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A Multi-Modal Investigation of the Smoking Cessation Medication Varenicline: Dopaminergic Modulation of Reward Processing and Cognitive Control

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00830739
First received: January 27, 2009
Last updated: October 23, 2014
Last verified: February 2013
  Purpose

Background:

  • Chronic nicotine exposure through cigarette smoking affects the level of the brain chemical dopamine. Smokers who attempt to quit experience lower levels of dopamine, which increases anxiety and triggers nicotine cravings that make quitting more difficult.
  • Varenicline (Chantix) is a smoking cessation medication that is designed to reduce nicotine craving and withdrawal by slightly increasing levels of dopamine in the brain. Research has shown that varenicline is a safe, well-tolerated, and effective treatment for nicotine dependence, but researchers are interested in learning more about how it affects the brain and its function. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) will help researchers study the brain s response to nicotine and varenicline.

Objectives:

- To explore how varenicline affects brain function and behavioral performance in current smokers and healthy volunteers.

Eligibility:

- Individuals between 18 and 55 years of age who are either current smokers (10 or more cigarettes per day) or healthy nonsmoking volunteers.

Design:

  • The study will involve nine testing and research visits over 5 to 6 weeks. The first visit will provide an initial assessment and training on the tasks that will be completed during the study.
  • Six testing visits will involve fMRI and EEG measurements of brain activity. Each visit will contain two 2-hour scanning sessions, and each session will involve thinking tests. During these visits, participants will receive varenicline and placebo tablets, and wear nicotine patches and placebo patches that do not contain nicotine. Participants will not be told which tablet or patch they are given. This is a crossover study so all participants eventually get nicotine and placebo, as well as varenicline and placebo.
  • Two other visits involve different thinking tasks. These visits will not require fMRI or EEG scans.

Condition
Tobacco Use Disorder
Nicotine Dependence

Study Type: Observational
Official Title: A Multi-Modal Investigation of the Smoking Cessation Medication Varenicline: Dopaminergic Modulation of Reward Processing and Cognitive Control

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To improve understanding of the neural and cognitive consequences of nicotine dependence, nicotine abstinence, and varenicline treatment.

Secondary Outcome Measures:
  • To better understand individual differences that may relate to the effects of nicotine in the brain to improve future smoking cessation treatments.

Estimated Enrollment: 100
Study Start Date: November 2008
Estimated Study Completion Date: February 2013
Detailed Description:

Objective. Chronic nicotine exposure is thought to lead to alterations in the dopamine (DA) system that leaves smokers in a hypo-dopaminergic state during periods of abstinence. Varenicline (Chantix), a new efficacious smoking cessation medication, is thought to lead to a modest but sustained increase of DA release thereby reducing nicotine craving and withdrawal. While numerous studies have shown that varenicline is a safe, well-tolerated, and effective pharmacological treatment for nicotine dependence, studies exploring the neurophysiological impact of this drug in the human brain have not been conducted. This protocol will utilize an array of reward processing and cognitive control tasks to explore the effects of subtle DA manipulations (induced by smoking cessation, transdermal nicotine, and varenicline) on brain function and behavioral performance. Brain function will be assessed using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).

Study Population. There will be two study populations: 1) healthy nicotine-dependent adults who smoke 10 or more cigarettes per day; and 2) healthy non-smoking, non-drug dependent controls. Participants must be generally healthy, right-handed, male or non-pregnant/non-lactating females between the ages of 18-55.

Design. After being medically cleared and giving informed consent, each participant will complete several imaging visits (6 visits, on separate days) before and after taking varenicline. Two of these visits will take place before varenicline administration (baseline), two visits after a two-week varenicline dosing period (post-varenicline), and another two after a two-week placebo-pill period (post-placebo-pill). Each set of two scans will involve the randomized, double blind administration of a nicotine transdermal or placebo patch. fMRI and EEG data will be collected after patch application and will involve several tasks designed to probe brain regions in a corticolimbic circuit that may mediate aspects of reward-processing, learning, attention, goal-directed behaviors, and drug abuse.

Outcome Measures. This study involves assessing neurophysiological and behavior differences between cohorts (smokers vs. non-smokers) and conditions (nicotine vs. placebo-patch; baseline vs. varenicline vs. placebo-pill). The primary outcome measures used to ascertain these differences will be: 1) percentage change in fMRI BOLD signal during performance of cognitive control and reward processing tasks; 2) change in ERP component (e.g., error-related negativity) amplitudes; 3) behavioral measures during task performance including reaction times and error rates; 4) scores on mood, personality, and smoking questionnaires; and 5) variations in genes related to nicotinic receptors and DA functioning.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

    1. between the ages of 18-55.
    2. right-handed.
    3. in good health.
    4. free of active DSM-IV dependence, or dependence in partial remission, on alcohol or any drug except nicotine. Past active dependence is acceptable provided it is at least five years in the past and total time of active dependence did not exceed 4 years. Those with past dependence may not have any current use (past 6 months) of the substance on which they were dependent.
    5. able to abstain from alcohol 24hrs before each of the imaging sessions and able to moderate their caffeine intake 12hrs before each session.

In addition, smokers must:

  1. smoke 10 or more cigarettes per day and have smoked for more than 2 years.
  2. be able to refrain from smoking for up to 12hrs (at 6 different time points) during the study.
  3. be able to tolerate the nicotine patch.

In addition, non-smokers must:

(1) Not have a history of daily cigarette smoking lasting more than a month and no smoking within the past 2 years.

EXCLUSION CRITERIA:

  1. 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.
  2. have coagulopathies, history of, current superficial, or deep vein thrombosis, musculoskeletal abnormalities restricting an individual s ability to lie flat for extended periods of time.
  3. have HIV or Syphilis.
  4. regularly use any prescription, over-the-counter or herbal medication that may alter CNS function, cardiovascular function, or neuronal-vascular coupling.
  5. have any current, or a history of, neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma, or CNS tumor.
  6. have any current, or a history of, major psychiatric disorders, substance-induced psychiatric disorders, suicidal ideations and/or suicide attempts, or currently under antidepressant or antipsychotic medication treatment.
  7. are cognitively impaired or learning disabled.
  8. have significant cardiovascular or cerebrovascular conditions.
  9. have moderate to severe renal impairment.
  10. are diabetic.
  11. have any other major medical condition that in the view of the investigators would compromise the safety of an individual during participation.
  12. pregnant, planning to become pregnant, or breastfeeding.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00830739

Locations
United States, Maryland
National Institute on Drug Abuse, Biomedical Research Center (BRC)
Baltimore, Maryland, United States, 21224
Sponsors and Collaborators
Investigators
Principal Investigator: Elliot Stein, Ph.D. National Institute on Drug Abuse (NIDA)
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00830739     History of Changes
Other Study ID Numbers: 999909044, 09-DA-N044
Study First Received: January 27, 2009
Last Updated: October 23, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Smoking Cessation
Dopamine
Cognitive Control
Reward Processing
Varenicline

Additional relevant MeSH terms:
Tobacco Use Disorder
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Dopamine Agents
Dopamine Agonists
Varenicline
Cholinergic Agents
Cholinergic Agonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Nicotinic Agonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 20, 2014