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Trial record 1 of 1 for:    NCT03838484
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Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia

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ClinicalTrials.gov Identifier: NCT03838484
Recruitment Status : Active, not recruiting
First Posted : February 12, 2019
Last Update Posted : April 16, 2020
Sponsor:
Collaborators:
National Institute of Mental Health (NIMH)
University of Florida
Information provided by (Responsible Party):
Alan Lewis, Vanderbilt University Medical Center

Tracking Information
First Submitted Date  ICMJE February 7, 2019
First Posted Date  ICMJE February 12, 2019
Last Update Posted Date April 16, 2020
Actual Study Start Date  ICMJE May 10, 2019
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2019)
  • False alarm error rate [ Time Frame: Week 1 ]
    Rate of incorrect responses during NoGo trials
  • False alarm error rate [ Time Frame: Week 2 ]
    Rate of incorrect responses during NoGo trials
  • Omission error rate [ Time Frame: Week 1 ]
    Rate of incorrect non-responses during Go trials
  • Omission error rate [ Time Frame: Week 2 ]
    Rate of incorrect non-responses during Go trials
  • Reaction time for correct hits [ Time Frame: Week 1 ]
    Time taken from stimulus presentation to button push during Go trials
  • Reaction time for correct hits [ Time Frame: Week 2 ]
    Time taken from stimulus presentation to button push during Go trials
  • Reaction time for false alarms [ Time Frame: Week 1 ]
    Time taken from stimulus presentation to button push during NoGo trials
  • Reaction time for false alarms [ Time Frame: Week 2 ]
    Time taken from stimulus presentation to button push during NoGo trials
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2019)
  • P3 amplitude [ Time Frame: Week 1 ]
    P3 event-related potential amplitude during correct Go trials
  • P3 amplitude [ Time Frame: Week 2 ]
    P3 event-related potential amplitude during correct Go trials
  • N2 amplitude [ Time Frame: Week 1 ]
    N2 event-related potential amplitude during correct Go trials
  • N2 amplitude [ Time Frame: Week 2 ]
    N2 event-related potential amplitude during correct Go trials
  • N2 amplitude [ Time Frame: Week 1 ]
    N2 event-related potential amplitude during incorrect Go trials
  • N2 amplitude [ Time Frame: Week 2 ]
    N2 event-related potential amplitude during incorrect Go trials
  • P3 amplitude [ Time Frame: Week 1 ]
    P3 event-related potential amplitude during incorrect Go trials
  • P3 amplitude [ Time Frame: Week 2 ]
    P3 event-related potential amplitude during incorrect Go trials
  • N2 amplitude [ Time Frame: Week 1 ]
    N2 event-related potential amplitude during correct NoGo trials
  • N2 amplitude [ Time Frame: Week 2 ]
    N2 event-related potential amplitude during correct NoGo trials
  • P3 amplitude [ Time Frame: Week 1 ]
    P3 event-related potential amplitude during correct NoGo trials
  • P3 amplitude [ Time Frame: Week 2 ]
    P3 event-related potential amplitude during correct NoGo trials
  • N2 amplitude [ Time Frame: Week 1 ]
    N2 event-related potential amplitude during incorrect NoGo trials
  • N2 amplitude [ Time Frame: Week 2 ]
    N2 event-related potential amplitude during incorrect NoGo trials
  • P3 amplitude [ Time Frame: Week 1 ]
    P3 event-related potential amplitude during incorrect NoGo trials
  • P3 amplitude [ Time Frame: Week 2 ]
    P3 event-related potential amplitude during incorrect NoGo trials
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 8, 2019)
  • Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale autonomic subscale score [ Time Frame: Week 1 ]
    The UKU side effect rating scale is designed to quantify the side effects of psychotropic drugs and will be used for standard rating of autonomic side effects experienced by subjects in response to study medication. The scale is patient-completed and asks to rate a specific side effect, with scores from 0 (not experienced at all) to 3 (severe levels or degree of the specific side effect). The scores for the autonomic subscale will be added together to create a single total subscale score. The overall range for the autonomic subscale is 0 (no side effects at all) to 33 (severe degree of all queried side effects).
  • Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale autonomic subscale score [ Time Frame: Week 2 ]
    The UKU side effect rating scale is designed to quantify the side effects of psychotropic drugs and will be used for standard rating of autonomic side effects experienced by subjects in response to study medication. The scale is patient-completed and asks to rate a specific side effect, with scores from 0 (not experienced at all) to 3 (severe levels or degree of the specific side effect). The scores for the autonomic subscale will be added together to create a single total subscale score. The overall range for the autonomic subscale is 0 (no side effects at all) to 33 (severe degree of all queried side effects).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia
Official Title  ICMJE Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia
Brief Summary The purpose of this study is to test whether nicotine, a drug that activates receptors called nicotinic acetylcholine receptors in the brain, improves the ability to make or withhold responses to faces that are either emotionally neutral or emotionally negative. This study will also test whether the drug affects brain activity while making or withholding responses using electroencephalography. Previous studies in people with schizophrenia have shown that more errors in response to negative emotional cues are related to greater likelihood of impulsive aggressive behavior. Therefore, the aim of this study is to determine whether nicotine might be a new strategy to reduce aggressive behavior. The investigators' goal is 25 individuals with schizophrenia and 25 healthy controls to complete the study at Vanderbilt.
Detailed Description

