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SchizophreniaNCT03838484

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

A study testing Nicotine Patch, 7 Mg/24 Hr in people with Schizophrenia and Impulsive Behavior, run by Vanderbilt University Medical Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 yearsHealthy volunteers can take part
Conditions the study is for
Schizophrenia, Impulsive Behavior
What is being tested?
Nicotine Patch, 7 Mg/24 Hr
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
18 participants
Where
1 siteUnited States
Study dates
10 May 2019to 24 Feb 2020
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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.
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  • 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.
  • 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.)

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Vanderbilt Psychiatric Hospital

    Nashville, Tennessee, 37212

Other trials in United States

About this study

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.

Read the 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.

Being tested
Nicotine Patch, 7 Mg/24 Hr, Placebo patch
Keywords
Nicotine, Nicotinic acetylcholine receptors, Schizophrenia, Schizoaffective disorder, Healthy control, Impulsive behavior, Aggression, Urgency
Medical subject headings
Schizophrenia, Impulsive Behavior, Psychotic Disorders, Aggression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nicotine Patch, 7 Mg/24 HrDrug

    Nicotine patch, 7 mg/24 hour will be applied to the skin.

  • Placebo patchDrug

    Placebo skin patch will be applied to the skin.

Study groups in NCT03838484
Study groupRoleWhat they receive
Healthy: placebo first, nicotine lastExperimentalHealthy 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.
Receives: Drug: Nicotine Patch, 7 Mg/24 Hr; Drug: Placebo patch
Healthy: nicotine first, placebo lastExperimentalHealthy 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.
Receives: Drug: Nicotine Patch, 7 Mg/24 Hr; Drug: Placebo patch
SCZ: placebo first, nicotine lastExperimentalSubjects 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.
Receives: Drug: Nicotine Patch, 7 Mg/24 Hr; Drug: Placebo patch
SCZ: nicotine first, placebo lastExperimentalSubjects 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.
Receives: Drug: Nicotine Patch, 7 Mg/24 Hr; Drug: Placebo patch

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Week 1

  2. 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.

    Measured: Week 2

  3. 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.

    Measured: Week 1

  4. 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.

    Measured: Week 2

  5. Reaction Time for Correct Hits

    Time taken from stimulus presentation to button push during Go trials

    Measured: Week 1

  6. Reaction Time for Correct Hits

    Time taken from stimulus presentation to button push during Go trials

    Measured: Week 2

  7. Reaction Time for False Alarms

    Time taken from stimulus presentation to button push during NoGo trials

    Measured: Week 1

  8. Reaction Time for False Alarms

    Time taken from stimulus presentation to button push during NoGo trials

    Measured: Week 2

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Feb 2019
  2. Study start10 May 2019
  3. Primary completion24 Feb 2020
  4. Study completion24 Feb 2020

Why it stopped: Recruitment challenges due to Covid19.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03838484
Sponsor's protocol ID
190021
Other IDs
7K23MH116339
Status last verified
Apr 2022
First submitted
7 Feb 2019
Last updated
29 Apr 2022
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 26895845
  • 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.

    PubMed 25595654
  • 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.

    PubMed 29536216

Questions about this trial

What is this clinical trial studying?

A study testing Nicotine Patch, 7 Mg/24 Hr in people with Schizophrenia and Impulsive Behavior, run by Vanderbilt University Medical Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 29 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

False Alarm Error Rate (time frame: Week 1). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03838484, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2022.

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