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

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

View full results

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

TERMINATED

Clinical Phase

NA

Total Enrollment

18 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-05-10

Study Completion Date

2020-02-24

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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.

Related Clinical Trials

Explore similar clinical trials based on study characteristics and research focus.

The Effects of Nicotine on Cognition in Schizophrenia

NCT00383747

Schizophrenia

COMPLETED PHASE4

Network-Targeted Neuromodulation for Nicotine Dependence in Schizophrenia

NCT06389266

Schizophrenia Nicotine Dependence

COMPLETED NA

The Effects of Nicotine Withdrawal on Reward Responsivity in Schizophrenia

NCT00373126

Schizophrenia Schizoaffective Disorder

COMPLETED PHASE4

Nicotine Effects on Endophenotypes of Schizophrenia

NCT01315002

Schizophrenia

COMPLETED NA

Effects of Nicotine on Areas of Impaired and Preserved Functioning in Schizophrenia

NCT01034085

Nicotine Dependence Schizophrenia

COMPLETED

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Schizophrenia Impulsive Behavior

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

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.

Group Type EXPERIMENTAL

Nicotine Patch, 7 Mg/24 Hr

Intervention Type DRUG

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

Placebo patch

Intervention Type DRUG

Placebo skin patch will be applied to the skin.

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.

Group Type EXPERIMENTAL

Nicotine Patch, 7 Mg/24 Hr

Intervention Type DRUG

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

Placebo patch

Intervention Type DRUG

Placebo skin patch will be applied to the skin.

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.

Group Type EXPERIMENTAL

Nicotine Patch, 7 Mg/24 Hr

Intervention Type DRUG

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

Placebo patch

Intervention Type DRUG

Placebo skin patch will be applied to the skin.

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.

Group Type EXPERIMENTAL

Nicotine Patch, 7 Mg/24 Hr

Intervention Type DRUG

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

Placebo patch

Intervention Type DRUG

Placebo skin patch will be applied to the skin.

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

Nicotine Patch, 7 Mg/24 Hr

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

Intervention Type DRUG

Placebo patch

Placebo skin patch will be applied to the skin.

Intervention Type DRUG

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

Inclusion Criteria

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.

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

Exclusion Criteria

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.

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.)

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes