
• During the all-day scanning visits, participants will receive two pills and one patch in the morning and they will be trained on simple computer tasks. In the afternoon, participants will have MRI scans and we will measure their brain activity while they rest and while they perform computer tasks in the scanner. Participants will also answer questionnaires during the scanning visits.

Conditions

Nicotine Dependence

Keywords

Cognitive Control; fMRI; Genetics; Dopamine

Outcome Measures

Primary Outcomes (1)

• The impact of rs16969968 genotype on the BOLD fMRI signal and functional connectivity (FC) within and between the three networks of interests (SN, ECN, DMN) at rest and during task performance.

  5 months

Interventions

Oral methylphenidate and Oral haloperidol DRUG

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants must be between 18-55 years of age. Justification: Many neural processes change with age, including the attributes of, and interactions between, the three brain networks assessed in the study. In addition, the risk of difficult-to-detect medical abnormalities such as silent cerebral infarcts increases with age. Assessment tool(s): driver s license, birth certificate, or other government-issued forms of identification.
• Participants must be right-handed. Justification: Some of the neural processes assessed in this protocol may be lateralized in the brain. In order to reduce potential variance, participants will be required to be right-handed. Assessment tool(s): Edinburgh Handedness Inventory.
• Participants must be in good health. Justification: Many illnesses may alter fMRI signals as well as neural functioning. Assessment tool(s): Participants will provide a brief health history during phone screening, and undergo a medical history and physical examination with an IRP clinician.
• Participants must be free of lifetime substance dependence, and free of substance abuse in the last 2 years, for any substance, including nicotine, alcohol, prescription drugs, and illicit drugs, according to DSM-IV diagnostic criteria. With respect to tobacco use, participants must not be current smokers and must never have been daily smokers for more than 1 month. In addition, the MAI and/or PI will use their medical/scientific judgment on a case-by-case basis to disqualify potential participants from participation at lower levels of use. Justification: Abuse or dependence on drugs or alcohol may result in unique CNS deficits that could confound results. This eligibility criterion is particularly important in the current study, which examines the neurobiological processes underlying susceptibility to drug dependence in the absence of, and preceding, chronic use and the development of such dependence. Assessment tool(s): The computerized SCID and clinical substance abuse/dependence assessment. While recreational/intermittent use of alcohol and/or marijuana will be tolerated, individuals will be excluded from participation if they meet lifetime DSM-IV diagnosis of abuse or dependence.
• Both male and female participants will be enrolled in the study.
• While we will target the A/A homozygotes and G/G homozygotes at the rs16969968 locus, we will also allow A/G heterozygotes to
• become enrolled in the study. The enrollment will be open to all racial and ethnic groups, including Caucasians, African Americans, and Asians, as well as Hispanic and non-Hispanics, and we will make an effort to include all racial and ethnic groups as long as all participants meet the rs16969968 genotype criteria. Justification: The allele frequencies at the rs16969968 locus vary greatly between racial and ethnic groups, making it extremely difficult to ensure a balance of ethnicities across the genotype groups. In particular, the minor A allele of rs16969968 (the Risk allele in the current study), associated with increased risk of heavy smoking and nicotine dependence, has a frequency of 0.42 in Caucasians, but is very rare in Asians (0.03) and African Americans (0.07) (Saccone et al., 2010b). Therefore, assuming Hardy-Weinberg Equilibrium, we will need to recruit approximately 275 Caucasian subjects in order to
• meet the enrollment target of n = 40 per genotype group (i.e., 40 A/A and 40 G/G), with the A/A homozygotes being the limiting factor. For comparison, because the A/A is very rare in African Americans (0.0049; or 49 in 10,000), we would need to recruit over 8,000 African American subjects to meet our enrollment target of n = 40 for that ethnic group; if we aimed at only 20 African American subjects in our sample (closer to the distribution in the Baltimore area), we would still have to recruit over 4,000 African American subjects. The frequency of the A/A homozygotes in Asian population is even more daunting (0.0009; or 9 in 10,000). Importantly, because the association between the rs16969968 locus and nicotine addiction severity has been demonstrated in all three ethnic groups in a recent meta-analysis (Chen et al., 2012), we argue that the racial and ethnic groups not enrolled in the current study will still benefit from basic, mechanistic knowledge gained from this study if translated to clinical treatment and prevention of nicotine abuse and dependence in the future. The estimated number of potential participants to be screened is 300. Assessment tools: Genotype group membership will be determined by genotyping. Racial and ethnic group membership will be initially determined by self-report. Additionally, we will examine ancestry information markers to verify and extend the self-reported ethnic background and to test for possible modulatory effects of specific genetic-ancestry groups with respect to the rs16969968 effects in our data.

You may not qualify if:

• Participants will be excluded if they:
• are not suitable to undergo an fMRI experiment due to certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia. Justification: MR scanning is one of the primary measurement tools used in the protocol. Assessment tool(s): Prospective participants will fill out an MRI screening questionnaire and undergo an interview with an MR technologist. Questions concerning suitability for scanning will be referred to the MR Medical Safety Officer. Prospective participants will be questioned about symptoms of claustrophobia and placed in the mock scanner during their first visit to assess for possible difficulty tolerating the confinement of the scanner and for ability to fit into the scanner.
• have HIV or Syphilis. Justification: HIV and Syphilis both can have central nervous system (CNS) sequelae, thus introducing unnecessary variability into the data. Assessment tool(s): Oral HIV followed by blood test if oral test is + and RPR+ (\>1:8 without history of adequate treatment).
• regularly use some prescriptions (e.g., antidepressants, benzodiazepines, antipsychotics, anticonvulsants, barbiturates), over-the-counter (e.g., cold medicine) or herbal medications (e.g., Kava, Gingko biloba, St. John s wort) that may alter CNS function, cardiovascular function, or neuronal-vascular coupling. Justification: The use of these substances may alter the fMRI signal and/or neural functions of interest in the current study. Assessment tool(s): History and comprehensive urine drug screening to detect antidepressants, benzodiazepines, antipsychotics, anticonvulsants, and barbiturates. The MAI/PI will use their medical/scientific judgment on a case-by-case basis.
• have any current, or a history of, major psychiatric disorders, including major depressive disorder (single past episode with at least three years symptom-free off medication will be allowed), schizophrenia, bipolar disorder or attention-deficit/hyperactivity disorder (ADHD), or are currently under antidepressant or antipsychotic medication treatment. Justification: Psychiatric disorders may be accompanied by alternations in brain structure and/or function. Assessment tool(s): Computerized SCID, Beck Depression Inventory, Beck Anxiety Inventory, Adult ADHD Self-Report Scales and clinical interview confirmation by clinician.
• are cognitively impaired or learning disabled. Justification: Cognitive impairment and learning disabilities may be associated with altered brain functioning in regions recruited during laboratory task performance. Cognitive impairment may affect one s ability to give informed consent. Assessment tool(s): History examination and Wechsler Abbreviated Scale of Intelligence (WASI). IQ estimate must be greater than or equal to 85.
• have significant cardiovascular or cerebrovascular conditions. Justification: Such conditions may alter blood flow, the fMRI signal and other autonomic signals, and increase risks associated with nicotine patch use. Assessment tool(s): History and physical exam, including EKG.
• have QTc greater than 450. Justification: Haloperidol may increases the risk of Torsades de Pointes and QTc prolongation. Assessment tool: EKG.
• Hemoglobin \< 10 g/dl
• White Blood Cell Count \< 2400/microL
• Liver Function Tests \> 3 times normal
• Serum glucose \> 200 mg/dl
• Urine protein \> 2+
• Estimated glomerular filtration rate \<60ml/min
• pregnant, planning to become pregnant, or breastfeeding. Justification: Study procedures and drugs used in the current protocol may complicate pregnancy or be transferred to nursing children. Assessment tool/s: Urine pregnancy tests will be conducted at the beginning of each scanning visit.

Sponsors & Collaborators

• National Institute on Drug Abuse (NIDA): lead

Study Sites (1)

National Institute on Drug Abuse

Baltimore, Maryland, 21224, United States

Location

Related Publications (4)

• Armstrong SM, Stuenkel EL. Progesterone regulation of catecholamine secretion from chromaffin cells. Brain Res. 2005 May 10;1043(1-2):76-86. doi: 10.1016/j.brainres.2005.02.040.

  PMID: 15862520 BACKGROUND

• Beckmann CF, DeLuca M, Devlin JT, Smith SM. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci. 2005 May 29;360(1457):1001-13. doi: 10.1098/rstb.2005.1634.

  PMID: 16087444 BACKGROUND

• Bentley P, Driver J, Dolan RJ. Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging. Prog Neurobiol. 2011 Sep 1;94(4):360-88. doi: 10.1016/j.pneurobio.2011.06.002. Epub 2011 Jun 17.

  PMID: 21708219 BACKGROUND

• Hill JA, Korponay C, Salmeron BJ, Ross TJ, Janes AC. Catecholaminergic Modulation of Large-Scale Network Dynamics Is Tied to the Reconfiguration of Corticostriatal Connectivity. Hum Brain Mapp. 2024 Dec 1;45(17):e70086. doi: 10.1002/hbm.70086.

  PMID: 39665506 DERIVED

MeSH Terms

Conditions

Tobacco Use Disorder

Interventions

Methylphenidate; Haloperidol

Condition Hierarchy (Ancestors)

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Butyrophenones; Ketones

Study Officials

• Elliot Stein, Ph.D.

  National Institute on Drug Abuse (NIDA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2013
• First Posted: August 16, 2013
• Study Start: August 14, 2013
• Primary Completion: September 5, 2018
• Study Completion: May 14, 2019
• Last Updated: May 16, 2019

Record last verified: 2019-05-14

Locations

US (1)