This human laboratory study seeks to test the hypothesis that activation of nicotinic acetylcholine receptors (nAChRs) in the brain will reduce impulsive behavior in response to negative emotional cues as compared to neutral emotional cues. Because impulsive action during negative mood states is strongly correlated with impulsive aggression in both healthy individuals and individuals with schizophrenia (discussed below), the investigators' overarching, long-term goal is to determine whether nAChRs in general as well as specific nAChR subclasses might represent novel treatment targets to reduce impulsive aggressive behavior, a significant public health problem.

Nicotinic acetylcholine receptors are a large family of excitatory, pentameric, ionotropic, ligand-gated ion channels located throughout the brain and the remainder of the body. Their endogenous ligand is acetylcholine, yet this family is defined by their common activation by nicotine. Interestingly, anti-aggressive, or "serenic" effects of nicotine have been demonstrated across a number of animal models, including mice, rats, and non-human primates, and multiple human laboratory studies demonstrate an anti-aggressive effect of nicotine in humans. The investigators' laboratory has also demonstrated that acute administration of nicotine at relatively low doses results in reduction of aggressive behaviors in mouse models. Because nicotine is active at all nAChRs, the investigators explored this mechanism further and found that hippocampal alpha-7 nAChRs were both necessary and sufficient for nicotine's serenic effect. Consistent with these findings, there is substantial evidence in humans that reduction of alpha-7 nAChR signaling enhances aggressive behavior, including in individuals with 15q13.3 microdeletion syndrome, a genetic disorder resulting from the deletion of the region of chromosome 15 containing the gene coding for alpha-7 nAChRs. The investigators have also translated these findings into human clinical populations, finding recently the safety and efficacy of transdermal nicotine to reduce aggression and irritability in young adults with autism spectrum disorder. This work, along with other previous case studies in humans, supports targeting nAChRs using transdermal nicotine to reduce aggressive behaviors.

Urgency is a behavioral construct defined as the tendency to act rashly in the context of strong positive or negative emotion, and explains a large degree of variance in the development of impulsive aggression in subjects with schizophrenia and other populations without psychiatric disorders. In patients with schizophrenia, degree of urgency correlates with structural and functional changes in a neuronal network involving prefrontal cortical and limbic/cognitive control brain regions. A number of previous studies have similarly demonstrated impulsivity in the context of negative emotion, called "negative urgency", correlates with history of aggression, as well as substance use and other risky behaviors. Urgency is a hereditable trait that may be considered an endophenotype of impulsive aggression.

Recent studies in humans have explored the relationship between mood-related impulsivity (i.e. urgency) and aggressive behavior using an Emotional Go/NoGo task. This task measures responding or response withholding to visual stimuli of neutral or emotional (typically negative) valence, and quantifies reaction time and commission/omission errors as a function of stimulus valence. Using an Emotional Go/NoGo task, Krakowski et al. studied healthy controls, patients with schizophrenia with or without a history of violence, and non-psychotic individuals with history of violence. In all groups, emotional valence had a significant effect on error commission. In schizophrenia patients, individuals with history of violence were significantly faster to make an incorrect response to negative stimuli (i.e. not withhold a response) than patients without history of violence, whereas the two groups did not differ in response times to neutral valence stimuli. Other studies have also demonstrated an interaction between emotional valence and impulsive errors in schizophrenia, as well as a relationship between emotional valence, impulsive errors, history of violence, and frontal cortex 5-HT1B receptor binding.

While the investigators' studies in mice suggest a direct effect of nAChR stimulation on aggression through activation of the alpha-7 nAChR and are supported by the results using transdermal nicotine in humans, to the investigators' knowledge no previous studies have directly examined the relationship between pharmacological targeting of nAChRs using transdermal nicotine and effects on impulsivity in the context of emotional cues in humans. The investigators now aim to directly test this hypothesis using an Emotional Go/NoGo task in subjects with schizophrenia and healthy controls to determine whether transdermal nicotine improves impulsive behavior and neural correlates in the context of negative and neutral valence cues. Given the relationship between impulsivity and aggressive behavior, the findings of this proposed study will strongly inform future studies of targeting nAChRs broadly and alpha-7 nAChRs more specifically to identify novel treatments for individuals with severe neuropsychiatric disorders struggling with persistent pathological impulsive aggression.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Schizophrenia
  • Impulsive Behavior
Intervention  ICMJE
  • Drug: Nicotine Patch, 7 Mg/24 Hr
    Nicotine patch, 7 mg/24 hour will be applied to the skin.
  • Drug: Placebo patch
    Placebo skin patch will be applied to the skin.
Study Arms  ICMJE
  • Experimental: Healthy: placebo first, nicotine last
    Healthy controls will apply placebo skin patch for up to two hours prior to behavioral and EEG task during the first visit in week 1. After a washout period, they will return and apply a nicotine patch (7 mg/24 hour dose) for up to two hours prior to behavioral and EEG task during the second visit in week 2.
    Interventions:
    • Drug: Nicotine Patch, 7 Mg/24 Hr
    • Drug: Placebo patch
  • Experimental: Healthy: nicotine first, placebo last
    Healthy controls will apply nicotine skin patch (7 mg/24 hour dose) for up to two hours prior to behavioral and EEG task during the first visit in week 1. After a washout period, they will return and apply a placebo patch for up to two hours prior to behavioral and EEG task during the second visit in week 2.
    Interventions:
    • Drug: Nicotine Patch, 7 Mg/24 Hr
    • Drug: Placebo patch
  • Experimental: SCZ: placebo first, nicotine last
    Subjects with schizophrenia (SCZ) will apply placebo skin patch for up to two hours prior to behavioral and EEG task during the first visit in week 1. After a washout period, they will return and apply a nicotine patch (7 mg/24 hour dose) for up to two hours prior to behavioral and EEG task during the second visit in week 2.
    Interventions:
    • Drug: Nicotine Patch, 7 Mg/24 Hr
    • Drug: Placebo patch
  • Experimental: SCZ: nicotine first, placebo last
    Subjects with schizophrenia (SCZ) will apply nicotine skin patch (7 mg/24 hour dose) for up to two hours prior to behavioral and EEG task during the first visit in week 1. After a washout period, they will return and apply a placebo patch for up to two hours prior to behavioral and EEG task during the second visit in week 2.
    Interventions:
    • Drug: Nicotine Patch, 7 Mg/24 Hr
    • Drug: Placebo patch
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: February 8, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2023
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for schizophrenia subjects:

  1. Men and women age 18 - 65.
  2. Communicative in English.
  3. Provide voluntary, written informed consent.
  4. Physically healthy by medical history,and ECG examination.
  5. BMI > 17.5 and < 45.
  6. Diagnosis of schizophrenia (ICD-10 F20) or schizoaffective disorder (ICD-10 F25) confirmed by Structured Clinical Interview for Diagnostic and Statistical Manual (DSM)-V (SCID) or diagnostic interview with a trained clinician.
  7. Stable medication regimen over at least the past two weeks, including the use of either an oral or intramuscular administration of an antipsychotic medication. Additionally, subjects may take any prescribed medication aside from a nicotine-containing product as long as it has been regularly taken over the past two weeks, including as-needed ("PRN") medication.
  8. Negative urine toxicology and negative urine cotinine (to confirm no recent nicotine use) at screening.
  9. Does not meet criteria for substance or alcohol use disorder per the SCID over the past 6 months
  10. For females, no longer of child-bearing potential, or agreeing to practice effective contraception during the study (e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device [IUD] or intrauterine system [IUS]; barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository; male partner sterilization; or true abstinence when this is in line with the preferred and usual lifestyle of the subject); and,
  11. For females of child-bearing potential, must have negative urine pregnancy test at time of screening visit and before each testing day.
  12. Not breastfeeding/nursing at time of screening or at any time during the study.

Exclusion Criteria for schizophrenia subjects:

  1. Age less than 18 or greater than 65.
  2. Not communicative in English.
  3. Unable to provide written informed consent.
  4. Active suicidal ideation or suicidal behavior.
  5. Current, unstable medical or neurological illness or significant abnormality on ECG.
  6. History of severe head trauma.
  7. BMI < 17.5 or > 45.
  8. History of allergy to transdermal patches.
  9. Screening visit resting heart rate > 110 or < 50 beats per minute, or known history of clinically significant cardiac rhythm abnormalities.
  10. Screening visit systolic blood pressure > 160 or < 90, or diastolic blood pressure > 95 or < 50.
  11. Positive urine toxicology or positive urine cotinine during screening.
  12. Meets criteria for diagnosis of substance or alcohol use disorder by SCID within the past 6 months.
  13. Reports any tobacco smoking or nicotine use over the past month.
  14. Not taking an antipsychotic medication.
  15. Positive urine pregnancy test at time of screening, before each testing day, or any potential concern for pregnancy at any time during the study
  16. Breastfeeding/nursing at time of screening or at any time during the study.

Inclusion Criteria for healthy volunteer subjects:

All of the above except for subjects will be psychiatrically healthy and not taking psychotropic or potentially psychoactive prescription medication.

Exclusion Criteria for healthy volunteer subjects:

All of the above and in addition:

  1. Current use of psychotropic or potentially psychoactive prescription medication.
  2. Major psychiatric disorder as determined by DSM-5 (schizophrenia, major depression, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder, etc.)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03838484
Other Study ID Numbers  ICMJE 190021
7K23MH116339 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Alan Lewis, Vanderbilt University Medical Center
Study Sponsor  ICMJE Vanderbilt University Medical Center
Collaborators  ICMJE
  • National Institute of Mental Health (NIMH)
  • University of Florida
Investigators  ICMJE
Principal Investigator: Alan S Lewis, MD, PhD Vanderbilt University Medical Center
PRS Account Vanderbilt University Medical Center
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP