Clinical trial NCT03838484
Conditions: Schizophrenia Impulsive Behavior
Keywords: Nicotine Nicotinic acetylcholine receptors Schizophrenia Schizoaffective disorder Healthy control Impulsive behavior Aggression Urgency
Sponsor: Vanderbilt University Medical Center
Start date: 2019-05-10; Completion date: 2020-02-24
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: 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 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. arm 3: 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 4: 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: intervention 1: Nicotine Patch, 7 Mg/24 Hr intervention 2: Placebo patch
Intervention descriptions: intervention 1: Nicotine patch, 7 mg/24 hour will be applied to the skin. intervention 2: Placebo skin patch will be applied to the skin.

Protocol documents:
ICF_005.pdf: 
Official title of study: Effects of transdermal nicotine on response inhibition to 
emotional cues in schizophrenia 
 
NCT number: NCT03838484 
 
Date of document: 10/23/2019 
 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Effects of transdermal nicotine on response inhibition to emotional cues in 
schizophrenia 
Version Date: 
PI: 
02 
10/23/2019 
Alan Lewis, MD, PhD 
  
 
 
 
 
1 
Name of participant: __________________________________________ Age: ___________ 
 
The following is given to you to tell you about this research study.  Please read this form with 
care and ask any questions you may have about this study.  Your questions will be answered.  
Also, you will be given a copy of this consent form.   
 
What is the purpose of this study?  
You are being asked to take part in this research study because you are an adult diagnosed with 
schizophrenia or schizoaffective disorder or are a healthy control subject. The purpose of this 
study is to test whether nicotine, a drug that activates receptors called nicotinic acetylcholine 
receptors in the brain, improves your 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 your brain activity while you are 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. We would like to enroll about 30 participants with 
schizophrenia and 30 healthy controls in this study at Vanderbilt. The main risks of this study 
relate to temporary uncomfortable effects of nicotine.  
 
You do not have to be in this research study. You may choose not to be in this study and get 
other treatments without changing your healthcare, services, or other rights.  You can stop 
being in this study at any time.  If we learn something new that may affect the risks or benefits 
of this study, you will be told so that you can decide whether or not you still want to be in this 
study.   Your medical record will contain a note saying you are in a research study and may 
contain some research information about you.  Anyone you authorize to receive your medical 
record will also get this information. 
 
Side effects and risks that you can expect if you take part in this study:  
Health Screen Risks: During the health screen, some questions may deal with personal or 
emotional matters. These matters may be stressful or upsetting to think about. You may refuse 
to answer any questions that make you too uncomfortable. 
 
To measure your heart rate and rhythm an electrocardiogram (ECG) will be done. This is a test 
that records the electrical activity of the heart. You will be asked to lie down and sticky patches 
will be fixed to your chest. You will be asked to lie still. The sticky pads used for the ECG may 
cause skin irritation. 
 
EEG risks: There is risk of mild discomfort to the scalp while wearing the EEG headcap.  


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Effects of transdermal nicotine on response inhibition to emotional cues in 
schizophrenia 
Version Date: 
PI: 
02 
10/23/2019 
Alan Lewis, MD, PhD 
  
 
 
 
 
2 
Nicotine may commonly result in side effects that are uncomfortable but temporary. 
Specifically, nicotine, like caffeine, can make some people feel stimulated. By this, you may 
notice that your heart is beating faster, or that you feel slightly anxious. You may feel mildly 
nauseous or lightheaded. Most individuals are not overly bothered by these symptoms, 
however, if these symptoms are intolerable, the patch will be removed from your skin and 
symptoms will resolve soon thereafter. 
 
Medication skin patches may also lead to mild skin irritation. Because the duration of wear is 
very short, this is unlikely, and any irritation will resolve after patch removal. 
 
Previous studies using single-dose nicotine for a short period have demonstrated no evidence 
for inciting nicotine addiction or withdrawal.  
 
Because there are risks associated with nicotine on fetuses or on young children who are 
breastfed by an individual exposed nicotine, you will not be permitted to take part in the study if 
you are pregnant, at risk of becoming pregnant, or are breastfeeding.  
   
Risks that are not known: 
Because this use of transdermal nicotine is “off-label”, meaning use of nicotine in this study is 
not an approved indication by the U.S. Food and Drug Administration (FDA), there may be risks 
that we do not know about at this time.   
 
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study: This study is designed 
to test a biological mechanism that may ultimately lead to new treatments for impulsivity and 
aggressive behavior. Therefore, participation in this study may, in time, benefit both individuals 
with schizophrenia as well as society at large. 
 
 
Payments for your time spent taking part in this study or expenses: 
You will be provided $25 for completion of the screening visit, which will be provided at the end 
of this visit regardless of your decision to enroll in the study. You will receive an additional $100 
at the completion of the second testing visit. You will not receive any payment if you only 
complete the first testing visit without completing the second testing visit. 
 
Your travel costs will be reimbursed. If driving, mileage will be reimbursed at the current 
Internal Revenue Service (IRS) rate for business purposes. If arriving by bus, you will be 
reimbursed upon provision of proper receipts. Taxi fare (including Uber or Lyft) will not be 
reimbursed.  


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Effects of transdermal nicotine on response inhibition to emotional cues in 
schizophrenia 
Version Date: 
PI: 
02 
10/23/2019 
Alan Lewis, MD, PhD 
  
 
 
 
 
3 
As an identifier for internal auditing purposes, your social security number is needed because 
you are receiving payment for taking part in this study. Vanderbilt University Medical Center is 
required to tell the IRS of any payments to you as a subject in research studies in a given 
calendar year totaling $600 or more. If that occurs, you will receive a 1099 form at the end of 
the year. No information identifying why you received payment is given to the Hospital’s 
accounting department or the government. This information is kept strictly confidential. 
 
Costs to you if you take part in this study:  
There is no cost to you for taking part in this study. 
 
Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of 
the tests or treatments that are done for research, then you and/or your insurance will not have 
to pay for the cost of immediate medical care provided at Vanderbilt to treat the injury.  
 
There are no plans for Vanderbilt or the National Institute of Mental Health to pay for any injury 
caused by the usual care you would normally receive for treating your illness or the costs of any 
additional care. There are no plans for Vanderbilt National Institute of Mental Health to give you 
money for the injury.  
 
Who to call for any questions or in case you are injured: 
If you should have any questions about this research study or if you feel you have been hurt by 
being a part of this study, please feel free to contact Alan Lewis, MD, PhD at 615-875-4027.   
 
For additional information about giving consent or your rights as a person in this study, to 
discuss problems, concerns, and questions, or to offer input, please feel free to call the VUMC 
Institutional Review Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
 
Reasons why the study doctor may take you out of this study:  
Dr. Lewis can remove you from the study at any time if it is in your best interest or the best 
interest of the study. Potential reasons can include development of adverse events from the 
study drug or study procedure that might lead to concerns about your safety, as well as difficulty 
with following study instructions or poor compliance. Dr. Lewis will tell you why if you are 
removed from the study without your permission. If there are any new significant findings that 
may affect your desire to take part in this study, you will be told right away. 
 
What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor.  Deciding to not 
be part of the study will not change your regular medical care in any way. 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Effects of transdermal nicotine on response inhibition to emotional cues in 
schizophrenia 
Version Date: 
PI: 
02 
10/23/2019 
Alan Lewis, MD, PhD 
  
 
 
 
 
4 
 
Clinical Trials Registry:  
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will 
include a summary of the results.  You can search this Web site at any time. 
 
Confidentiality:   
All efforts, within reason, will be made to keep your personal information in your research 
record confidential but total confidentiality cannot be guaranteed. Electronic databases 
containing identifiable subject information will be password encoded. Written information 
containing subject identifiers (informed consent, payment forms, etc.) will be stored in 
locked file cabinets in offices within the Department of Psychiatry. Subjects will be assigned 
an alphanumeric code that will be used to label all research data including all questionnaires. 
 
This study may have some support from the National Institutes of Health (NIH). If so, your study 
information is protected by a Certificate of Confidentiality.  This Certificate allows us, in some 
cases, to refuse to give out your information even if requested using legal means.  
  
It does not protect information that we have to report by law, such as child abuse or some 
infectious diseases.  The Certificate does not prevent us from disclosing your information if we 
learn of possible harm to yourself or others, or if you need medical help.  
  
Disclosures that you consent to in this document are not protected. This includes putting 
research data in the medical record or sharing research data for this study or future 
research. Disclosures that you make yourself are also not protected.  
 
Privacy: 
Any samples and information about you may be made available to others to use for research.  To 
protect your privacy, we will not release your name.  You will not receive any benefit as a result 
of the tests done on your samples.  These tests may help us or other researchers learn more about 
the causes, risks, treatments, or how to prevent this and other health problems.  
 
Study Results: 
Your individual study results will not be shared with you. The final results of the study will be 
made available through www.clinicaltrials.gov and potentially through publication in the 
scientific literature.  
 
 
 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Effects of transdermal nicotine on response inhibition to emotional cues in 
schizophrenia 
Version Date: 
PI: 
02 
10/23/2019 
Alan Lewis, MD, PhD 
  
 
 
 
 
5 
Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information.  By 
signing this document, you agree that your health care providers (including both Vanderbilt 
University Medical Center and others) may release your private health information to us, and 
that we may use any and all of your information that the study team believes it needs to 
conduct the study.  Your private information may include things learned from the procedures 
described in this consent form, as well as information from your medical record (which may 
include information such as HIV status, drug, alcohol or STD treatment, genetic test results, or 
mental health treatment).    
  
Who will see, use or share the information? 
The people who may request, receive or use your private health information include the 
researchers and their staff.  Additionally, we may share your information with other people at 
Vanderbilt, for example if needed for your clinical care or study oversight.  By signing this form, 
you give permission to the research team to share your information with others outside of 
Vanderbilt University Medical Center.  This may include the sponsor of the study and its agents 
or contractors, outside providers, study safety monitors, government agencies, other sites in the 
study, data managers and other agents and contractors used by the study team.   We try to 
make sure that everyone who sees your information keeps it confidential, but we cannot 
guarantee that your information will not be shared with others.  If your information is disclosed 
by your health care providers or the research team to others, federal and state confidentiality 
laws may no longer protect it.  
  
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
  
How long will your information be used or shared? 
Your Authorization for the collection, use, and sharing of your information does not 
expire.  Additionally, you agree that your information may be used for similar or related future 
research studies. 
  
What if you change your mind? 
You may change your mind and cancel this Authorization at any time.  If you cancel, you must 
contact the Principal Investigator in writing to let them know by using the contact information 
provided in this consent form.  Your cancellation will not affect information already collected in 
the study, or information that has already been shared with others before you cancelled your 
authorization. 
 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Effects of transdermal nicotine on response inhibition to emotional cues in 
schizophrenia 
Version Date: 
PI: 
02 
10/23/2019 
Alan Lewis, MD, PhD 
  
 
 
 
 
6 
If you decide not to take part in this research study, it will not affect your treatment, payment 
or enrollment in any health plans or affect your ability to get benefits. You will get a copy of 
this form after it is signed.  
 
 
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature of patient/volunteer  
 
 
 
 
 
Consent obtained by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title  
 
Time: ______________  
 
 
 

Prot_SAP_004.pdf: 
 
 
 
 
Official title of study: Effects of transdermal nicotine on response inhibition to 
emotional cues in schizophrenia 
 
NCT number: NCT03838484 
 
Date of document: 10/23/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 


1 
 
 
 
Effects of transdermal nicotine on response inhibition  
to emotional cues in schizophrenia  
 
Protocol short title: Nicotine and response inhibition 
 
 
Protocol Number: 190021 
 
 
 
Alan Lewis, M.D., Ph.D. 
Department of Psychiatry and Behavioral Sciences 
Vanderbilt University Medical Center 
465 21st Avenue S. MRBIII, Room 6140B, Nashville, TN, 37240 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
 
Table of Contents: 
1 
Background ............................................................................................................. 4 
2 
Rationale and specific aims .................................................................................... 4 
3 
Animal studies and previous human studies ........................................................ 6 
3.1 
Animal studies .................................................................................................... 6 
3.2 
Human studies .................................................................................................... 6 
4 
Inclusion/exclusion criteria .................................................................................... 7 
4.1 
Inclusion criteria for schizophrenia subjects ........................................................ 7 
4.2 
Exclusion criteria for schizophrenia subjects ....................................................... 8 
4.3 
Inclusion criteria for healthy controls ................................................................... 8 
4.4 
Exclusion criteria for healthy controls .................................................................. 8 
5 
Enrollment/randomization ...................................................................................... 9 
5.1 
Subject recruitment and enrollment .................................................................... 9 
5.2 
Process of consent ............................................................................................. 9 
5.3 
Evaluation of subject capacity to provide informed consent .............................. 10 
5.4 
Randomization.................................................................................................. 10 
6 
Study Procedures .................................................................................................. 10 
6.1 
Baseline: day 0 ................................................................................................. 10 
6.2 
Testing: days 1 and 2 ....................................................................................... 11 
7 
Study drug ............................................................................................................. 12 
7.1 
Background ...................................................................................................... 13 
7.2 
Drug source ...................................................................................................... 13 
7.3 
Storage, preparation and use ........................................................................... 13 
7.4 
Justification for the use of placebo .................................................................... 13 
8 
Risks, minimizing risks, and potential benefits .................................................. 13 
8.1 
Risks ................................................................................................................ 13 
8.1.1 
Study medication: transdermal nicotine...................................................... 13 
8.1.2 
Psychological assessments and Emotional Go/NoGo task ........................ 14 
8.1.3 
Electroencephalography (EEG) ................................................................. 15 
8.2 
Minimizing Risks ............................................................................................... 15 
8.2.1 
Risk of study medication ............................................................................ 15 
8.2.2 
Risk of psychological assessments and Emotional Go/NoGo task ............. 15 
8.2.3 
Electroencephalography (EEG) ................................................................. 15 
8.2.4 
Risk of breach of data security and privacy ................................................ 15 
8.2.5 
Subject Monitoring and Emergency Procedures ........................................ 16 
8.3 
Potential benefits .............................................................................................. 16 
9 
Research alternatives and economic considerations ......................................... 16 
9.1 
Alternatives to participation in the study ............................................................ 16 
9.2 
Payments for participation ................................................................................ 16 
9.3 
Costs for participation ....................................................................................... 17 
9.4 
Medical treatment in case of injury .................................................................... 17 
10 
Reporting of adverse events or unanticipated problems involving risk to 
participants or others ................................................................................................. 17 
10.1 
Greater than minimal risk Data and Safety Monitoring Plan ............................ 17 
10.1.1 
Personnel responsible for the safety review and its frequency ................. 18 
10.1.2 
Attribution of adverse events .................................................................... 18 
10.1.3 
Plan for grading adverse events............................................................... 18 
10.1.4 
Plan for determining seriousness of adverse events ................................ 18 
10.1.5 
Plan for reporting Unanticipated Problems Involving Risks to Subjects or 
Others (UPIRSOs, including Adverse Events) to the IRB ....................................... 19 


3 
 
 
 
10.1.6 
Plan for reporting adverse events to co-investigators on the study, DSMBs, 
study sponsors, funding and regulatory agencies, and regulatory and decision-
making bodies. ...................................................................................................... 19 
11 
Study withdrawal/discontinuation ...................................................................... 20 
12 
Statistical considerations ................................................................................... 20 
12.1 
Power analysis ............................................................................................... 20 
12.2 
Data analysis plan .......................................................................................... 21 
12.3 
Inclusion of men and women .......................................................................... 21 
13 
Privacy/confidentiality issues............................................................................. 21 
14 
Follow-up and record retention .......................................................................... 21 
 
 


4 
 
 
 
1 
Background 
 
Aggressive behavior can be largely divided into either instrumental aggression, which is 
purposeful aggression to obtain a desired outcome, or impulsive aggression, which is 
sudden, inappropriate aggression mounted in the context of strong emotion such as 
anger or frustration.1 Impulsive aggression frequently complicates severe 
neuropsychiatric disorders occurring across the lifespan, worsens outcomes,2 and 
isolates patients from their communities. Management of persistent impulsive 
aggression is an unmet challenge for diverse healthcare settings such as residential and 
nursing treatment facilities, civil and forensic psychiatric hospitals, and criminal justice 
settings.3, 4 For example, while the majority of people with schizophrenia spectrum 
disorders are not violent, such conditions confer an aggregate increased risk of violence 
and aggression,5-7 with more than half of patients in forensic psychiatric settings 
diagnosed with schizophrenia.8 In recent decades, such patients have increasingly been 
institutionalized in prisons and jails9 at a cost of more than $14 billion,10 yet still receive 
substandard care11 and have high rates of reincarceration.10 Vast expenditures to treat 
aggression also occur in non-correctional settings. For example, one-third of the total 
$236 billion cost to treat Alzheimer’s disease in the U.S. is spent to manage behavioral 
and psychological symptoms, including aggression.12, 13 Current treatment approaches 
for aggression in neuropsychiatric disorders incorporate environmental, behavioral, and 
pharmacological interventions,4 yet aggressive behaviors commonly remain treatment-
resistant.3, 14-16 For these patients, psychopharmacological agents with diverse 
pharmacological actions are trialed off-label, despite limited pathophysiological rationale, 
inconsistent clinical benefit,5, 17 and increased morbidity or mortality.18 To address this 
growing need with important individual and societal implications, novel therapeutic 
approaches must be designed based on an increased understanding of the neural 
circuits governing aggressive behavior.  
 
2 
Rationale and specific aims 
 
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), our 
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,19 and multiple human laboratory studies demonstrate an anti-
aggressive effect of nicotine in humans.20-22 As detailed in section 3.1, our laboratory has 
also demonstrated that acute administration of nicotine at relatively low doses results in 
reduction of aggressive behaviors in mouse models.23, 24 Because nicotine is active at all 
nAChRs, we explored this mechanism further and found that hippocampal alpha-7 
nAChRs were both necessary and sufficient for nicotine’s serenic effect.23, 24 Consistent 
with these findings, there is substantial evidence in humans that reduction of alpha-7 
nAChR signaling enhances aggressive behavior,25 including in individuals with 15q13.3 


5 
 
 
 
microdeletion syndrome, a genetic disorder resulting from the deletion of the region of 
chromosome 15 containing the gene coding for alpha-7 nAChRs.26, 27 We have also 
translated these findings into human clinical populations. We recently demonstrated the 
safety and efficacy of transdermal nicotine to reduce aggression and irritability in young 
adults with autism spectrum disorder,28 described in section 3.2. This work, along with 
other previous case studies in humans,29-31 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,32 and explains a large degree of variance in the 
development of impulsive aggression in subjects with schizophrenia33 and other 
populations without psychiatric disorders.34 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.33 A number of previous 
studies have similarly demonstrated impulsivity in the context of negative emotion, called 
“negative urgency”, correlates with history of aggression,35, 36 as well as substance use 
and other risky behaviors 37. Urgency is a hereditable trait38 that may be considered an 
endophenotype of impulsive aggression.39  
 
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.36 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,40 as well as a 
relationship between emotional valence, impulsive errors, history of violence, and frontal 
cortex 5-HT1B receptor binding.41  
 
While our studies in mice suggest a direct effect of nAChR stimulation on aggression 
through activation of the alpha-7 nAChR23, 24 and are supported by our results using 
transdermal nicotine in humans,28, 31 to our 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. We 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 
 
 
 
3 
Animal studies and previous human studies 
 
3.1 
Animal studies 
There exists an extensive literature on the effects of nicotine on animal behavior. As 
noted above, nicotine has a substantial evidence base suggesting it may have specific 
serenic effects, i.e. the ability to reduce aggressive behavior (reviewed in 42). Our 
laboratory has performed several lines of studies aimed at understanding how nAChRs, 
in particular alpha-7 nAChRs, regulate aggressive and related behaviors in mice.23, 43 We 
first replicated previous studies demonstrating a dose-dependent reduction in aggressive 
behavior by intraperitoneal administration of nicotine. We then found that blockade of 
alpha-7 nAChRs, but not beta-2-containing nAChRs, blocked the serenic effects of 
nicotine, implicating a specific role for alpha-7 nAChRs in nicotine’s serenic effects. We 
also found that specific agonism of alpha-7 nAChRs through the alpha-7 nAChR partial 
agonist GTS-21 recapitulated nicotine’s serenic effects. Consistent with alpha-7 nAChRs 
localization on GABAergic inhibitory interneurons in the dentate gyrus of the 
hippocampus, we found that GTS-21 reduces activation of the dentate gyrus, and that 
knockdown of alpha-7 nAChRs reduces GTS-21’s serenic effect.24 These findings 
suggest that nicotine exerts its effect, at least in part, via hippocampal inhibition thorugh 
alpha-7 nAChR signaling, consistent with findings from human neuroimaging studies.44  
 
Effects of nicotine and nAChR stimulation on impulsivity in rodents have also been 
studied, in part inspired by the relationship between higher levels of smoking in 
individuals with neuropsychiatric disorders demonstrating poor impulsive control, such 
as attention deficit hyperactivity disorder (ADHD) and schizophrenia.45 Mice performing 
an operant task that measured premature and signaled nose pokes and performance 
efficiency found that acute administration of nicotine improved performance efficiency, 
however chronic nicotine and nicotine withdrawal did not affect performance efficiency.46 
However, interestingly forms of motor of choice impulsivity do not rely on beta-2-
contaning nAChRs.47 Mice with genetic deletion of the alpha-7 nAChR demonstrate 
increased impulsivity compared to wildtype mice in the five-choice serial reaction time 
task,48 whereas no other nAChR knockout mouse line demonstrated changes on this 
task. Interestingly, encenicline (EVP-6124), also an alpha-7 nAchR partial agonist, 
demonstrated improvements in impulsive action in rats in the 5 choice-continuous 
performance task.49 These findings support the relationship between the alpha-7 nAChR 
and regulation of impulsivity, as well as the potential to improve impulsive responding 
through its pharmacological targeting by nicotine.  
 
