Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia
Effects of Transdermal Nicotine on Response Inhibition to Emotional Cues in Schizophrenia
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.
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.
Inclusion Criteria for schizophrenia subjects:

 1. Men and women age 18 - 65.

 2. Communicative in English.

 3. Provide voluntary, written informed consent.

 4. Physically healthy by medical history,and ECG examination.

 5. BMI > 17.5 and < 45.

 6. Diagnosis of schizophrenia (ICD-10 F20) or schizoaffective disorder (ICD-10 F25)
 confirmed by Structured Clinical Interview for Diagnostic and Statistical Manual
 (DSM)-V (SCID) or diagnostic interview with a trained clinician.

 7. Stable medication regimen over at least the past two weeks, including the use of
 either an oral or intramuscular administration of an antipsychotic medication.
 Additionally, subjects may take any prescribed medication aside from a
 nicotine-containing product as long as it has been regularly taken over the past two
 weeks, including as-needed ("PRN") medication.

 8. Negative urine toxicology and negative urine cotinine (to confirm no recent nicotine
 use) at screening.

 9. Does not meet criteria for substance or alcohol use disorder per the SCID over the
 past 6 months

 10. For females, no longer of child-bearing potential, or agreeing to practice effective
 contraception during the study (e.g., established use of oral, injected or implanted
 hormonal methods of contraception; placement of an intrauterine device [IUD] or
 intrauterine system [IUS]; barrier methods: condom with spermicidal
 foam/gel/film/cream/suppository or occlusive cap [diaphragm or cervical/vault caps]
 with spermicidal foam/gel/film/cream/suppository; male partner sterilization; or true
 abstinence when this is in line with the preferred and usual lifestyle of the
 subject); and,

 11. For females of child-bearing potential, must have negative urine pregnancy test at
 time of screening visit and before each testing day.

 12. Not breastfeeding/nursing at time of screening or at any time during the study.

 Exclusion Criteria for schizophrenia subjects:

 1. Age less than 18 or greater than 65.

 2. Not communicative in English.

 3. Unable to provide written informed consent.

 4. Active suicidal ideation or suicidal behavior.

 5. Current, unstable medical or neurological illness or significant abnormality on ECG.

 6. History of severe head trauma.

 7. BMI < 17.5 or > 45.

 8. History of allergy to transdermal patches.

 9. Screening visit resting heart rate > 110 or < 50 beats per minute, or known history of
 clinically significant cardiac rhythm abnormalities.

 10. Screening visit systolic blood pressure > 160 or < 90, or diastolic blood pressure >
 95 or < 50.

 11. Positive urine toxicology or positive urine cotinine during screening.

 12. Meets criteria for diagnosis of substance or alcohol use disorder by SCID within the
 past 6 months.

 13. Reports any tobacco smoking or nicotine use over the past month.

 14. Not taking an antipsychotic medication.

 15. Positive urine pregnancy test at time of screening, before each testing day, or any
 potential concern for pregnancy at any time during the study

 16. Breastfeeding/nursing at time of screening or at any time during the study.

 Inclusion Criteria for healthy volunteer subjects:

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

 Exclusion Criteria for healthy volunteer subjects:

 All of the above and in addition:

 1. Current use of psychotropic or potentially psychoactive prescription medication.

 2. Major psychiatric disorder as determined by DSM-5 (schizophrenia, major depression,
 bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder, etc.)