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Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia

Primary Purpose

Schizophrenia, Impulsive Behavior

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Nicotine Patch, 7 Mg/24 Hr
Placebo patch
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Schizophrenia focused on measuring Nicotine, Nicotinic acetylcholine receptors, Schizophrenia, Schizoaffective disorder, Healthy control, Impulsive behavior, Aggression, Urgency

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.)

Sites / Locations

  • Vanderbilt Psychiatric Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Healthy: placebo first, nicotine last

Healthy: nicotine first, placebo last

SCZ: placebo first, nicotine last

SCZ: nicotine first, placebo last

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

False Alarm Error Rate
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The False Alarm Error Rate will be measured by the proportion of incorrect responses.
False Alarm Error Rate
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The False Alarm Error Rate will be measured by the proportion of incorrect responses.
Omission Error Rate
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The Omission Error Rate will be measured by the proportion of questions asked with a failure to respond.
Omission Error Rate
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The Omission Error Rate will be measured by the proportion of questions asked with a failure to respond.
Reaction Time for Correct Hits
Time taken from stimulus presentation to button push during Go trials
Reaction Time for Correct Hits
Time taken from stimulus presentation to button push during Go trials
Reaction Time for False Alarms
Time taken from stimulus presentation to button push during NoGo trials
Reaction Time for False Alarms
Time taken from stimulus presentation to button push during NoGo trials

Secondary Outcome Measures

Full Information

First Posted
February 7, 2019
Last Updated
April 27, 2022
Sponsor
Vanderbilt University Medical Center
Collaborators
National Institute of Mental Health (NIMH), University of Florida
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1. Study Identification

Unique Protocol Identification Number
NCT03838484
Brief Title
Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia
Official Title
Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Terminated
Why Stopped
Recruitment challenges due to Covid19.
Study Start Date
May 10, 2019 (Actual)
Primary Completion Date
February 24, 2020 (Actual)
Study Completion Date
February 24, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
National Institute of Mental Health (NIMH), University of Florida

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia, Impulsive Behavior
Keywords
Nicotine, Nicotinic acetylcholine receptors, Schizophrenia, Schizoaffective disorder, Healthy control, Impulsive behavior, Aggression, Urgency

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Healthy: placebo first, nicotine last
Arm Type
Experimental
Arm Description
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.
Arm Title
Healthy: nicotine first, placebo last
Arm Type
Experimental
Arm Description
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.
Arm Title
SCZ: placebo first, nicotine last
Arm Type
Experimental
Arm Description
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.
Arm Title
SCZ: nicotine first, placebo last
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Nicotine Patch, 7 Mg/24 Hr
Intervention Description
Nicotine patch, 7 mg/24 hour will be applied to the skin.
Intervention Type
Drug
Intervention Name(s)
Placebo patch
Intervention Description
Placebo skin patch will be applied to the skin.
Primary Outcome Measure Information:
Title
False Alarm Error Rate
Description
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The False Alarm Error Rate will be measured by the proportion of incorrect responses.
Time Frame
Week 1
Title
False Alarm Error Rate
Description
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The False Alarm Error Rate will be measured by the proportion of incorrect responses.
Time Frame
Week 2
Title
Omission Error Rate
Description
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The Omission Error Rate will be measured by the proportion of questions asked with a failure to respond.
Time Frame
Week 1
Title
Omission Error Rate
Description
Participants will be shown fearful, sad, angry, and disgust faces (negative valence) and neutral faces performed in 5 blocks (3 emotional blocks with angry/fearful/sad/disgust faces and 2 non-emotional blocks). In each block the subject is instructed on the go/no-go targets and will press a key ("Go") or withhold pressing a key ("NoGo"). The Omission Error Rate will be measured by the proportion of questions asked with a failure to respond.
Time Frame
Week 2
Title
Reaction Time for Correct Hits
Description
Time taken from stimulus presentation to button push during Go trials
Time Frame
Week 1
Title
Reaction Time for Correct Hits
Description
Time taken from stimulus presentation to button push during Go trials
Time Frame
Week 2
Title
Reaction Time for False Alarms
Description
Time taken from stimulus presentation to button push during NoGo trials
Time Frame
Week 1
Title
Reaction Time for False Alarms
Description
Time taken from stimulus presentation to button push during NoGo trials
Time Frame
Week 2

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria for schizophrenia subjects: Men and women age 18 - 65. Communicative in English. Provide voluntary, written informed consent. Physically healthy by medical history,and ECG examination. BMI > 17.5 and < 45. 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. 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. Negative urine toxicology and negative urine cotinine (to confirm no recent nicotine use) at screening. Does not meet criteria for substance or alcohol use disorder per the SCID over the past 6 months 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, For females of child-bearing potential, must have negative urine pregnancy test at time of screening visit and before each testing day. Not breastfeeding/nursing at time of screening or at any time during the study. Exclusion Criteria for schizophrenia subjects: Age less than 18 or greater than 65. Not communicative in English. Unable to provide written informed consent. Active suicidal ideation or suicidal behavior. Current, unstable medical or neurological illness or significant abnormality on ECG. History of severe head trauma. BMI < 17.5 or > 45. History of allergy to transdermal patches. Screening visit resting heart rate > 110 or < 50 beats per minute, or known history of clinically significant cardiac rhythm abnormalities. Screening visit systolic blood pressure > 160 or < 90, or diastolic blood pressure > 95 or < 50. Positive urine toxicology or positive urine cotinine during screening. Meets criteria for diagnosis of substance or alcohol use disorder by SCID within the past 6 months. Reports any tobacco smoking or nicotine use over the past month. Not taking an antipsychotic medication. Positive urine pregnancy test at time of screening, before each testing day, or any potential concern for pregnancy at any time during the study 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: Current use of psychotropic or potentially psychoactive prescription medication. Major psychiatric disorder as determined by DSM-5 (schizophrenia, major depression, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder, etc.)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alan S Lewis, MD, PhD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt Psychiatric Hospital
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37212
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26895845
Citation
Krakowski MI, De Sanctis P, Foxe JJ, Hoptman MJ, Nolan K, Kamiel S, Czobor P. Disturbances in Response Inhibition and Emotional Processing as Potential Pathways to Violence in Schizophrenia: A High-Density Event-Related Potential Study. Schizophr Bull. 2016 Jul;42(4):963-74. doi: 10.1093/schbul/sbw005. Epub 2016 Feb 19.
Results Reference
background
PubMed Identifier
25595654
Citation
Egashira K, Matsuo K, Nakashima M, Watanuki T, Harada K, Nakano M, Matsubara T, Takahashi K, Watanabe Y. Blunted brain activation in patients with schizophrenia in response to emotional cognitive inhibition: a functional near-infrared spectroscopy study. Schizophr Res. 2015 Mar;162(1-3):196-204. doi: 10.1016/j.schres.2014.12.038. Epub 2015 Jan 13.
Results Reference
background
PubMed Identifier
29536216
Citation
Lewis AS, van Schalkwyk GI, Lopez MO, Volkmar FR, Picciotto MR, Sukhodolsky DG. An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder. J Autism Dev Disord. 2018 Aug;48(8):2748-2757. doi: 10.1007/s10803-018-3536-7.
Results Reference
background

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Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia

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