 
3.2 
Human studies 
While the effects of nicotine on response inhibition to emotional cues are unknown, 
previous studies of acutely administered nicotine in humans have shown effects on 
closely related behavioral constructs and effects on hippocampal inhibition, which we 
believe is mechanistically important for nicotine’s serenic effects.43 Transdermal nicotine 
improves performance on the Continuous Performance Test Identical Pairs (CPT-IP) 
Version in both healthy controls and non-smoking patients with schizophrenia, with 
improvements to a greater extent in the schizophrenia patients.50 These findings extend 
previous work demonstrating positive effects on attention in patients with schizophrenia 
of acutely administered nicotine.51, 52 Clinical trials and case series have demonstrated 
effects of nicotine on reduction of agitation and aggression in subjects with 
schizophrenia presenting to an emergency department53 and in elderly subjects with 
severe dementia.29, 30 Nicotine was also shown in subjects experiencing nicotine 


7 
 
 
 
withdrawal to return provoked aggression in a laboratory paradigm back to baseline 
levels.22 
 
Multiple lines of evidence suggest that pan-activation of nAChRs by nicotine, and more 
selective activation of alpha-7 nAChRs may influence aggression and related behaviors 
through effects on regulatory circuitry of affect. For instance, an open label study of 
transdermal nicotine recently demonstrated substantially improvement in mood 
symptoms in a population of older adults with late-life depression,54 in agreement with 
multiple previous studies reporting improvement in mood symptoms by transdermal 
nicotine.55-57 Our group also found in a secondary analysis of data from a randomized, 
double blind, placebo controlled study of GTS-21 in patients with schizophrenia that 
GTS-21 exerts a specific beneficial effect on affect and mood, as measured by the Brief 
Psychiatric Rating Scale.58 
 
Several studies have explored the effects of acute administration of nicotine and 
selective alpha-7 nAChR agonists on brain activity in regions important for cognition, 
impulsivity, and aggression.59 For example, acute administration of transdermal nicotine, 
7 mg, in subjects with schizophrenia restored connectivity in the ventral attention 
network during a go/no-go task with environmental noise distractors,60 as well as 
modulated neuronal responses in several brain regions during an auditory selective 
attention task with environmental noise distractors.61 An alpha-7 partial agonist was also 
shown to reduce hippocampal hyperexcitability during a smooth pursuit eye movement 
task in subjects with schizophrenia,44 as well as influence default mode network activity 
in schizophrenia.62 Positron Emission Tomography (PET) studies also interestingly 
demonstrated an interaction between trait hostility and brain metabolism in smokers and 
non-smokers administered acute nicotine by transdermal patch performing a provoked 
aggression task.63, 64    
 
Taken together, previous investigation suggests that acute administration of nicotine in 
subjects with schizophrenia can influence cognitive processes related to impulsivity and 
aggression, and target neural substrates overlapping with key brain regions for 
aggression and impulsivity identified from mouse models. These studies provide strong 
rationale to directly test the effects of nicotine on response inhibition to emotional cues, 
which would provide strong evidence to support targeting nAChRs for aggression and 
related behaviors in clinical populations. 
 
 
4 
Inclusion/exclusion criteria 
 
4.1 
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 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-


8 
 
 
 
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 urinary 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. 
 
4.2 
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. 
 
4.3 
Inclusion criteria for healthy controls 
All of the above except for subjects will be psychiatrically healthy and not taking 
psychotropic or potentially psychoactive prescription medication. 
 
4.4 
Exclusion criteria for healthy controls 
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.) 


9 
 
 
 
5 
Enrollment/randomization 
 
5.1 
Subject recruitment and enrollment 
The research team will identify potential subjects by morning reports at the Psychotic 
Disorders Research Program at the Vanderbilt Psychiatric Hospital and other IRB 
approved screening information, and/or by review of provider’s caseloads at Vanderbilt 
using eStar/EPIC. Potential subjects may also be identified by broadly targeted 
advertisements with IRB approval. Patient information will be reviewed only for the 
purposes of determining possible eligibility for the study. All screening information 
obtained during these reviews will be documented on a screening form or in a password-
protected database. Screening databases will include inclusion/exclusion information, as 
well as the patient’s name, medical record number, appointment times/dates (for 
outpatients), and the name of the clinical care provider. All identifying information, such 
as name, medical record number, and contact information, will be stored in a password-
protected database. These databases and subject screening forms will be kept for 
internal monitoring purposes only (i.e., tracking of primary reasons for exclusion from the 
study). When adult patients (ages 18 to 65) are recruited directly from a mental health 
clinic or hospital, the subject’s clinical care provider will first determine whether or not it 
is appropriate for us to invite the subject for participation in the study, and the subject 
must agree to being approached. Adolescent patients (13-17 years old) will not be 
recruited for this study. Advertising materials may be distributed to physicians’ offices 
and outpatient clinic waiting rooms for the purpose of informing the patient and clinical 
care providers about the study, but providers who are not part of our study staff will not 
be asked to describe any part of the study to the patient. Providers will only be asked to 
inquire about the patient’s interest in hearing about research in general. Providers may 
be contacted by study staff through email, phone, secure EPIC messaging, face-to-face, 
or by flagging patient charts through front desk staff or inpatient unit staff. Information 
will not be provided to front desk staff or inpatient unit staff regarding which study the 
patient is being considered for. We will only recruit patients who are stable. Patients who 
initiate contact with study personnel in response to an advertisement or flyer will be 
carefully prescreened and have a thorough clinical evaluation by the study doctor, study 
coordinator, or study personnel to determine stability of mood and medication. Patient 
information contained in subject databases may be used to telephone potential subjects. 
These databases will be comprised of subjects who have given prior consent to be 
contacted by various researchers about participation in research.  
 
 
5.2 
Process of consent 
Consent will be obtained from participants in a private office at the VPH on the screening 
visit. The subject and one of the investigators will necessarily be present for the consent 
process. Participants who are accompanied by a family member or caregiver will be 
allowed the option of having that person in the room if desired. The inclusion and 
exclusion criteria will ensure that participants have capacity for informed consent (see 
below). Participants will be given ample time to ask questions during the consent 
procedure, and to consult family members or caregivers prior to making a decision if 
they so wish. Participants will be informed during the initial telephonic contact that they 
will be monetarily compensated for this initial visit whether or not they decide to 
participate in the study.  
 


10 
 
 
 
5.3 
Evaluation of subject capacity to provide informed consent 
During the screening process, the details of the study will be explained carefully to the 
subject. After time has been permitted for the participant to ask any clarifying questions, 
the subject will be asked to summarize their understanding of the procedures, risks and 
benefits of the study using a “talk back” method. The study personnel will address any 
inaccuracies, but after two attempts at clarification, if a subject is unable to give a 
reasonable account of the study procedures, risks and benefits, they will be considered 
to not have capacity for consent. As a board-certified psychiatrist, Dr. Lewis has 
extensive experience in capacity evaluations of individuals with psychiatric disorders, 
and will ensure research staff is trained to appropriately determine capacity to consent to 
the research study.  
 
 
5.4 
Randomization 
Treatment order will be block randomized by a member of the Center for Cognitive 
Medicine within the Department of Psychiatry at VUMC who is not otherwise involved in 
this study. All investigators and subjects will be blinded to treatment order. 
 
6 
Study Procedures 
 
All study procedures will take place at the Vanderbilt Psychiatric Hospital. We will recruit 
clinically stable outpatient adult men and women with schizophrenia or schizoaffective 
disorder, age 18-65, with similar clinical characteristics to those described in a previous 
clinical study of acute transdermal nicotine administration in subjects with schizophrenia 
and healthy controls.61 Inclusion and exclusion criteria are listed above in section 4. All 
participants will provide written informed consent. This study population, including non-
smoking patients with schizophrenia, has been consistently successfully recruited for 
imaging studies in the lab of Dr. Stephan Heckers, in the quantities necessary for the 
current project. 
 
6.1 
Baseline: day 0 
Subjects completing a telephone or other initial screen will be invited to complete a 
baseline screening day in person. At this visit, a primary diagnosis of schizophrenia or 
schizoaffective disorder will be confirmed by clinical interview and/or the Structured 
Clinical Interview for DSM-V (SCID). A full screening interview will be performed to 
include medical, psychiatric, and substance use history, and mental status exam. 
Inclusion and exclusion criteria will again be fully reviewed with the potential subject. The 
consent documentation will be reviewed with the subject and all participants will provide 
written informed consent. Subjects will be monetarily compensated for their time spent in 
the initial screening visit regardless of their subsequent involvement in the study. 
 
Similar to previous studies related to impulsive aggression in schizophrenia,36 at 
baseline subjects will be administered the Brief Psychiatric Rating Scale (BPRS), the 
Barratt Impulsiveness Scale to measure trait impulsivity,65 the short version of the 
UPPS-P (S-UPPS-P) to measure urgency and related impulsive constructs,66 the Buss-
Perry Aggression Questionnaire67 to determine aggressive attitudes, and the Kaufman 
Brief Intelligence Test-2 (K-BIT-II). Subjects will provide urine samples to test for cotinine 
to confirm smoking abstinence, and they will also provide urine samples for urine 
pregnancy testing (if female) and toxicology. Electrocardiograms will be obtained as part 
of the screening medical evaluation. At the conclusion of the screening visit, if the 


11 
 
 
 
subject qualifies for the study and gives informed consent, the subject will be scheduled 
to return for day 1 of the study.  
 
In some instances, the screening visit will be combined with the first testing session. This 
is to reduce the logistical burden for subjects for whom transportation may be difficult, as 
well as for individuals who may have difficulty getting time off from work. It is anticipated 
that this will reduce the number of subjects who drop out from the study without 
compromising subject safety.   
 
6.2 
Testing: days 1 and 2 
Testing occurs on two days separated by approximately one week, but no sooner than 5 
days apart (Figure 1) to facilitate drug washout.68 Subjects will report to the Vanderbilt 
Psychiatric 
Hospital. Female 
subjects will be 
administered a 
point of care 
urine pregnancy 
test to confirm 
absence of 
pregnancy. 
Subjects will 
have affixed to 
their skin a 7 mg 
nicotine patch or 
identical 
appearing 
placebo, 
covered by 
surgical tape so 
that neither the 
subject nor the investigator can determine the identity. Previous studies of serum 
nicotine concentration suggests two hours post-patch application represents an 
approximate time of peak serum concentration in most subjects69 and is consistent with 
previously published protocols.60, 61 Subjects will begin the behavioral task accompanied 
by EEG monitoring at the latest 120 minutes after patch placement, and will complete 
the task approximately 12 minutes later. At they time they will provide a saliva sample. 
This sample will be affixed solely with a non-identifiable code, frozen, and shipped to Dr. 
William Kem, University of Florida, for analysis of salivary nicotine which has been 
shown to correlate with serum nicotine levels70 and eliminates the need for venipuncture. 
The patch will then be removed. 
 
As noted above, up to two hours after nicotine or placebo patch placement, subjects will 
begin participation in an Emotional Go/NoGo task, based on the procedure described by 
Egashira et al,40 which compared medicated subjects with schizophrenia to healthy 
subjects and found the patient group was significantly more affected by negative 
emotional valence than were healthy controls despite only modest group differences with 
neutral valence stimuli. Subjects will also undergo electroencephalography during 
performance of the behavioral task.  Fearful, sad, angry, and disgust faces (negative 
valence) and neutral faces will be taken from UPenn’s publicly available PERT-96 color 
emotional stimuli bank.71 The entire task takes ~12 mins, including breaks, and is 


12 
 
 
 
performed in 5 blocks of 32 trials, with 3 emotional blocks with angry/fearful/sad/disgust 
faces and 2 non-emotional blocks (Figure 1). Each stimulus is presented for 1 s with a 1 
s interstimulus interval. In each block the subject is instructed on the go/no-go targets, 
each comprising 50% of the task stimuli, with instructions changing at the halfway point 
in each block. Each block contains two instructions. For example: Emotional blocks: go-
angry/nogo-fear or go-fear/nogo-angry; Non-emotional blocks: go-male/nogo-female or 
go-female/nogo-male (Figure 2). Error rates and reaction times are recorded. 
 
Figure 2 Emotional Go/NoGo schematic. Subjects are given a target instruction at the start of each 
block for 6 seconds. There is 1 second of blank screen between each 1 second stimulus presentation. 
In this schematic, the subject would press a key (“Go”) when presented with the first stimulus 
(angry; green border represents the correct response is “Go”. This border would not be present in 
the actual task), and withhold pressing a key for the second stimulus (sad; red border).  
 
Subjects will be monitored for at least 30 minutes after patch removal to confirm the 
absence of side effects that would compromise their safety upon leaving the hospital.  
 
Subjects will return for day 2 of testing not less than 5 days following day 1. On day 2, 
subjects will receive the treatment they did not receive on day 1. They will be asked a 
series of standard questions to assess for the presence of any side effects following their 
initial study day. If female, they will again be administered a urine pregnancy test to 
confirm the absence of pregnancy. The remainder of the procedure will be identical to 
day 1.   
 
7 
Study drug 
 


13 
 
 
 
7.1 
Background 
Please see section 3.2 for a description of acute transdermal nicotine use in humans for 
cognitive and behavioral outcomes. 
 
7.2 
Drug source 
Nicotine patches will be purchased from a commercial source and provided to subjects 
free of charge. The investigators will provide the study drug through project funding by 
the National Institutes of Health and Vanderbilt University Medical Center Department of 
Psychiatry and Behavioral Sciences.  
 
7.3 
Storage, preparation and use 
Nicotine patches will be stored according to manufacturer’s instruction. Prior to use, all 
patches will be covered with surgical tape. Patches will be prepared by an unblinded 
staff member of the Vanderbilt Center for Cognitive Medicine (CCM) who is not affiliated 
with the study but is responsible for drug randomization. For subjects who are to receive 
active drug on that day, the backing will be peeled off the patch and affixed to the 
subject’s arm and sealed in place by surgical tape. For subjects who are to receive 
placebo on that day, the backing will be not be peeled off the patch, and the patch will be 
affixed to the subject’s arm and sealed in place by surgical tape. The CCM staff member 
will affix the patch in all cases, in general to the upper arm so that the patch will 
subsequently be hidden below sleeves. 
 
7.4 
Justification for the use of placebo 
The study is a crossover trial whereby all participants will receive one dose of nicotine 
and all participants will receive one dose of placebo. As this study is not designed to 
treat symptoms for a clinical benefit, we anticipate no potential harm that may come to 
the participant as a result of receiving placebo. Subjects will continue on their outpatient 
medications during this study. 
 
8 
Risks, minimizing risks, and potential benefits 
 
8.1 
Risks 
The reasonably foreseeable risks to subjects in this study include a) study medication, b) 
psychological and behavioral assessments, and c) breach of data security and privacy. 
There may also be unknown or unanticipated adverse effects. 
 
8.1.1 Study medication: transdermal nicotine 
Side effects of transdermal nicotine exposure have been well characterized, and 
participants may experience nausea, headache, skin irritation, palpitations, and 
dizziness. These side effects were found to be dose related in healthy, non-smoking 
subjects, with 15 mg nicotine patch significantly less likely to cause side effects than 
higher dose such as 30 mg.72 Specifically, in this study 8 non-smoking patients were 
given a 15 mg nicotine patch. Five of 8 patients experienced mild nausea and 
lightheadedness after one hour, while 3 of 8 did not have any side effects. Seven of 8 
patients continued with the study. Other studies have demonstrated that development of 
nicotine side effects is highly related to rate of increase and peak concentration of 
plasma nicotine.69 Studies of chronic transdermal nicotine in non-smoking populations 
are very encouraging regarding tolerability. In a large study of transdermal nicotine for 
treating mild cognitive impairment in older adults, tolerability was excellent in the over 30 


14 
 
 
 
subjects randomized to nicotine treatment.73 Transdermal nicotine use has been 
successfully reported in case series or trials of patients with advanced dementia and 
age, a population that is likely to be increasingly sensitive to nicotine than younger, 
healthier subjects in this study.29, 30, 73-75  
 
The question of development of physiological dependence or even nicotine use disorder 
secondary to patch exposure in non-smoking participants is an important one. The 
likelihood can be based on previous studies in non-smoking participants that were 
conducted for significantly longer periods of time than in the proposed study. Nicotine 
patch has been used for 4-weeks in patients with mild-moderate Alzheimer’s Disease for 
16 hours per day, initially using 5 mg patches for 7 days, 10 mg patches for 14 days, and 
finally 5 mg patches for 7 days.74 In general, patches were well tolerated, with only one 
of 8 subjects discontinuing. There were no observed nicotine withdrawal symptoms in 
these participants. Sleep interruption was not problematic as the patches were removed 
at bedtime. An almost identical study was performed with 15 subjects with age-
associated memory impairment using the same nicotine patch dose.75 Only one of 15 
subjects withdrew from this study due to nicotine-related side effects, in this case, 
nausea. In this study, the most common side effects were local skin irritation, mild 
nausea and abdominal discomfort, and lightheadedness. Two subjects reported 
palpitations, but there was no change in body weight, blood pressure, or heart rate in 
subjects receiving nicotine compared to receiving placebo. No subjects appeared 
physiologically or psychologically dependent on the nicotine patches. In a 6-month trial 
of transdermal nicotine or placebo to treat mild cognitive impairment, no subjects (0 of 
34 subjects) developed withdrawal or continued to use nicotine products following the 
study.73 Data from studies of smokers, who might be predisposed to difficulty 
discontinuing nicotine-containing products, demonstrated that difficulty with 
discontinuation of transdermal nicotine after use for smoking cessation was rare (2%), 
with the percentage of smokers continuing to use nicotine replacement products 
proportional to the rate of nicotine delivery.76 Taken together, these previous studies are 
reassuring regarding the safety of nicotine products from an addiction potential 
standpoint in non-smoking subjects.  
 
8.1.2 Psychological assessments and Emotional Go/NoGo task  
At screening, subjects will undergo non-invasive psychological assessment of a 
structured nature that has been consistently used without adverse effects in previous 
studies with a similar subject population. On testing days, subjects will perform the 
Emotional Go/NoGo task to measure impulsivity in an emotional context, a behavioral 
construct related to impulsive aggression. This task has been administered to healthy 
controls as well as patients with schizophrenia without report of adverse events.36 There 
is the potential risk that subjects may become fatigued during the performance of 
screening assessments or behavioral tasks, and that discussion of personal issues with 
study personnel in the context of screening issues may be stressful or uncomfortable. 
Because subjects participating in this study will be stable outpatients, it is unlikely that 
the stress posed by such measures will exacerbate baseline psychiatric symptoms.  
 


15 
 
 
 
8.1.3 Electroencephalography (EEG) 
Subjects will undergo (EEG) using an EEG cap while performing the emotional Go/NoGo 
task. The risks of EEG are minimal and include risk of mild discomfort while wearing the 
EEG cap.  
 
 
8.2 
Minimizing Risks 
8.2.1 Risk of study medication 
Dependance: Please see above for a discussion regarding the risk of development of 
dependence. We chose transdermal delivery of nicotine because its slow rate of delivery 
significantly reduces the risk of dependence development.76  
 
Discomfort: The potential for discomfort will be clearly explained to subjects. Subjects 
experiencing discomfort who wish to have the patch removed will immediately have their 
patch removed, and symptoms will subside shortly thereafter. Placebo patches will be 
handled in exactly the same manner, with the same ability to remove as described 
above. It should be noted that nicotine patches have been used successfully in 
populations with cardiovascular disease.77 Although subjects with known cardiac 
conduction abnormalities or poorly treated hypertension as assessed during screening 
will be excluded, these data are reassuring given the possibility of enrolling a subject 
with a previously undiagnosed cardiovascular condition.   
 
8.2.2 Risk of psychological assessments and Emotional Go/NoGo task 
The primary protection against risk for this aspect of the study is the continuous 
explanation of study procedures, the reasoning for their use, ongoing confirmation that 
subjects understand these explanations, and consistent communication of the voluntary 
nature of the study. While it is very unlikely, there is always the theoretical risk of 
exacerbation of psychiatric symptoms in individuals with schizophrenia due to stressful 
experiences. Again, a thorough understanding of assessments and behavioral tasks 
mitigates this risk. The use of standardized Subject Monitoring and Emergency 
Procedures, described below, will further guard against harm to subjects in the event of 
exacerbation of psychiatric symptoms.  
8.2.3 Electroencephalography (EEG) 
The risks of EEG are minimal. Potential discomfort of wearing the EEG cap will be 
minimized by ensuring the correct fitting on the subject’s head.  
 
8.2.4 Risk of breach of data security and privacy  
Data obtained from human subjects will be confidential and accessed only by members 
of the study team with appropriate IRB and HIPAA training, as assured by standard 
training protocols at VUMC. Data is maintained and secured in locked file cabinets or on 
encrypted, password protected computers, located in locked offices, and following 
Health Insurance Portability and Accountability Act (HIPAA) guidelines and the policies 
and procedures of VU and VUMC. Individuals will be identified by a numerical code that 
will be kept separate from study data.   
 


16 
 
 
 
8.2.5 Subject Monitoring and Emergency Procedures 
Throughout the baseline assessment and two study days subjects are closely monitored 
by an experienced clinical research team, under the supervision of Dr. Lewis. Subjects 
performing the Emotional Go/NoGo task and electroencephalographic recording will be 
monitored by at least one member of the research team. All members of the research 
team are familiar with the established VU/VUMC emergency plans in the case of a 
medical or psychiatric emergency. In the case of a medical emergency, a medical 
response team at VPH will provide immediate first aid and if deemed necessary, 
emergency medical services will be called by the VPH staff. VUMC’s Emergency 
Department is located one block away from VPH enabling rapid medical care. In the 
case of a psychiatric emergency, a crisis response team at VPH will respond, which has 
extensive training in crisis situations. Further crisis evaluation can be performed at VPH 
or VUMC Emergency Department, and though extraordinarily unlikely, inpatient 
psychiatric care can be provided through VPH. Dr. Lewis is a credentialed attending 
physician at VPH and can help arrange for this level of treatment should the need arise. 
 
8.3 
Potential benefits 
Subjects participating in these studies will receive basic medical and EKG assessments 
at no cost to them. Otherwise, there are no direct benefits to the subjects participating in 
this research. The long-term potential benefit of this study is a mechanistically directed 
approach toward treatment of impulsive aggression arising in serious psychiatric 
disorders. Every research study requires the potential benefits to outweigh the potential 
risks of the study. The potential benefit of reducing the burden of impulsive aggression is 
significant for public health, including for patients, their families, communities, healthcare 
systems, and criminal justice systems. While the study procedure confers greater than 
minimal risk, the low likelihood of serious adverse effects is outweighed by the potential 
public health benefits stemming from the potential results of this study and subsequent 
studies based on these results.  
  
 
9 
Research alternatives and economic considerations 
 
9.1 
Alternatives to participation in the study 
This is not a treatment study. Therefore, the study subjects may continue their usual 
outpatient treatment. If the subject is interested in identifying outpatient treatment 
options for their psychiatric disorder, the study staff may help the subject identify 
appropriate locations. 
 
9.2 
Payments for participation 
All study subjects will be remunerated $25 for completion of the screening visit, 
regardless of their decision to enroll in the study or their eligibility to enroll. Because of 
the crossover nature of the study, subjects only yield meaningful primary outcome data if 
they complete both testing session. They will therefore be compensated an additional 
$100 at the completion of their second testing visit. They will not be compensated if they 
only complete one testing visit. This incentivization is designed to yield greater benefit 
from the research, thereby improving the risk/benefit ratio of the study. Subjects driving a 
private vehicle will also be reimbursed for travel expenses at the current IRS business 
mileage rate and reimbursed for four hours of parking or reimbursed for the cost of an 
entire day of bus fare. Taxi fare or related (i.e. Uber, Lyft) will not be reimbursed. 
Subjects must provide appropriate receipts to the study staff.   


17 
 
 
 
 
9.3 
Costs for participation  
As noted above, subjects will be reimbursed for travel to the study site. All procedures 
will be provided to subjects at no cost. This includes an electrocardiogram, as described 
above in detail. Study drug will be provided at no cost. 
 
9.4 
Medical treatment in case of injury  
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct 
result of the tests or treatments that are done for research, the subject will be provided 
immediate medical care at Vanderbilt to treat the injury at no cost to the subject or the 
subject’s insurance. In the absence of an immediate need for medical care, there will be 
no additional medical treatment available to subjects above and beyond what was 
available prior to initiating the study. Either licensed physicians or study staff working 
directly with licensed physicians will conduct the study visits. Emergency medical 
treatment is available at VUMC, less than one block from VPH. All study subjects will be 
able to contact study staff throughout their enrollment in the study. Study subjects will be 
informed regarding the policy noted above. Subjects will obtain treatment either from 
their current outpatient physicians or via emergency medical services, as recommended 
by the study physician. There are no limits to the treatment provided. Treatment 
decisions will be made entirely by the patient’s outpatient physician or emergency 
medical provider and will not be affected by the individual’s participation in the study. 
This is clearly described in the consent form. Study subjects will have the contact 
information of a licensed study physician at all times who will be available for 
consultation to determine whether the patient should seek medical treatment during the 
study. 
 
10 Reporting of adverse events or unanticipated problems involving risk 
to participants or others 
 
The investigator’s assessment of the overall risk level for subjects participating in this 
study is moderate. 
 
The risks associated with the current study are deemed greater than minimal for the 
following reasons:  
 
1. We do not view the risks associated with transdermal nicotine administration as 
minimal risks. 
2. Given the established safety of transdermal nicotine in prior work, we do not view 
the proposed studies as high risk. 
 
Although we have assessed the proposed study as one of greater than minimal risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or 
otherwise, to occur since it is not possible to predict with certainty the absolute risk in 
any given individual or in advance of first-hand experience with the proposed study 
methods. Therefore, we provide a plan for monitoring the data and safety of the 
proposed study as follows: 
 
10.1 Greater than minimal risk Data and Safety Monitoring Plan 
 


18 
 
 
 
10.1.1 Personnel responsible for the safety review and its frequency 
The principal investigator, Alan Lewis, M.D., Ph.D., will be responsible for monitoring the 
data, assuring protocol compliance, and conducting the safety reviews at the specified 
frequency, which must be conducted at a minimum of every 6 months (including when 
reapproval of the protocol is sought). He will perform this duty in close consultation with 
his academic mentors, Paul Newhouse, M.D. and Stephan Heckers, M.D. During the 
review process, the principal investigator will evaluate whether the study should continue 
unchanged, require modification/amendment, or close to enrollment. The principal 
investigator (Dr. Lewis), mentors (Drs. Newhouse and Heckers), or the IRB have the 
authority to stop or suspend the study or require modifications. A review of the study will 
be submitted annually to the Vanderbilt Human Research Protections Program 
(HRPP)/IRB as well as to the NIMH included in the annual progress report 
 
10.1.2 Attribution of adverse events 
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design by the principal investigator (Alan Lewis, 
M.D., Ph.D.) according to the following categories: 
 
1. Definite: Adverse event is clearly related to investigational 
procedures(s)/agent(s). 
2. Probable: Adverse event is likely related to investigational 
procedures(s)/agent(s). 
3. Possible: Adverse event may be related to investigational 
procedures(s)/agent(s). 
4. Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
5. Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s). 
 
10.1.3 Plan for grading adverse events 
The following scale will be used in grading the severity of adverse events noted during 
the study: 
 
1. Mild adverse event 
2. Moderate adverse event 
3. Severe  
 
10.1.4 Plan for determining seriousness of adverse events 
Serious Adverse Events: 
In addition to grading the adverse event, the PI will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered 
serious if it results in any of the following outcomes: 
 
1. Death; 
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization;  
3. A persistent or significant disability or incapacity;  


19 
 
 
 
4. A congenital anomaly or birth defect; OR 
5. Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the other outcomes listed in this definition.  
 
An adverse event may be graded as severe but still not meet the criteria for a Serious 
Adverse Event. Similarly, an adverse event may be graded as moderate but still meet 
the criteria for an SAE. It is important for the PI to consider the grade of the event as well 
as its “seriousness” when determining whether reporting to the IRB is necessary. 
 
10.1.5 Plan for reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs, including Adverse Events) to the IRB 
 
 
The principal investigator will report the following types of events to the IRB:  
Any incident, experience or outcome that meets ALL 3 of the following criteria: 
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) 
the research procedures described in the protocol-related documents, such 
as the IRB-approved protocol and informed consent document and (b) the 
characteristics of the subject population being studied; AND  
2. Is related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, legal, or social harm) than was 
previously known or recognized. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be 
medical or non-medical in nature, and include – but are not limited to – serious, 
unexpected, and related adverse events and unanticipated adverse device effects. 
Adverse events will be reported to the IRB as UPIRSOs only if they meet all 3 
criteria listed above. 
 
These UPIRSOs/SAEs will be reported to the VU IRB/HRPP via telephone. All related 
events involving risk but not meeting prompt reporting requirements will be reported to 
the IRB in summary form at the time of continuing review. If appropriate, such summary 
may be a simple brief statement that events have occurred at the expected frequency 
and level of severity as previously documented.  
 
10.1.6 Plan for reporting adverse events to co-investigators on the study, DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making 
bodies. 
 
The following individuals, funding, and/or regulatory agencies will be notified: 
• 
All Co-Investigators listed on the protocol. 


20 
 
 
 
• 
National Institutes of Health/National Institute of Mental Health. Notification will 
be to the attention of the Program Official assigned to the award supporting this 
study, Mark Chavez, Ph.D., mark.chavez@nih.gov, (301) 443-8942. 
 
The principal investigator (Alan Lewis, M.D., Ph.D.) will conduct a review of all adverse 
events upon completion of every study subject. The principal investigator will evaluate 
the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required. 
 
11 Study withdrawal/discontinuation 
 
Subjects may request to withdraw from the study at any time for any reason by 
contacting the study principal investigator or research team. Requests may be made via 
email, phone, or in writing, and study coordinator contact information will be provided on 
the study consent document. If the subject does not provide a reason for discontinuation, 
the study team will ask the subject if he/she would like to provide a reason for 
discontinuation, in the hopes to improve subject retention in the future.    
 
Every reasonable effort will be made to maximize subject retention. However, reasons 
for removal of participants from the study include the following: 
• 
Adverse experience: The participant has experienced an adverse event that, in 
the opinion of the investigator, requires early termination.  
• 
Death 
• 
Safety risk: Any participant who becomes a safety risk during the trial will be 
withdrawn. 
• 
Protocol violation: The participant fails to meet protocol entry criteria or did not 
adhere to protocol requirements. 
• 
Non-compliance: The participant is non-compliant with completion of study-
related evaluations and or use of study drugs. 
• 
In the investigator’s judgment, it is in the participant’s best interest to discontinue 
participation in the treatment/study. 
• 
Consent is withdrawn. The participant wishes to withdraw from the study, or the 
legally authorized representative wish the participant to be withdrawn.  
• 
Lost to follow up. Participant could not be recalled back to conduct treatment 
visit(s) 
 
12 Statistical considerations 
 
12.1 Power analysis 
Power analysis for error rates and reaction times is based on effect sizes from previous 
studies of the Emotional Go/NoGo task in subjects with schizophrenia40 and our 
preliminary data from a secondary analysis of a clinical trial of the alpha-7 nicotinic 
agonist GTS-21. With a sample size of 25 subjects, we will achieve 80% power at lpha 
= 0.05 to detect a difference from 35% to 10% in the omission error between two 
experimental conditions within a subject (expected correlation of 0.60) and to detect an 
effect size of 0.6 in the mean reaction times between the control and intervention 
conditions within a person using paired t-test at alpha = 0.05. The dropout rate in a 
similar published acute crossover study of schizophrenia patients was ~15%.78 We thus 
anticipate needing to enroll 30 subjects to result in 25 completers for an appropriately 
powered study. We will match this group with a healthy control sample of similar size. 


21 
 
 
 
 
12.2 Data analysis plan 
Omission error rate will be analyzed using non-linear mixed effects modeling of a binary 
outcome omission error (0/1), while reaction time will be analyzed with a linear mixed 
effects model. In both models, there will be a random effect for subject, a primary fixed 
independent predictor treatment condition (nicotine or placebo), an independent 
adjustment variable block valence (emotional vs. non-emotional task), and the 
interaction of the latter two predictors to examine whether the omission error rate or 
reaction time between two treatment conditions is moderated by the valence. 
Significance will be established at alpha = 0.05. 
 
We expect nicotine will reduce error rates in control blocks consistent with previous 
reports of improved attention with acute dosing of transdermal nicotine.51, 52 We expect 
to find an interaction between valence and treatment such that performance improves 
with nicotine to a significantly greater extent in negative valence blocks. We further 
expect this increase to be more prominent in individuals with schizophrenia than in 
healthy controls. We expect salivary nicotine concentration, which is proportional to 
serum nicotine,70 will correlate with improvement in response inhibition. Based on 
previous findings in the Emotional Go/NoGo task,40 we do not expect to find an effect of 
antipsychotic exposure, as measured by chlorpromazine equivalents. 
 
12.3 Inclusion of men and women 
We do not expect significant difficulties in patient recruitment based on previous studies 
with similar patient populations conducted in the Heckers Lab. Men and women will be 
included in this study. Unlike highly sexually dimorphic rodent aggression, multiple 
studies find no significant gender difference in physical aggression amongst inpatients 
with schizophrenia.79, 80 Given these previous findings and the above power analysis, it is 
outside the scope or resources of this focused study to power sufficiently to include 
sex/gender as a formal variable in our experimental design. However, all efforts will be 
made to recruit similar numbers of men and women to the study, final reported data will 
be disaggregated by sex/gender, and hypothesis-generating comparative analyses will 
be performed that can be pursued in future, hypothesis-testing prospective studies. 
Previous studies of nicotine for cognition in schizophrenia enrolled men and women, but 
no differences in their response to drug were reported.60, 61 The inclusion of drug plasma 
levels can mitigate pharmacokinetic-based differential responses between men and 
women, and will be done in the proposed study.  
 
13 Privacy/confidentiality issues 
 
Data obtained from human subjects will be confidential and accessed only by members 
of the study team with appropriate IRB/HIC and HIPAA training, as assured by standard 
training protocols at Vanderbilt University Medical Center. Data is maintained and 
secured in locked file cabinets or on encrypted, password protected computers, located 
in locked offices, and following Health Insurance Portability and Accountability Act 
(HIPAA) guidelines and the policies and procedures of Vanderbilt University and 
Vanderbilt University Medical Center. Individuals will be identified by a numerical code 
that will be kept separate from study data.   
 
14 Follow-up and record retention 
 


22 
 
 
 
The estimated duration of the data collection phase of the study is four years. Identifying 
information will be deleted (in the case of digital data) or destroyed by shredding using 
clinical shredding bins by the principal investigator or trained study personnel at the 
conclusion of the data collection phase of the study. The non-identifying study data will 
be transferred to a portable hard drive and stored in a locked filling cabinet. Non-
identifying data stored in the above manner will be retained indefinitely. Only the PI, 
study coordinator, and research staff will have access to the information.   
 
  
 
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