Clinical trial NCT04277936
Conditions: Schizophrenia; Psychosis
Keywords: Hippocampus
Sponsor: Vanderbilt University Medical Center
Start date: 2020-05-11; Completion date: 2020-08-31
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test whether administration of levetiracetam (LEV), a commonly used anti-epileptic that alters neurotransmitter release, can reduce hippocampal hyperactivity. Specifically, we will utilize two functional magnetic resonance imaging (MRI) techniques: 1) blood oxygen level dependence (BOLD) contrast will assess activity with a visual scene processing task that engages the anterior hippocampus and 2) arterial spin labeling (ASL) will assess baseline activity. This study will also assess whether patients have improvement in their symptoms after receiving LEV. Previous studies in people with psychotic disorders have shown that the hippocampus is hyperactive and more activity correlates with worsening of clinical symptoms. Therefore, the aim of this study is to use an intervention to further understand the underlying mechanisms of the hippocampus in psychosis.

Detailed description:

Arms: arm 1: Participants will take their first dose of 500 mg LEV. After a two hour time window, the participants will complete MRI study. After MRI, patients will begin a 2-week intervention with 250 mg BID oral LEV.
Interventions: intervention 1: Levetiracetam 500 mg
Intervention descriptions: intervention 1: Levetiracetam (LEV) regulates neuronal synaptic exocytosis and calcium-induced neurotransmitter release and has a therapeutic effect on the excitation-inhibition balance of the hippocampus.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 1.3 
Date: February 29, 2020 
1 
 
 
 
 
 
 
 
 
 
 
 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
 
Stephan Heckers, MD MSc 
Professor and Chair 
Department of Psychiatry and Behavioral Sciences 
Vanderbilt University Medical Center 
1601 23rd Ave. S Suite 3060 
Nashville, TN 37212 
 
 


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Table of Contents: 
 
Study Schema 
1.0   
Background 
2.0   
Rationale and Specific Aims 
3.0   
Animal Studies and Previous Human Studies 
4.0   
Inclusion/Exclusion Criteria 
5.0   
Enrollment 
6.0   
Study Procedures 
7.0   
Risks – Study Drug 
8.0   
Risks – Other than Study Drug 
9.0   
Reporting of Adverse Events or Unanticipated Problems Involving Risk to Participants or Others 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 
 
 


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1.0 BACKGROUND 
The purpose of this study is to test whether administration of levetiracetam (LEV), a commonly used anti-
epileptic that alters neurotransmitter release, can reduce hippocampal hyperactivity. Specifically, we will utilize 
two functional magnetic resonance imaging (MRI) techniques: 1) blood oxygen level dependence (BOLD) 
contrast will assess activity with a visual scene processing task that engages the anterior hippocampus and 2) 
arterial spin labeling (ASL) will assess baseline activity. This study will also assess whether patients have 
improvement in their symptoms after receiving LEV. Previous studies in people with psychotic disorders have 
shown that the hippocampus is hyperactive and more activity correlates with worsening of clinical symptoms. 
Therefore, the aim of this study is to use an intervention to further understand the underlying mechanisms of 
the hippocampus in psychosis.  
 
Background and Significance 
 
The lifetime prevalence of schizophrenia is about 0.7% (Saha et al., 2005), and the burden of illness is 
significant not only for patients but also society at large (Lehman et al., 2004). One contribution to this massive 
disease burden is the lack of optimal treatments, as only 20% of diagnosed individuals reach favorable 
treatment outcomes (Association, 2016). An important factor in the lack of treatment development for psychotic 
disorders is the unavailability of predictors that can be used to determine if therapeutic candidates elicit their 
targeted biological effects (Tregellas, 2014).  
 
A growing body of literature demonstrates that the anterior hippocampus is hyperactive in patients with 
schizophrenia (Schobel et al., 2009; Talati et al., 2014) and clinical high risk patients that progress to 
developing schizophrenia (Modinos et al., 2018; Schobel et al., 2013). This hyperactivity is the result of an 
excitation-inhibition imbalance in the hippocampus (Heckers and Konradi, 2015; Uhlhaas, 2013). Excitatory, 
glutamatergic pyramidal cells comprise 90% of hippocampus neurons (Olbrich and Braak, 1985). The 
remaining neurons are inhibitory, GABAergic interneurons that modulate and synchronize overall activity to 
exert ultimate hippocampus activity (Freund, 2003; Klausberger and Somogyi, 2008). Different models have 
attributed the hippocampal excitation-inhibition imbalance to alterations in neurotransmitters glutamate or 
GABA (Benes, 1999; Stan et al., 2015) or interneuron abnormalities (Heckers and Konradi, 2015; Lodge et al., 
2009). 
 
This human laboratory study seeks to use an intervention to further understand the underlying 
mechanisms of the hippocampus in psychosis. This will be accomplished by using LEV. While the exact 
mechanism of action of LEV continues to be evaluated, evidence shows that it regulates neuronal synaptic 
exocytosis and calcium-induced neurotransmitter release (Lynch et al., 2004). Therefore, LEV may have a 
therapeutic effect on excitation-inhibition imbalance of the hippocampus. LEV has an overwhelming amount of 
evidence for modulating neuronal activity and has been established as a FDA-approved anti-epileptic drug for 
almost two decades (Lyseng-Williamson, 2011). Most other anti-epileptic medications affect ion channels, 
which are functionally "upstream" from synaptic exocytosis. Because of this, LEV has a more favorable side-
effect profile when compared to other FDA-approved anti-epileptic drugs. Additionally, LEV has a lower risk of 
pharmacokinetic interactions with antipsychotics, and a lower risk of cognitive side effects when compared to 
other anti-epileptic drugs (Patsalos, 2000).  
 
Neuroimaging studies provide the best opportunity to test the hypothesis of an excitation-inhibition imbalance 
in the hippocampus (Logothetis, 2008). Our lab has recently developed a functional MRI task that allows for 
robust, individual-subject level analysis of the hippocampus (McHugo et al., 2019). Based on the evidence 
provided above, LEV is an ideal intervention to assess hippocampal activity. Because hippocampal activity 
correlates to clinical symptoms (Friston et al., 1992; Gur et al., 1995; Liddle et al., 1992), can predict clinical 
progression, has translational capabilities (Gozzi et al., 2010, 2008; Stevens and Wear, 1997), and has 
recently been shown to function as a therapeutic target for schizophrenia (Bakker et al., 2012; Gill and Grace, 


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2014; Gomes et al., 2016; Koh et al., 2018; Perez and Lodge, 2014; Smucny and Tregellas, 2017), it is an 
ideal neural mechanism to study. 
 
2.0 RATIONALE AND SPECIFIC AIMS 
 
Our central hypothesis is that in psychotic disorders, LEV will safely normalize hippocampal 
hyperactivity. This will result in an increase in recruitment and activity of the hippocampus during tasks that 
specifically engage the hippocampus. Secondarily, we hypothesize that LEV will improve the symptomatology 
of psychotic disorders. In this project, we will test our hypothesis in 30 psychotic patients and 30 healthy 
control subjects. Following baseline clinical assessments, neuropsychological testing, and neuroimaging, 
participants will receive an initial dose of LEV. At this time they will undergo a second neuroimaging procedure. 
After the second brain imaging study, they will begin two weeks of oral LEV. Finally, participants will repeat all 
testing at the end of the 2-week study period, to allow us to assess the effects of a LEV intervention. 
 
Primary Aim: To determine whether administration of oral LEV over two weeks modulates hippocampal 
hyperactivity 
Hypothesis 1: Oral LEV will decrease, in a dose-response relationship, hippocampal activity in healthy 
control subjects and psychotic patients (ASL study).  
Hypothesis 2: Oral LEV will normalize hippocampal recruitment in patients (Scene-processing fMRI 
study). 
Hypothesis 3: Compared with healthy control subjects, psychotic patients will show higher hippocampal 
activity (ASL study) and reduced hippocampal recruitment (Scene-processing fMRI study). 
 
Secondary Aim: To determine whether administration of oral LEV over two weeks improves clinical 
symptoms in patients with psychotic disorders 
Hypothesis 1: Oral LEV will improve cognitive symptoms in psychotic patients (eye-tracking relational 
memory task). 
Hypothesis 2: Oral LEV will reduce positive and negative psychotic symptom severity (Positive and 
Negative Syndrome Scale, PANSS). 
 
3.0 ANIMAL STUDIES AND PREVIOUS HUMAN STUDIES 
 
3.1 Animal Studies:  
 
Animal models have been used to study the relationship between hippocampal activity and variety of different 
diseases and conditions. Treatment with LEV has been found to improve memory in both aging (Devi and 
Ohno, 2013; Koh et al., 2010; Suberbielle et al., 2013) and Alzheimer’s disease (Devi and Ohno, 2013; Hall et 
al., 2015; Sanchez et al., 2012; Suberbielle et al., 2013) animal models that are associated with increased 
neural activity in the hippocampus.  
 
Importantly, all of these studies used doses substantially lower than those used in seizure models. Koh et al. 
(2010) demonstrated improvements in spatial memory task performance at both 5 and 10 mg/kg. Typical 
antiepileptic doses of LEV in rodent seizure models are in a range of 50-150 mg/kg. Devi and Ohno (2013) 
used 10-20 mg/kg to improve memory in a contextual fear conditioning paradigm. Hall et al. (2015) used a 
dose of 75 mg/kg/day to reverse ion channel depletion associated with hippocampal dendritic hyperexcitability 
and to reverse abnormalities in a spatial memory behavioral task. Suberbielle et al. (2013) also used 75 
mg/kg/day to demonstrate improvements in learning and memory. Sanchez et al. (2012) reported that LEV 
loses both its antiepileptic effect and its beneficial effect on behavioral and molecular abnormalities in mice 
when given at high doses. Only low doses of LEV reversed learning and memory abnormalities and abnormal 


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alterations in the expression of synaptic activity. Importantly, of seven FDA-approved anti-epileptics tested with 
differing methods of action, only LEV had this effect (Sanchez et al., 2012). 
 
Treatment with LEV in animal models of schizophrenia has also demonstrated improvements in cognitive 
symptoms. The inability to filter brain responses to repetitive stimuli, as evidenced by poor inhibition of early 
(50 ms post-stimulus) evoked brain response to the second of two closely paired, identical auditory click stimuli 
is a feature of schizophrenia (Potter et al., 2006). This is measured in preclinical models using in vivo 
recordings of auditory-evoked potentials from the mouse hippocampus. Drugs that improve gating in rodents 
have demonstrated similar effects in human patients, supporting the utility of this gating model as a 
translational tool (Olincy and Stevens, 2007). A 10 mg/kg dose of LEV was found to improve auditory gating in 
a mouse model of schizophrenia (Smucny et al., 2015). 
 
A more recent study tested LEV’s ability, alongside and in combination with the antipsychotic risperidone, to 
alleviate memory impairment in an animal model of schizophrenia that recapitulates neural hyperactivity and 
memory problems similar to those seen in schizophrenia patients (Koh et al., 2018). LEV, but not risperidone, 
improved memory performance dose-dependently in a hippocampal-dependent memory task. Furthermore, 
LEV remained effective when administered concurrently with risperidone, providing evidence that LEV could be 
used as adjunctive therapy to treat the cognitive deficits in schizophrenia patients with antipsychotic therapy. 
 
3.2. Human Studies: 
 
An extensive amount of research has been done in humans for LEV to obtain FDA-approval as an anti-
epileptic drug. There are currently no studies that have published results investigating the effect of LEV in 
schizophrenia patients. However, two NIMH-supported studies using LEV in schizophrenia patients are 
currently under way [PI: Goff, D., NCT03129360; PI: Tregellas, J., NCT NCT02647437]. In addition, there are, 
to the best of our knowledge, five studies using human imaging techniques that have investigated the effects of 
LEV on brain activity (Bakker et al., 2015, 2012; Wandschneider et al., 2014; Zhang et al., 2018, 2017).  
 
Bakker et al. (2012) studied a population of amnesic mild cognitive impairment (aMCI) patients with 
hippocampal hyperactivity. This study employed a longitudinal, randomized, placebo-controlled crossover 
design that required aMCI patients to take 2 weeks of LEV. By using a low dose of LEV (125 mg BID), 
hippocampal activation in the aMCI group was reduced to a level that did not differ from healthy controls using 
fMRI. Additionally, aMCI patients taking LEV significantly improved their performance in a hippocampal-
dependent memory MRI task when compared to aMCI patients taking a placebo. A follow-up study (Bakker et 
al., 2015) using the same study design, including utilizing fMRI to investigate hippocampal activation and a 
hippocampal-dependent memory task replicated this finding. Altogether, these results suggest that LEV may 
have clinical benefit in disease populations other than epilepsy at does much lower than typically given 
(Smucny et al., 2015). 
 
Wandschneider et al. (2014) studied a population of patients with temporal lobe epilepsy (TLE). This 
population has previously been shown to be unable to deactivate their diseased hippocampi with increasing 
cognitive demands (Stretton et al., 2012). In a retrospective study design, about 55% of TLE patients received 
varying doses of LEV (median (interquartile range) = 2,500 mg/day (1,000)) in addition to other anti-epileptic 
drugs. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in 
right TLE during a right-lateralizing visual-spatial task, and in the left temporal lobe during a verbal task. Post-
hoc analysis showed that both hippocampi were more abnormally activated in patients with lower doses. These 
findings suggest that LEV is associated with restoration of normal activation patterns in the hippocampus. 
 
Two additional studies have used LEV as an intervention in a fMRI study in epilepsy patients (Zhang et al., 
2018, 2017). Although they did not employ cognitive tasks in the fMRI study, we highlight them here to 
demonstrate that fMRI is sufficient tool to detect group level changes with an intervention of LEV. 


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4.0 INCLUSION/EXCLUSION CRITERIA 
Inclusion criteria for psychosis subjects 
1. Men and women age 18 - 65. 
2. Communicative in English. 
3. Provide voluntary, written informed consent. 
4. Physically healthy by medical history.  
5. BMI > 17.5 and < 45. 
6. Diagnosis of a psychotic disorder 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. 
8. 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, 
9. For females of child-bearing potential, must have negative urine pregnancy test at time of screening visit and 
before each testing day. 
10. Not breastfeeding/nursing at time of screening or at any time during the study. 
 
Exclusion criteria for psychosis subjects 
1. Age less than 18 or greater than 65. 
2. Not communicative in English. 
3. Unable to provide written informed consent. 
4. Current medical or neurological illness.  
5. History of severe head trauma. 
6. BMI < 17.5 or > 45. 
7. Meets criteria for diagnosis of substance or alcohol use disorder within the past month. 
8. Positive urine pregnancy test at time of screening, before each testing day, or any potential concern for 
pregnancy at any time during the study. 
9. Breastfeeding/nursing at time of screening or at any time during the study. 
10. Conditions that preclude MR scanning (as defined in the Screening Form) 
11. Conditions that preclude study drug administration (as defined in the Screening Form) 
 
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. 
 
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-V (major depression, bipolar disorder, obsessive 
compulsive disorder, post-traumatic stress disorder, etc) 
 
5.0 ENROLLMENT 
5.1. Recruitment: Study participants will be recruited from the following sources: 
 


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5.1.a Psychiatric Genotype/Phenotype Repository (PGPR, IRB #080606): The PGPR study 
includes a clinical interview during which diagnostic and clinical history data is collected. At the end of 
this interview, individuals will be asked by one of the key research personnel listed on this application if 
they are interested in participating in the study. The PI of this study is the same PI for the PGPR study. 
Subjects will be read a script describing the study. Subjects will be told that the study is separate from 
their participation in the PGPR study and choosing not to participate in the study will not affect their 
participation in the PGPR study. In addition, individuals that have previously completed the PGPR study 
may be contacted and asked if they would like to participate in the study. The consent form for the 
PGPR study states that subjects may be contacted and asked if they would like to take part in future 
studies, if they agree. Subjects will be read a script telling them about the study. The telephone 
screening form used for the Psychiatric Genotype/Phenotype study will be re-administered to make 
sure that they still meet the original criteria for participating in the Psychiatric Genotype/Phenotype 
Study (i.e. age, physical health, and MRI requirements). 
 
5.1.b Vanderbilt Psychiatric Hospital and Adult Outpatient Clinic: Adult individuals who will likely 
meet criteria for one of the proposed study diagnoses (as determined by chart review, participation in 
another clinic study, etc.) will be approached by their treatment provider (or Research Assistant if they 
are participating in another study) to see if they are willing to discuss participation in this study. If the 
patient assents, their name will be given to a research staff member who will make contact with them to 
schedule a meeting. At the meeting, the purpose of the study, specific procedures, risks, and inclusion 
and exclusion criteria will be discussed with the subject. The informed consent form will be reviewed 
with the subject. The subject will be encouraged to carefully read the consent form and ask questions. 
The subject will then undergo an informed consent survey to ensure that he or she understands the 
consent form. After written informed consent is obtained, Study Procedures will be performed.  
 
5.1.c Greater Nashville Area: Individuals who may meet criteria for one of the proposed study 
diagnoses (as determined by self-identification) and healthy non-psychiatric control subjects will be 
recruited through mass email ads through the Vanderbilt University Medical Center email system, study 
advertisements distributed/posted in the community, Vanderbilt General Clinical Research normal 
volunteer program, the Vanderbilt Kennedy Center, and mass email ads through the Vanderbilt 
University Medical Center email system. If potential subjects are interested in participating in this study 
and appear to meet inclusion and exclusion criteria (based on initial screening), a meeting with the RA 
will be scheduled. At this meeting, the informed consent form will be reviewed with the subject. The 
subject will be encouraged to carefully read the consent form and ask questions. If the subject appears 
to meet inclusion and exclusion criteria and wishes to participate in this study, informed consent will be 
obtained, and Study Procedures will be performed. 
 
5.2 Monetary Compensation: All study subjects will be remunerated $25 for completion of the screening and 
consent visit, regardless of their decision to enroll in the study or their eligibility to enroll. Because of the study 
design, subjects only yield meaningful primary outcome data if they complete the long-term intervention phase 
session. They will therefore be compensated an additional $475 at the completion of the remaining study visits. 
This incentivization is designed to yield greater benefit from the research, thereby improving the risk/benefit 
ratio of the study.  
 
5.3 Recruitment: We will make every effort to recruit equal numbers of men and women. We will not exclude 
subjects based on gender or minority status. We minimize coercion throughout the study by repeatedly 
informing subjects that they may discontinue study procedures at any point, or opt-out of any specific part of 
the study they become uncomfortable with completing. 
 
We plan to recruit up to 60 subjects (up to 30 healthy control subjects and up to 30 patients with psychotic 
disorders) for the study. We hope to acquire analyzable data from at least 20 control subjects and 20 patients. 


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Subjects who were recently recruited in other psychiatry studies also conducted by this PI (e.g. 
genotype/phenotype studies) may not be required to participate in components of this study that would 
duplicate efforts (e.g. SCID interview). We plan to include data from those studies in the analyses of data from 
this study. Participants will be compensated for all activities they complete. 
 
6.0 STUDY PROCEDURES 
Overview: There are nine components of the study: 
1. Screening and Consent 
2. Diagnostic Interview 
3. Clinical Assessment (psychosis patients only) 
4. Neurocognitive Assessment 
5. MRI Scanning 
6. Drug Administration 
7. Blood draws 
8. Urine pregnancy test 
9. Mid-intervention phone call 
 
Each component will be described in detail below. The entire study will be completed in about two weeks. The 
number of study visits depends on whether the planned study procedures can be completed in the specified 
time period and the availability of both the participant and necessary resources (i.e. availability of the MRI 
scanner). The specific rating scales completed will be dependent upon diagnosis and the time since an 
individual participated in the PGPR study, as many of the measures overlap and assess symptomatology 
based on specific time-intervals (i.e., the last 2 weeks).  
 
6.1 Screening and Consent: Subjects will be asked if they would like to participate in the current study. This 
screening will occur over the phone or in person using the Screening Form. Informed consent will be obtained 
by study personnel directly involved in the research (i.e. research staff or graduate student). Personnel have 
completed IRB training and have considerable experience running studies on psychiatric populations.  
Informed consent will be obtained in the research offices at the Psychiatric Neuroimaging Program.  A 
research staff member will explain the applicable procedures and the possible risks and benefits to the 
subjects.  The details of the informed consent procedure are as follows: 
 
1. The investigator or research staff and the subject will read together the entire consent form 
2. The subject will be asked details about the study. To document that the subject has read the consent 
form and has the capacity to understand the most important details, the investigator will use the 
appropriate Informed Consent Survey. The questions will be read by the investigator or research staff 
and the answers will be recorded (appropriate response listed in Italics in the Informed Consent 
Survey).  If the subject is unable to answer any of the questions, or if the subject demonstrates a lack of 
understanding, the investigator or research staff member will then review the details of the study again.  
Subjects who are unable to answer the questions, even after additional information is provided, will be 
excluded from the study. 
3. The subject will be informed that regardless of whether or not they take part in this research study, it 
will not affect their treatment, payment or enrollment in any health plans or affect their ability to get 
benefits or care in any way. 
4. The subject will be provided with copies of the signed consent form and the Informed Consent Survey 
(including the answers given) at the time of the initial visit. 
 
It will be emphasized to all subjects that their participation is completely voluntary, and that even after signing 
the consent document they are still free to withdraw from the study at any time; in which case they will be 
compensated for the portion(s) of the protocol they did complete. 


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6.2 Diagnostic Assessment: Under the supervision of the PI, a trained research assistant will administer the 
Structured Clinical Interview for DSM-V (SCID), a clinician-rated assessment of psychiatric disorder. 
Diagnoses are made both for current and lifetime periods. The SCID is reliable and valid in psychiatric 
populations (significantly superior to standard clinical interview).  We will supplement the SCID with the 
psychotic disorders module from the Diagnostic Interview for Genetics Studies (DIGS), which provides more 
information for the accurate differential diagnosis of psychotic disorders. The Informed Consent Form will 
include check box indicating if the study participant is being asked to complete the Diagnostic Interview. 
 
As stated previously, subjects who were recently recruited in other psychiatry studies also conducted by this PI 
(PGPR) may not be required to participate in components of this study that would duplicate efforts (e.g. SCID 
interview). We plan to include data from those studies in the analyses of data from this study. If an excessive 
time has passed since an individual participated in a PGPR study, portions of the diagnostic interview may be 
re-administered to determine if there have been any interval changes in a patient’s diagnostic status. 
 
6.3 Clinical Assessment (individuals with psychosis only): Almost all of the clinical and cognitive tests 
have been used in our past studies. They are not burdensome and we allow breaks. All scales will be 
completed before or on the day of the neuroimaging procedures. All patients are asked to review their 
substance abuse and current medications at every visit. The clinical assessments will be completed twice in 
this study (baseline assessment and after two week intervention). 
 
6.3.a Structured Clinical Interview for DSM-5 (SCID): A research staff member is trained to 
administer the Structured Clinical Interview for DSM-V (SCID) (First, 2015), a clinician-rated 
assessment of psychiatric disorder. Diagnoses are made both for current and lifetime periods. The 
SCID is reliable and valid in psychiatric populations, with coefficients of agreement between .70 and 1.0 
for depressive, anxiety, and substance use disorders (significantly superior to standard clinical 
interview). If significant suicidal thought is noted during the evaluation, the patients will be encouraged 
to talk to their treatment providers. If the patient is judged to be at imminent risk of self- or other-harm, 
standard procedures in the clinics will be followed. The SCID can take from 30 minutes to several hours 
to complete. 
 
6.3.b Hamilton Depression Rating Scale (HAM-D): Administrated by a clinician or rater in order to 
gather data about symptoms independent of the biases inherent in self-report. The version of the HAM-
D (Hamilton, 1960) used here incorporates atypical symptoms. It has been used by our group in 
previous studies, and has been associated with excellent reliability. We will also be using a measure to 
assess suicidal history and behavior which was developed internally and is composed of questions 
which would be assessed in any clinical interview. This assessment takes about 15-20 minutes to 
complete. 
 
6.3.c Positive and Negative Syndrome Scale (PANSS): a 30-item clinician-rated scale designed to 
rate both presence of active psychotic symptoms and of cognitive symptoms, like alogia, anhedonia, 
and flattened affect (Kay et al., 1987). This measure has fair to good psychometrics (Peralta and 
Cuesta, 1994) and takes about one hour to complete. 
 
6.3.d Personal and Social Performance Scale (PSP): Administered to assess patient’s functioning in 
four main areas: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) 
disturbing and aggressive behaviors. This measure has high reliability and takes about 5 minutes to 
complete (Morosini et al., 2000). 
 


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6.3.e Young Mania Rating Scale (YMRS): an 11-item clinician-rated measure of manic symptoms.  
Items are rated on various scales using pre-defined anchors ranging from absent to severe.  The 
measure has adequate psychometrics and takes about 20 minutes to complete (Young et al., 1978). 
 
6.3.f Side Effects and Treatment Compliance: Side effects are assessed using the Veterans 
Administration neurotoxicity rating scale (VANRS) (Cramer et al., 1983). This scale is used to quantify 
impairment of change in neurological status and systemic toxicities in patients starting an antiepileptic 
drug in the setting of a clinical trial (Perucca and Gilliam, 2012). Compliance is assessed with a 
medication count and the Medication Adherence Questionnaire (MAQ) (Morisky et al., 1986). 
Altogether, these assessments should take less than 20 minutes to complete. 
 
6.4 Cognitive Assessment: Subjects will be asked to complete a relational memory experimental study.  
Subjects will be taken to a private interview room in the offices of the Psychiatric Neuroimaging Program. Eye 
tracking equipment will be used during the study to record eye movement behavior (ISCAN, Inc.). The eye 
tracking system uses a headmounted camera to track the subject’s pupils in relation to a computer screen 
placed in front of the subject. Subjects will be shown the eye tracking system and given a brief explanation of 
the headmounted camera. The camera will be placed on the subject’s head and the system software will be 
calibrated to the individual’s pupil according to software specifications. Software may be recalibrated between 
each block of images to ensure accurate eye tracking.  Subjects will view face and scene image pairs on a 
computer screen while eye movements are tracked. Faces and scenes will be drawn from a standard set of 
images which have been used in similar research studies (Hannula et al., 2010). Faces and scenes will be 
shown in color.  Faces and scenes used are considered neutral, in that they should not elicit strong emotions 
(i.e., fear, anxiety, happiness). Subjects will be told to study each face/scene pair so that they can later identify 
a match between a particular face and scene. Subjects will view multiple blocks of face/scene pairs during 
during the familiarization phase. During the testing phase, subjects will be shown blocks of previously seen 
scene images with multiple faces overlaid on the image. Subjects will be asked to choose the face previously 
related to the scene by button press while eye movements are tracked. Subjects will be fully debriefed 
following completion of all test phase blocks. Faces and scenes will be randomized to lists, and lists will be 
rotated and counterbalanced across subjects to ensure that each scene is paired equally with each face across 
the study. The relational memory experimental paradigm will require up to 1 hour, including calibration of the 
eye tracking software. There will be a total of two cognitive assessments in this study (baseline assessment 
and after two-week intervention). 
 
6.5 MRI Procedures: MRI scans of the brain will be obtained using the MRI scanners in the Center for Human 
Studies in the Vanderbilt University Institute for Imaging Science (VUIIS), located in the Vanderbilt Hospital and 
Medical Center North. This will require approximately 60-90 minutes. There will be a total of three MRI scans in 
this study (baseline assessment, two hours after the initial LEV dose, and after two-week intervention of LEV). 
  
6.5.a MRI Screening: The participant will fill out the MRI Procedure Screening Form. The purpose of 
this form is to ensure that there are no implanted medical devices or metals that could injure the subject 
if exposed to a high magnetic field. This form will be filled out in a private room adjacent to the MRI 
scanner and reviewed by the MR Technologist and the research assistant.   
  
6.5.b Scanning Procedures: Imaging studies will take place on a Phillips 3.0 T MRI scanner.  The 
magnet and the magnet’s control console are in separate rooms, but the investigator and the subject 
will be in voice communication at all times, and the investigator will be able to see the subject through a 
window.   All data acquired on the scanner will be securely transferred over the Vanderbilt network to 
the Institute of Imaging Science’s server. Imaging data will be de-identified and only be accessible to 
the PI, co-investigators, and VUIIS personnel. Scanning procedures may include: 1) Structural imaging, 
2) Resting state functional imaging, 3) ASL imaging to non-invasively measure cerebral blood flow, and 
4) Functional imaging with task – while in the scanner, participants will view images that include faces, 


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objects and scenes. Images are projected to a mirror above the participants head from a projector 
located outside the scanner room. Some runs will repeat the same face or object, some runs will 
present different images. Participants will complete between 1-8 runs of this task. To maximize 
participant’s attention to the images, participants will be instructed to push a button to detect targets. 
Targets may include image repeats or changes in the image (e.g., image size). This task is similar to 
the reported in McHugo et al., 2019. 
 
6.6 Study Drug Administration: After completing the baseline clinical assessment, cognitive assessment, and 
MRI, eligible participants will be instructed to take their first dose of 500 mg LEV. After a two hour time window, 
the participants will complete the same MRI battery. After the second MRI, patients will begin a 2-week 
intervention with 250 mg BID oral LEV. Clinical assessment, cognitive assessment, and MRI will be repeated 
after this 2-week intervention phase. 
 
6.6.a Dosage Rationale: We selected 250 mg BID dosage because of other studies that have been 
able to safely demonstrate changes in cognitive performance and changes in hippocampal activation 
(Bakker et al., 2015, 2012) using dosages of LEV intervention in patient cohorts outside the FDA-
approved indications for LEV. This dosage is well below the typical ranges for efficacy as an 
antiepileptic with doses of 1,000-3,000 mg/day. Studies using a dosage of 125 mg BID have reported 
drug levels to be 4.4 mcg/ml +/- 0.53 (mean and SEM), while dosages of 1,000-3,000 mg/day achieve 
levels of 10-40 mcg/ml (Bakker et al., 2015, 2012; Lyseng-Williamson, 2011). Human results indicating 
effects with lower dosages are consistent with the animal literature. Studies that have targeted rats with 
cognitive impairment and excess hippocampal activity have demonstrated improvements in memory 
performance using a dosage of 10 mg/kg (Koh et al., 2018, 2010). In another animal model of 
schizophrenia, dosages of 10 mg/kg improved a sensory gating task performance (Smucny et al., 
2015). Typical antiepileptic doses of LEV in rodent seizure models are in a range of 50-150 mg/kg (Ji-
Qun et al., 2005; Stratton et al., 2003). 
 
6.6.b. Timing Rationale: We selected a two-hour duration for the first imaging assessment based on 
LEV’s absorption and clearance data. The pharmacokinetics will be reviewed in more detail in sections 
7.2 and 7.3. Briefly, LEV is rapidly and almost completely absorbed after oral administration, with peak 
serum concentrations occurring approximately one hour after dose (Gambardella et al., 2008). Based 
on a study that measured LEV plasma concentrations (µmol/L) over time after oral ingestion of varying 
doses of LEV (500-5000mg) in healthy volunteers, LEV levels will be approximately 9.75 mcg/mL (57.3 
µmol/L) at two hours (Patsalos, 2004). Therefore, two hours after LEV administration is the earliest 
time-point where we can assess study participants at a sub-therapeutic epilepsy dose (10-40 mcg/mL) 
of LEV (Bakker et al., 2015, 2012; Lyseng-Williamson, 2011). 
 
6.6.c Duration Rationale: We selected a 2-week duration because of other studies that have been 
able to safely demonstrate changes in cognitive performance and changes in hippocampal activation 
(Bakker et al., 2015, 2012) after 2 weeks of LEV intervention in patient cohorts outside the FDA-
approved indications for LEV. 
 
6.6.d Compliance: We will assess compliance using the Medication Adherence Questionnaire, a 
medication count after two weeks, and a test for LEV blood levels. 
 
6.6.e Concomitant medications: We will allow concomitant use of any medication approved by the US 
FDA unless specified in our inclusion/exclusion criteria (e.g. normal controls using psychotropic 
medications). Reviews have indicated that LEV does not affect the metabolism of other drugs, including 
antipsychotics (Besag and Berry, 2006). 
 
6.7 Blood Draw: Subjects will undergo three separate blood draws. The first blood draw will occur during the 


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Screening and Enrollment visit. The second blood draw will occur during the short-term intervention 
assessment. The third blood draw will occur during the long-term intervention assessment. Both visits will use 
blood draws to assess GFR and CBC, as addressed in the study drug risks below. During the short-term 
intervention visit, we will check LEV levels for the study of a dose-response relationship with blood flow. During 
the long-term intervention visit, participants will undergo a blood draw to check LEV levels to ensure 
compliance with taking the study medication. 
 
6.8 Urine pregnancy test: All females will be required to take a urine pregnancy test during the screening and 
enrollment visit, baseline visit, and two-week follow-up visit, as addressed in the study drug risks below. 
 
6.9 Mid-Intervention Phone Call: After the visit where LEV is administered and before the two week follow-up 
visit, we will call the participant. This will be to 1) ensure that they are taking the study medication as 
prescribed and remind them to continue to do so. 2) Ask about any issues or side effects they may be 
experiencing because of the study. We believe this phone call will increase the likelihood that participants 
complete the study and will help us identify any side effect complications earlier. 
 
 
7.0 RISKS - STUDY DRUG 
7.1 Risks: Side effects of LEV exposure have been well characterized in clinical trials using LEV dose ranges 
of 1000-3000 mg/day. The most common symptoms are neurological, including somnolence (15% of patients), 
asthenia (15%), headache (14%), dizziness (13%), and ataxia (3%) (Ben-Menachem and Falter, 2000; 
Cereghino et al., 2000; Shorvon et al., 2000). Patients also reported a slightly higher incidence of infection 
(13% of patients). Up to 13% of patients also experienced adverse neuropsychiatric symptoms. In most of 
these patients, the symptoms have been mild, including agitation, hostility, apathy, anxiety, emotional lability, 
and depression (Gambardella et al., 2008). About 1% of patients have experienced serious neuropsychiatric 
symptoms including hallucinations, suicidal ideations, or psychosis (Kossoff et al., 2001; Mula et al., 2003). In 
these reports, symptoms occurred mostly within the first month of therapy. Dose reduction or discontinuation 
has led to resolution of symptoms in cases reported. Conversely, LEV has no major adverse effects on 
cognitive function (Neyens et al., 1995), which is an improvement over more traditional anti-epileptic agents 
(Dooley and Plosker, 2000). Presently, there are no sufficient data to recommend treatment with LEV during 
pregnancy. Case reports have indicated Stevens-Johnson Syndrome (SJS) is an exceedingly rare side effect 
of LEV administration (Zou et al., 2012). In a meta-analysis of 26 double-blind, randomized, placebo-controlled 
trials (2832 patients), no dose-response relationship was found for any side effects (Verrotti et al., 2015). 
 
7.2 Absorption and Distribution: LEV is rapidly and almost completely (>95%) absorbed (Rossetti and 
Bromfield, 2005) after oral administration of doses ranging from 250 to 5000 mg, with peak serum 
concentrations occurring approximately 1 hour after dose and steady state concentrations are reached within 
48 hours (Gambardella et al., 2008). The oral bioavailability of LEV tablets is 100%. Food does not affect the 
absorption of LEV. The volume of distribution is 0.5-0.7 L/kg(Patsalos, 2004).  LEV does not bind to plasma 
proteins and has linear pharmacokinetics that are time-invariant with low intra- and inter-subject variability 
(Patsalos, 2004, 2000).   
 
7.3 Metabolism and Elimination: LEV is not extensively metabolized in humans. The major metabolic 
pathway is the enzymatic hydrolysis of the acetamide group by a plasma hydroxylase. This produces the 
inactive compound carboxylic acid metabolite ucb L057 (24% of dose). LEV does not undergo hepatic 
metabolism (Nicolas et al., 1999). The serum half-life is 6 to 8 hours (Krasowski, 2010). LEV is eliminated from 
systemic circulation by renal excretion as unchanged drug (66% of the dose). Total body clearance is 0.96 
mL/min/kg and renal clearance is 0.6 mL/min/kg. The metabolite ucb L057 is renally excreted with a renal 
clearance of 4 mL/min/kg. Clearance is rapid, so that within 48 hours approximately 93% of an oral dose is 
eliminated. In patients with renal impairment, doses should be reduced in accordance with creatinine clearance 
(Patsalos, 2004). 


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7.4 Interactions with other Drugs: Reviews have indicated that LEV does not affect the metabolism of other 
drugs, including antipsychotics (Besag and Berry, 2006). 
 
7.5 Minimizing Risk for Study Drug: 
 
7.5.a Dosage: As mentioned above, clinical indications for LEV use in epilepsy range from 1000-3000 
mg/day. Our study will be using 250 mg BID. As reviewed in both section 3.0 and 6.6.b, human 
functional MRI studies have demonstrated that low doses decrease hippocampal activity and improve 
memory task performance in patient cohorts outside the FDA-approved indications for LEV. 
 
7.5.b Screening Process: The screening visit will include a Screening Form that has a LEV Screening 
section. It will assess neuropsychological history to address the neuropsychological side effects and 
assess history of rashes in response to medications to address the possibility of a SJS reaction. 
Additionally, a blood draw to obtain a CBC and BMP will assess creatinine levels, to address renal 
function, and white blood count, to address possibility of infection, in each patient at each visit. Blood 
draws for a CBC and BMP will not occur if there is a record of recent CBC or BMP values (within past 
45 days). Lastly, females will perform a pregnancy test at each visit to ensure no teratogenic effects. 
 
7.5.c Usage as add-on therapy for psychosis cohort: LEV has no known major drug interactions. 
Therefore, the psychosis cohort will use LEV as an add-on therapy with the antipsychotic medications. 
 
7.5.d Driving after drug administration: Because somnolence is a major side effect of LEV, we 
require that participants who drive themselves to Vanderbilt Psychiatric Hospital on Day 1 (first day of 
drug administration) will take a Standardized Field Sobriety Test to ensure they are safe to drive 
themselves home. This test is based on available data provided by the National Highway Traffic Safety 
Administration. It will be administered before initial drug administration and as the final assessment on 
Day 1 immediately before the participant leaves. It takes about 5 minutes to complete. If the participant 
scores above an impairment threshold on any portion of the test, we will purchase a car service 
(Uber/Lyft) to drive the participant home and back to Vanderbilt Psychiatric Hospital on another day to 
obtain their vehicle. 
 
7.6 Risk/Benefit Ratio: When the safety record outlined above is considered, the risks of participation in this 
study are low. Long-term safety of LEV appears to be very favorable. Subjects participating in these studies 
will receive MRI assessment and basic drug and pregnancy screening (when applicable) 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 identifying a reliable biomarker for psychotic 
disorders. Every research study requires the potential benefits to outweigh the potential risks of the study. The 
potential benefit of establishing a biomarker is significant for public health, including for patients, their families, 
communities, and healthcare 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. 
 
With respect to MRI scanning, the MR system requires the use of rapidly varying magnetic gradient fields and 
strong radio frequency fields. These switched gradient and radio frequency fields conform to the guidelines 
established by the US FDA for time varying magnetic fields in MR devices. No serious or lasting incidents or 
side effects associated with the use of high field magnets have been reported. Based on this experience, and 
valid scientific evidence, the FDA has found that this does not pose a significant risk to human subjects. 
 
8.0 RISKS – OTHER THAN THE STUDY DRUG 
8.1 Psychological and Behavioral Assessment Risks: At screening, subjects will undergo non-invasive 


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psychological assessment of a structured nature that has been consistently used without adverse effects in 
previous studies with a similar subject population. 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. 
 
Minimizing the Risk of Psychological and Behavioral Assessment: The risk of the diagnostic evaluation 
involves the possibility that participants may be asked questions which cause them distress. These would be 
questions consistent with any clinical evaluation. In order to address this risk, participants will be told they can 
decline to answer any questions and can stop the evaluation at any time. 
 
8.2 MRI Scan Risk: 
1. Ferromagnetic objects brought into the room will be pulled toward the magnet. 
2. Due to the magnetic properties of the scanner, if a subject has implanted metal or medical devices they may 
experience abnormal torques or failure to function properly. This may cause injury to the body areas where the 
device is located. 
3. There is a risk of tissue heating if there is excessive power deposition of radiofrequency (RF) magnetic 
waves. Excessive RF waves emitted could cause the atoms to transmit high-frequency RF wave at such a rate 
as to cause the neighboring tissue to heat. 
4. There is a risk of peripheral nerve stimulation if gradients are switched too rapidly. Switching a gradient will 
increase the magnetic field strength in specific area. This in turn, increases the current it that area. If the field 
strength is switched too rapidly, the amount of current will increase to the point of tissue excitation. 
5. The subjects may experience a claustrophobic reaction in the magnet. 
6. There are loud banging noises with MR imaging that may be uncomfortable. 
 
Regarding the MRI procedures we will employ the following protections: 
1. The subject will be instructed not to bring metal objects into the magnet room and will be provided with 
lockable facilities for personal belongings. 
2. The use of the MRI screening form will exclude from the study potential subjects with implanted metal or 
medical devices. 
3. The FDA has strict limits regarding power deposition. Safeguards built into the operating system prevent 
exceeding those limits. 
4. The FDA has strict limits regarding gradients strengths and rise times. Safeguards built into the operating 
system prevent exceeding those limits. 
5. Subjects will be warned of the potential for claustrophobic reactions and those with a prior history of such 
reactions will be excluded from the study. If a subject experiences an unexpected and severe claustrophobic 
reaction, the study will be terminated. 
6. Subjects will be provided with hearing protection. 
 
Potential Risks to Subjects (Rare/Unforeseen): There have been no appropriate studies that either rule out 
or demonstrate negative health effects of MRI on fetuses. We will inform women with child-bearing potential of 
this information and pregnant women will not be allowed to participate. If new information becomes available to 
suggest that MRI may not be safe for pregnant women or their fetuses we will inform the subjects of such 
information. 
 
8.3 Blood draw risk: Commonly, there may be discomfort or pain at the site at the time of venipuncture, or 
bleeding or bruising post-venipuncture. Uncommonly, there is a very small risk of infection, which can be 
treated. Participants will be asked to contact their PCP and the study PI in the event of any adverse outcome. 
 
8.4 Minimizing risk of Breach of Data Security and Privacy: Data obtained from human subjects will be 


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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. 
 
9.0 REPORTING OF ADVERSE EVENTS OR UNANTICIPATED PROBLEMS INVOVLING RISK TO 
PARTICIPANTS OR OTHERS 
We define an adverse event as any adverse change in health or development of a side effect occurring in a 
study participant after enrollment.  These may be expected events (known drug effects, as detailed in the 
consent form, safety monitoring plan, or package insert) or unexpected events. The PI and Co-investigators 
will review any AE's that occurred during a participant's study experience, and determine their magnitude and 
causal attribution using the scale below. Every six months the PI and Co-investigators will review the 
magnitude and frequency of AE's and report such information to the IRB. 
 
AE's of grade three or higher in the scale below will be reported immediately to the IRB using the Report of 
Adverse Events form and to the Program Director of the appropriate funding agency. In conjunction with the 
IRB, the PI then will determine if modifications to the protocol are warranted. 
 
The primary method for ensuring data accuracy and protocol compliance will be the involvement of the PI in all 
aspects of the project. The PI and IRB have the authority to stop or modify the study at any time. During the 
semi-annual reviews, the PI and IRB will together decide if the study should continue unchanged, be modified, 
or closed to further enrollment. 
 
Scaling of Adverse Events: Attribution of Cause: 
a. Definite: Adverse event (AE) will clearly be related to investigational agents or other intervention.  
b. Probable: AE will likely be related to investigational agents or other intervention. 
c. Possible: AE may be related to investigational agents or other intervention. 
d. Not Likely: AE will doubtfully be related to investigational agents or other intervention. 
e. Unrelated: AE will clearly not be related to investigational agents or other intervention. 
 
Grading of Severity 
0: No AE or within normal limits. 
1: Mild AE. 
2: Moderate AE. 
3: Severe AE resulting in inpatient hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect. 
4: Life-threatening or disabling AE. 
5: Fatal AE 
 
10.0 STUDY WITHDRAWAL/DISCONTINUATION 
Subjects will be withdrawn from the study for safety considerations, non-compliance with study procedures, 
difficulties with scheduling or participation, excess movement or anxiety during scanning, or other reasons that 
the PI or study coordinators conclude will impair the scientific utility of the study.  Subjects will be provided an 
explanation by the investigator if they are withdrawn from the study. In addition, subjects can voluntarily 
withdraw from the study at any time. 
 
11.0 STATISTICAL CONSIDERATIONS 
11.1 Data Management: All study data will be stored in a REDCap study database.  The exception is for the 
raw and processed MRI scans that will be stored in the Vanderbilt XNAT Image Database system.  


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11.2 Statistical Analyses:  
 
11.2.a. Drug levels: We will collect serum drug levels at the time of imaging to create a dose-response 
curve. The response will be defined as the change of a specific measure (hippocampal activity) from 
baseline. We will utilize nonlinear regression methods to create curves. Many studies have established 
a dose-response curve for epilepsy efficacy and safety (Boon et al., 2002; Meencke and Buyle, 2006; 
Rhee et al., 2017), but no dose-response curve currently exists for other measures such as imaging 
markers. 
 
11.2.b. Clinical Data: The data will be analyzed both within and across diagnostic groups (patient, 
healthy control) and time-points (baseline assessment, after LEV intervention). Analyses of variance 
and linear mixed models will be used to compare group scores and the strength of the relation between 
neurocognitive and imaging outcome measures. 
 
11.2.c. Neurocognitive Data: The data will be analyzed both within and across diagnostic groups 
(patient, healthy control) and time-points (baseline assessment, after LEV intervention). Analyses of 
variance and linear mixed models will be used to compare group scores. 
 
11.2.d. Imaging Data: All images will be converted to an analyzable format. Spatial preprocessing will 
be performed using SPM5 (Functional Imaging Laboratory, London, UK) and FSL software (Analysis 
Group, FMRIB, Oxford, UK) or other comparable software. This will allow for realignment and 
transformation into a standardized space. Pairwise subtractions will then be performed, yielding images 
of mean difference and standard deviation, which can be used to produce z-scores and statistical 
parametric maps (SPMs). Statistical parametric maps will be constructed using a mixed effects model 
(subjects are considered random effects, conditions are considered fixed effects). SPM or other 
comparable software will allow us to test for condition effects, group effects, and group-by-condition 
interactions. Duration of illness and treatment will be assessed as confounding variables using an 
analysis of covariance. The duration of illness will be added into the fixed effects statistical model for 
the within group analysis as a covariate. Alternative methods will be employed when the data suggest a 
more appropriate method. The effects of duration of illness and treatment on structural imaging data will 
be assessed by correlation analysis. 
 
11.3 Power: We calculated power for our primary aim of modulation of hippocampal activity based on a similar 
study that detected changes in hippocampal activation between healthy controls and a group of aMCI patients 
receiving two weeks of oral LEV (Bakker et al., 2012). Using the effect sizes demonstrated in this paper, at N = 
40 (healthy control sample N = 20; psychosis patient sample N = 20) and alpha = 0.05, we will have 80.3% 
power to detect a change in hippocampal activity. 
 
12.0 PRIVACY/CONFIDENTIALITY ISSUES 
The data files generated by the MRI scanner are coded using a project name and unique number generated 
sequentially. The scanner technicians will not have access to the key for this information. Image analysis will 
use the coded files. The safety surveys described above include questions about sensitive health issues. This 
information will remain with the signed consent form in a secured area near the scanner. Electronic databases 
containing identifiable subject information will be password encoded. Written information containing subject 
identifiers (informed consent, lab results, interview questionnaires, subject payment, etc.) will be stored in file 
cabinets in offices within the departments of Radiology and Psychiatry. Subjects will be assigned an 
alphanumeric code that will be used to label all research data including all questionnaires and MRI data. 
 


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13.0 FOLLOW-UP AND RECORD RETENTION 
We anticipate participant recruitment and contact with subjects to be completed within one month. Study 
records will be maintained for at least two years after the study is closed with the IRB. In accordance with 
Vanderbilt guidelines, and as outlined to the subjects in the consent form, the subjects’ confidentiality will be 
ensured throughout the study. Image data will be acquired by the 3 Tesla scanner and will be stored both on 
digital media (which will not leave the secured scanner area) and on Vanderbilt’s secure REDCap database. 
The data may be maintained for an indefinite period of time since scientific progress may indicate that new 
analyses be carried out on previously obtained data. Future studies/analyses will be carried out with approval 
of the IRB. If paper records are to be destroyed those containing subject identifiers will be shredded directly or 
transferred to the hospital’s shredding service. If electronic data containing subject identifiers is to be destroyed 
it will be disposed of using a medium-appropriate destruction method to prevent recovery. Data not containing 
subject identifiers will be disposed of by any convenient method. 
 
In compliance with the National Institute of Health data sharing initiative, imaging data without any personal 
information attached may be shared with other investigators or public data repositories, which provides the 
research community with open access to datasets contributed by labs around the world. Information will be 
completely anonymized with demographics limited to age (accurate to the year up to 90 years old, or “90+” for 
older individuals), gender (male, female), group membership (e.g., disease/treatment state) and handedness. 
Data will be transferred using secure file transfer protocols. 
 
14.0 REFERENCES 
Association, A.P., 2016. Diagnostic an Statistical Manual of Mental Disorders, BMC Med. 
https://doi.org/10.1176/appi.books.9780890425596.744053 
Bakker, A., Albert, M.S., Krauss, G., Speck, C.L., Gallagher, M., 2015. Response of the medial temporal lobe 
network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory 
task performance. NeuroImage Clin. 7, 688–698. https://doi.org/10.1016/j.nicl.2015.02.009 
Bakker, A., Krauss, G.L., Albert, M.S., Speck, C.L., Jones, L.R., Stark, C.E., Yassa, M.A., Bassett, S.S., 
Shelton, A.L., Gallagher, M., 2012. Reduction of Hippocampal Hyperactivity Improves Cognition in 
Amnestic Mild Cognitive Impairment. Neuron 74, 467–474. https://doi.org/10.1016/j.neuron.2012.03.023 
Ben-Menachem, E., Falter, U., 2000. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with 
refractory partial seizures: A multicenter, double-blind, responder-selected study evaluating monotherapy. 
Epilepsia 41, 1276–1283. https://doi.org/10.1111/j.1528-1157.2000.tb04605.x 
Benes, F.M., 1999. Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol. Psychiatry 46, 
589–599. https://doi.org/10.1016/S0006-3223(99)00136-5 
Besag, F.M.C., Berry, D., 2006. Interactions between antiepileptic and antipsychotic drugs. Drug Saf. 29, 95–
118. https://doi.org/10.2165/00002018-200629020-00001 
Boon, P., Chauvel, P., Pohlmann-Eden, B., Otoul, C., Wroe, S., 2002. Dose-response effect of levetiracetam 
1000 and 2000 mg/day in partial epilepsy. Epilepsy Res. 48, 77–89. https://doi.org/10.1016/S0920-
1211(01)00323-0 
Cereghino, J.J., Biton, V., Abou-Khalil, B., Dreifuss, F., Gauer, L.J., Leppik, I., Abou-Khalil, B., Bashuk, R., 
Beydoun, A., Biton, V., Bromficld, E., Browne, T.R., Celesia, G.G., Cereghino, J., Dean, J.C., Dengler, J., 
Dreifuss, F.E., Ferrendelli, J.A., Granner, M., Harden, C., Harvey, J., Hier, D.B., Hoch, D., Mutton, J.T., 
Iyer, V.G., Jacobson, M., King, J.A., Kirby, L.C., Lebow, S.S., Leppik, I.E., Locke, G., Matsuo, F., 
Newsom, M., Penovich, P., Radtke, R.A., Ramani, V., Remler, M.P., Rowan, A.J., Ruggles, K., Singer, 
R.P., Treiman, D.M., Michael, M., Wcstbrook, E., Willmore, L.J., Wilner, A., 2000. Levetiracetam for partial 
seizures: Results of a double-blind, randomized clinical trial. Neurology 55, 236–242. 
https://doi.org/10.1212/WNL.55.2.236 
Cramer, J.A., Smith, D.B., Mattson, R.H., Escueta, A.V.D., Collins, J.F., Browne, T.R., Crill, W.E., Homan, 
R.W., Mayersdorf, A., McCutchen, C.B., McNamara, J.O., Rosenthal, N.P., Treiman, D.M., Wilder, B.J., 
Williamson, P.D., 1983. A method of quantification for the evaluation of antiepileptic drug therapy. 


Protocol Version: 1.3 
Date: February 29, 2020 
18 
Neurology 33, 26–37. 
Devi, L., Ohno, M., 2013. Effects of levetiracetam, an antiepileptic drug, on memory impairments associated 
with aging and Alzheimer’s disease in mice. Neurobiol. Learn. Mem. 102, 7–11. 
https://doi.org/10.1016/j.nlm.2013.02.001 
Dooley, M., Plosker, G.L., 2000. Levetiracetam: A review of its adjunctive use in the management of partial 
onset seizures. Drugs 60, 871–893. https://doi.org/10.2165/00003495-200060040-00004 
First, M.B., 2015. Structured Clinical Interview for the DSM (SCID). Encycl. Clin. Psychol. 1–6. 
https://doi.org/10.1002/9781118625392.wbecp351 
Freund, T.F., 2003. Interneuron Diversity series: Rhythm and mood in perisomatic inhibition. Trends Neurosci. 
26, 489–495. https://doi.org/10.1016/S0166-2236(03)00227-3 
Friston, K.J., Liddle, P.F., Frith, C.D., Hirsch, S.R., Frackowiak, R.S.J., 1992. The left medial temporal region 
and schizophrenia: A pet study. Brain 115, 367–382. https://doi.org/10.1093/brain/115.2.367 
Gambardella, A., Labate, A., Colosimo, E., Ambrosio, R., Quattrone, A., 2008. Monotherapy for partial 
epilepsy: Focus on levetiracetam. Neuropsychiatr. Dis. Treat. 4, 33–38. https://doi.org/10.2147/ndt.s1655 
Gill, K., Grace, A., 2014. The Role of &#945;5 GABAA Receptor Agonists in the Treatment of Cognitive Deficits 
in Schizophrenia. Curr. Pharm. Des. 20, 5069–5076. 
https://doi.org/10.2174/1381612819666131216114612 
Gomes, F. V., Rincón-Cortés, M., Grace, A.A., 2016. Adolescence as a period of vulnerability and intervention 
in schizophrenia: Insights from the MAM model. Neurosci. Biobehav. Rev. 70, 260–270. 
https://doi.org/10.1016/j.neubiorev.2016.05.030 
Gozzi, A., Crestan, V., Turrini, G., Clemens, M., Bifone, A., 2010. Antagonism at serotonin 5-HT2A receptors 
modulates functional activity of frontohippocampal circuit. Psychopharmacology (Berl). 209, 37–50. 
https://doi.org/10.1007/s00213-009-1772-4 
Gozzi, A., Herdon, H., Schwarz, A., Bertani, S., Crestan, V., Turrini, G., Bifone, A., 2008. Pharmacological 
stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat. 
Psychopharmacology (Berl). 201, 273–284. https://doi.org/10.1007/s00213-008-1271-z 
Gur, R.E., Mozley, P.D., Resnick, S.M., Mozley, L.H., Shtasel, D.L., Gallacher, F., Arnold, S.E., Karp, J.S., 
Alavi, A., Reivich, M., Gur, R.C., 1995. Resting Cerebral Glucose Metabolism in First-Episode and 
Previously Treated Patients with Schizophrenia Relates to Clinical Features. Arch. Gen. Psychiatry 52, 
657–667. https://doi.org/10.1001/archpsyc.1995.03950200047013 
Hall, A.M., Throesch, B.T., Buckingham, S.C., Markwardt, S.J., Peng, Y., Wang, Q., Hoffman, D.A., Roberson, 
E.D., 2015. Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of 
Alzheimer’s disease. J. Neurosci. 35, 6221–6230. https://doi.org/10.1523/JNEUROSCI.2552-14.2015 
Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. 
https://doi.org/10.1136/jnnp.23.1.56 
Hannula, D.E., Ranganath, C., Ramsay, I.S., Solomon, M., Yoon, J., Niendam, T.A., Carter, C.S., Ragland, 
J.D., 2010. Use of eye movement monitoring to examine item and relational memory in schizophrenia. 
Biol. Psychiatry 68, 610–616. https://doi.org/10.1016/j.biopsych.2010.06.001 
Heckers, S., Konradi, C., 2015. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. 
Schizophr. Res. 167, 4–11. https://doi.org/10.1016/j.schres.2014.09.041 
Ji-Qun, C., Ishihara, K., Nagayama, T., Serikawa, T., Sasa, M., 2005. Long-lasting antiepileptic effects of 
levetiracetam against epileptic seizures in the spontaneously epileptic rat (SER): Differentiation of 
levetiracetam from conventional antiepileptic drugs. Epilepsia 46, 1362–1370. 
https://doi.org/10.1111/j.1528-1167.2005.29604.x 
Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr. Bull. 13, 261–276. https://doi.org/10.1093/schbul/13.2.261 
Klausberger, T., Somogyi, P., 2008. Neuronal diversity and temporal dynamics: The unity of hippocampal 
circuit operations. Science (80-. ). https://doi.org/10.1126/science.1149381 
Koh, M.T., Haberman, R.P., Foti, S., McCown, T.J., Gallagher, M., 2010. Treatment strategies targeting excess 
hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology 35, 1016–
1025. https://doi.org/10.1038/npp.2009.207 


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Date: February 29, 2020 
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Koh, M.T., Shao, Y., Rosenzweig-Lipson, S., Gallagher, M., 2018. Treatment with levetiracetam improves 
cognition in a ketamine rat model of schizophrenia. Schizophr. Res. 193, 119–125. 
https://doi.org/10.1016/j.schres.2017.06.027 
Kossoff, E.H., Bergey, G.K., Freeman, J.M., Vining, E.P.G., 2001. Levetiracetam psychosis in children with 
epilepsy. Epilepsia 42, 1611–1613. https://doi.org/10.1046/j.1528-1157.2001.32101.x 
Krasowski, M.D., 2010. Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications. Pharmaceuticals 
3, 1909–1935. https://doi.org/10.3390/ph3061909 
Lehman, A.F., Lieberman, J.A., Dixon, L.B., McGlashan, T.H., Miller, A.L., Perkins, D.O., Kreyenbuhl, J., 
McIntyre, J.S., Charles, S.C., Altshuler, K., Cook, I., Cross, C.D., Mellman, L., Moench, L.A., Norquist, G., 
Twemlow, S.W., Woods, S., Yager, J., Gray, S.H., Askland, K., Pandya, R., Prasad, K., Johnston, R., 
Nininger, J., Peele, R., Anzia, D.J., Benson, R.S., Lurie, L., Walker, R.D., Kunkle, R., Simpson, A., 
Fochtmann, L.J., Hart, C., Regier, D., 2004. Practice Guideline for the Treatment of Partients with 
Schizophrenia, Second Edition. Am. J. Psychiatry 161. 
https://doi.org/10.1176/appi.books.9780890423363.45859 
Liddle, P.F., Friston, K.J., Frith, C.D., Hirsch, S.R., Jones, T., Frackowiak, R.S.J., 1992. Patterns of cerebral 
blood flow in schizophrenia. Br. J. Psychiatry 160, 179–186. https://doi.org/10.1192/bjp.160.2.179 
Lodge, D.J., Behrens, M.M., Grace, A.A., 2009. A Loss of Parvalbumin-Containing Interneurons Is Associated 
with Diminished Oscillatory Activity in an Animal Model of Schizophrenia. J. Neurosci. 
https://doi.org/10.1523/JNEUROSCI.5419-08.2009 
Logothetis, N.K., 2008. What we can do and what we cannot do with fMRI. Nature 453, 869–878. 
https://doi.org/10.1038/nature06976 
Lynch, B.A., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S.M., Matagne, A., Fuks, B., 2004. The 
synaptic vesicle is the protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. 
Acad. Sci. U. S. A. 101, 9861–9866. https://doi.org/10.1073/pnas.0308208101 
Lyseng-Williamson, K.A., 2011. Levetiracetam: A review of its use in epilepsy. Drugs 71, 489–514. 
https://doi.org/10.2165/11204490-000000000-00000 
McHugo, M., Talati, P., Armstrong, K., Vandekar, S.N., Blackford, J.U., Woodward, N.D., Heckers, S., 2019. 
Hyperactivity and Reduced Activation of Anterior Hippocampus in Early Psychosis. Am. J. Psychiatry 
appi.ajp.2019.1. https://doi.org/10.1176/appi.ajp.2019.19020151 
Meencke, H.J., Buyle, S., 2006. Assessment of a dose-response relationship of levetiracetam. Eur. J. Neurol. 
13, 942–946. https://doi.org/10.1111/j.1468-1331.2006.01381.x 
Modinos, G., Şimşek, F., Azis, M., Bossong, M., Bonoldi, I., Samson, C., Quinn, B., Perez, J., Broome, M.R., 
Zelaya, F., Lythgoe, D.J., Howes, O.D., Stone, J.M., Grace, A.A., Allen, P., McGuire, P., 2018. Prefrontal 
GABA levels, hippocampal resting perfusion and the risk of psychosis. Neuropsychopharmacology 43, 
2652–2659. https://doi.org/10.1038/s41386-017-0004-6 
Morisky, D.E., Green, L.W., Levine, D.M., 1986. Concurrent and predictive validity of a self-reported measure 
of medication adherence. Med. Care 24, 67–74. https://doi.org/10.1097/00005650-198601000-00007 
Morosini, P.L., Magliano, L., Brambilla, L., Ugolini, S., Pioli, R., 2000. Development, reliability and acceptability 
of a new version of the DSM- IV Social Occupational Functioning Assessment Scale (SOFAS) to assess 
routine social functioning. Acta Psychiatr. Scand. 101, 323–329. https://doi.org/10.1034/j.1600-
0447.2000.101004323.x 
Mula, M., Trimble, M.R., Yuen, A., Liu, R.S.N., Sander, J.W.A.S., 2003. Psychiatric adverse events during 
levetiracetam therapy. Neurology 61, 704–706. https://doi.org/10.1212/01.WNL.0000078031.32904.0D 
Neyens, L.G.J., Alpherts, W.C.J., Aldenkamp, A.P., 1995. Cognitive effects of a new pyrrolidine derivative 
(levetiracetam) in patients with epilepsy. Prog. Neuropsychopharmacol. Biol. Psychiatry 19, 411–419. 
https://doi.org/10.1016/0278-5846(95)00022-N 
Nicolas, J.M., Collart, P., Gerin, B., Mather, G., Trager, W., Levy, R., Roba, J., 1999. In vitro evaluation of 
potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab. Dispos. 27, 250–
254. 
Olbrich, H.G., Braak, H., 1985. Ratio of pyramidal cells versus non-pyramidal cells in sector CA1 of the human 
Ammon’s horn. Anat. Embryol. (Berl). 173, 105–110. https://doi.org/10.1007/BF00707308 


Protocol Version: 1.3 
Date: February 29, 2020 
20 
Olincy, A., Stevens, K.E., 2007. Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to 
men. Biochem. Pharmacol. 74, 1192–1201. https://doi.org/10.1016/j.bcp.2007.07.015 
Patsalos, P.N., 2004. Clinical pharmacokinetics of levetiracetam. Clin. Pharmacokinet. 43, 707–724. 
https://doi.org/10.2165/00003088-200443110-00002 
Patsalos, P.N., 2000. Pharmacokinetic profile of levetiracetamtoward ideal characteristics. Pharmacol. Ther. 
85, 77–85. https://doi.org/10.1016/S0163-7258(99)00052-2 
Peralta, V., Cuesta, M.J., 1994. Psychometric properties of the Positive and Negative Syndrome Scale 
(PANSS) in schizophrenia. Psychiatry Res. 53, 31–40. https://doi.org/10.1016/0165-1781(94)90093-0 
Perez, S.M., Lodge, D.J., 2014. New approaches to the management of schizophrenia: Focus on aberrant 
hippocampal drive of dopamine pathways. Drug Des. Devel. Ther. 8, 887–896. 
https://doi.org/10.2147/DDDT.S42708 
Perucca, P., Gilliam, F.G., 2012. Adverse effects of antiepileptic drugs. Lancet Neurol. 11, 792–802. 
https://doi.org/10.1016/S1474-4422(12)70153-9 
Potter, D., Summerfelt, A., Gold, J., Buchanan, R.W., 2006. Review of clinical correlates of P50 sensory gating 
abnormalities in patients with schizophrenia. Schizophr. Bull. 32, 692–700. 
https://doi.org/10.1093/schbul/sbj050 
Rhee, S. jin, Shin, J.W., Lee, S.H., Moon, J., Kim, T.J., Jung, K.Y., Park, K. Il, Lee, S.T., Jung, K.H., Yu, K.S., 
Jang, I.J., Chu, K., Lee, S.K., 2017. Population pharmacokinetics and dose-response relationship of 
levetiracetam in adult patients with epilepsy. Epilepsy Res. 132, 8–14. 
https://doi.org/10.1016/j.eplepsyres.2017.02.011 
Rossetti, A.O., Bromfield, E.B., 2005. Levetiracetam in the treatment of status epilepticus in adults: A study of 
13 episodes. Eur. Neurol. 54, 34–38. https://doi.org/10.1159/000087385 
Saha, S., Chant, D., Welham, J., McGrath, J., 2005. A systematic review of the prevalence of schizophrenia. 
PLoS Med. 2, 0413–0433. https://doi.org/10.1371/journal.pmed.0020141 
Sanchez, P.E., Zhu, L., Verret, L., Vossel, K.A., Orr, A.G., Cirrito, J.R., Devidze, N., Ho, K., Yu, G.Q., Palop, 
J.J., Mucke, L., 2012. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and 
cognitive deficits in an Alzheimer’s disease model. Proc. Natl. Acad. Sci. U. S. A. 109. 
https://doi.org/10.1073/pnas.1121081109 
Schobel, S.A., Chaudhury, N.H., Khan, U.A., Paniagua, B., Styner, M.A., Asllani, I., Inbar, B.P., Corcoran, 
C.M., Lieberman, J.A., Moore, H., Small, S.A., 2013. Imaging Patients with Psychosis and a Mouse Model 
Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver. 
Neuron 78, 81–93. https://doi.org/10.1016/j.neuron.2013.02.011 
Schobel, S.A., Lewandowski, N.M., Corcoran, C.M., Moore, H., Brown, T., Malaspina, D., Small, S.A., 2009. 
Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related 
psychotic disorders. Arch. Gen. Psychiatry 66, 938–946. 
https://doi.org/10.1001/archgenpsychiatry.2009.115 
Shorvon, S.D., Löwenthal, A., Janz, D., Bielen, E., Loiseau, P., 2000. Multicenter double-blind, randomized, 
placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. 
Epilepsia 41, 1179–1186. https://doi.org/10.1111/j.1528-1157.2000.tb00323.x 
Smucny, J., Stevens, K.E., Tregellas, J.R., 2015. The antiepileptic drug levetiracetam improves auditory gating 
in DBA/2 mice. npj Schizophr. 1. https://doi.org/10.1038/npjschz.2015.2 
Smucny, J., Tregellas, J.R., 2017. Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence 
from neurophysiology to neuroimaging. J. Psychopharmacol. 31, 801–811. 
https://doi.org/10.1177/0269881117705071 
Stan, A.D., Ghose, S., Zhao, C., Hulsey, K., Mihalakos, P., Yanagi, M., Morris, S.U., Bartko, J.J., Choi, C., 
Tamminga, C.A., 2015. Magnetic resonance spectroscopy and tissue protein concentrations together 
suggest lower glutamate signaling in dentate gyrus in schizophrenia. Mol. Psychiatry 20, 433–439. 
https://doi.org/10.1038/mp.2014.54 
Stevens, K.E., Wear, K.D., 1997. Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal 
auditory gating in two animal models. Pharmacol. Biochem. Behav. 57, 869–874. 
https://doi.org/10.1016/S0091-3057(96)00466-2 


Protocol Version: 1.3 
Date: February 29, 2020 
21 
Stratton, S.C., Large, C.H., Cox, B., Davies, G., Hagan, R.M., 2003. Effects of lamotrigine and levetiracetam 
on seizure development in a rat amygdala kindling model. Epilepsy Res. 53, 95–106. 
https://doi.org/10.1016/S0920-1211(02)00254-1 
Stretton, J., Winston, G., Sidhu, M., Centeno, M., Vollmar, C., Bonelli, S., Symms, M., Koepp, M., Duncan, 
J.S., Thompson, P.J., 2012. Neural correlates of working memory in Temporal Lobe Epilepsy - An fMRI 
study. Neuroimage 60, 1696–1703. https://doi.org/10.1016/j.neuroimage.2012.01.126 
Suberbielle, E., Sanchez, P.E., Kravitz, A. V., Wang, X., Ho, K., Eilertson, K., Devidze, N., Kreitzer, A.C., 
Mucke, L., 2013. Physiologic brain activity causes DNA double-strand breaks in neurons, with 
exacerbation by amyloid-β. Nat. Neurosci. 16, 613–621. https://doi.org/10.1038/nn.3356 
Talati, P., Rane, S., Kose, S., Blackford, J.U., Gore, J., Donahue, M.J., Heckers, S., 2014. Increased 
hippocampal CA1 cerebral blood volume in schizophrenia. NeuroImage Clin. 5, 359–364. 
https://doi.org/10.1016/j.nicl.2014.07.004 
Tregellas, J.R., 2014. Neuroimaging biomarkers for early drug development in schizophrenia. Biol. Psychiatry 
76, 111–119. https://doi.org/10.1016/j.biopsych.2013.08.025 
Uhlhaas, P.J., 2013. Dysconnectivity, large-scale networks and neuronal dynamics in schizophrenia. Curr. 
Opin. Neurobiol. 23, 283–290. https://doi.org/10.1016/j.conb.2012.11.004 
Verrotti, A., Prezioso, G., Di Sabatino, F., Franco, V., Chiarelli, F., Zaccara, G., 2015. The adverse event 
profile of levetiracetam: A meta-analysis on children and adults. Seizure 31, 49–55. 
https://doi.org/10.1016/j.seizure.2015.07.004 
Wandschneider, B., Stretton, J., Sidhu, M., Centeno, M., Kozák, L.R., Symms, M., Thompson, P.J., Duncan, 
J.S., Koepp, M.J., 2014. Levetiracetam reduces abnormal network activations in temporal lobe epilepsy. 
Neurology 83, 1508–1512. https://doi.org/10.1212/WNL.0000000000000910 
Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating scale for mania: Reliability, validity and 
sensitivity. Br. J. Psychiatry 133, 429–435. https://doi.org/10.1192/bjp.133.5.429 
Zhang, Q., Yang, F., Hu, Z., Xu, Q., Bernhardt, B.C., Quan, W., Li, Q., Zhang, Z., Lu, G., 2018. Antiepileptic 
drug of levetiracetam decreases centrotemporal spike-associated activation in rolandic epilepsy. Front. 
Neurosci. 12. https://doi.org/10.3389/fnins.2018.00796 
Zhang, Q., Yang, F., Hu, Z., Zhang, Z., Xu, Q., Dante, M., Wu, H., Li, Z., Li, Q., Li, K., Lu, G., 2017. Resting-
state fMRI revealed different brain activities responding to valproic acid and levetiracetam in benign 
epilepsy with central-temporal spikes. Eur. Radiol. 27, 2137–2145. https://doi.org/10.1007/s00330-016-
4531-z 
Zou, L.P., Ding, C.H., Song, Z.J., Li, X.F., 2012. Stevens-Johnson syndrome induced by levetiracetam. Seizure 
21, 823–825. https://doi.org/10.1016/j.seizure.2012.09.005 
 


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ICF_001.pdf: 
VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
1 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
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.   
 
Key information about this study:  
You are being asked to take part in this research study because you are a healthy control subject. The 
purpose of this study is to test whether levetiracetam (otherwise known as LEV), a drug that alters brain 
activity, changes the activity of a brain region called the hippocampus when you use it during a MRI 
scan. This study will also test whether the drug affects memory performance using a brief memory test. 
Lastly, this study will test if this drug affects clinical symptoms of psychotic disorders. Previous studies in 
schizophrenia have shown that the hippocampus is hyperactive. An abnormal hippocampus can result in 
changes in memory performance and may be responsible for psychosis clinical symptoms. Therefore, 
the aim of this study is to understand the effects of LEV on hippocampus activity, memory, and clinical 
symptoms. We would like to enroll about 30 participants with schizophrenia and 30 healthy controls in 
this study at Vanderbilt. We will not be assessing you for any clinical symptoms of psychosis in this study 
because you are a healthy control subject.  
 
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:  
Levetiracetam: Levetiracetam is an FDA-approved anti-epileptic medication. This study requires that you 
take this medication. Side effects have been well established in daily doses 2-6 times higher than the 
doses we will use in this study (1,000-3,000 mg/day): 10% of individuals experience headache, dizziness, 
asthenia (weakness, lack of energy or strength), neuropsychiatric symptoms (mild agitation, hostility, 
apathy, anxiety, or emotional lability), vomiting (occurs in 15%), or report infection while using this drug. 
Somnolence (sleepiness or drowsiness) occurs in 8-45% of patients. Very rarely, participants have 
experienced serious symptoms including hallucinations, suicidal ideation (thinking about or planning 
suicide), or psychosis (a mental disorder in which thought and emotions are so impaired that one 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
2 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
becomes disconnected from reality). Discontinuation of the drug led to resolution of symptoms. An 
exceedingly rare side effect of the drug is skin irritation and blistering. 
 
Blood sampling: The blood draw may cause redness, slight discomfort, mild bruising, and possibility of 
infection. However this risk is low, as all blood samples will be taken by trained staff. 
 
Risks of Neuropsychological Testing: It is not uncommon to experience some stress or frustration during 
the neuropsychological testing. However, you may stop or take a break from testing at any time if you 
wish. 
 
Risks of MRI: There are no known major risks with an MRI scan. However, it is possible that harmful 
effects could be found out in the future. This is not an “open MRI” and the tunnel is closed and open 
only on either end, so it may bother you to be placed in a tight space (claustrophobia), and to hear the 
noise made by the magnet during the scan. You will be given earplugs to reduce the noise. You may also 
feel the table vibrate and/or move slightly during the scan. It may be hard to lie on the table during the 
scan. If you have any metal pieces in your body, they could move during the scan and damage nearby 
tissue or organs. 
 
If you use a transdermal patch (medicated patches applied to the skin), you may need to take it off 
during the MRI scan. Transdermal patches slowly deliver medicines through the skin. Some patches have 
metal in the layer of the patch that is not in contact with the skin (the backing). You may not be able to 
see the metal in the backing of these patches. Patches that contain metal can overheat during an MRI 
scan and cause skin burns in the immediate area of the patch. Tell the study doctor that you are using a 
patch and why you are using it (such as, for pain, smoking cessation, hormones). Ask your doctor for 
guidance about removing and disposing of the patch before having an MRI scan and replacing it after 
the procedure. Tell the MRI facility that you are using a patch. You should do this when making your 
appointment and during the health history questions you are asked when you arrive for your 
appointment.  
 
Loss of Confidentiality: There is also the potential risk of loss of confidentiality. Every effort will be made 
to keep your information confidential, however, this cannot be guaranteed. 
   
Risks that are not known: 
As with any research, there may be risks of participation or from the study medication that we cannot 
predict. Because this treatment is investigational, meaning non-FDA approved, there may be risks that 
we do not know about at this time. If you experience any unpleasant effects during this study not 
mentioned in this consent form, please contact the study coordinator as soon as possible. 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
3 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
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 schizophrenia. Therefore, 
participation in this study may, in time, benefit both individuals with schizophrenia and society at large. 
 
Procedures to be followed: 
If you agree to be in this study, you will first be asked to sign and date this consent form. The study takes 
place over the course of about 2 weeks. After we determine if you are eligible to participate in the 
study, participation will involve the use and monitoring of LEV. Before starting LEV, you will have a brief 
neurocognitive (memory) test and a brain MRI scan. You will have another brain scan after taking your 
first dose of LEV. You will repeat the testing and brain scan after 2 weeks of receiving the medication. 
 
Screening and Consent Visit: You are here today so we can evaluate if you are eligible for this study. If 
you agree to this consent form, we will need to take a blood sample to make sure this study is safe for 
you. If these levels come back within normal ranges, we will contact you about starting the study on a 
later day. If there is a problem where you cannot be in the study because of your blood levels, a 
research team member will discuss that with you. 
 
Day 1 Visit: During the first visit, you will meet the study coordinator. Your medical, psychiatric, and 
social history will be carefully reviewed if we do not already have this information. We may assess your 
current and past medication use. You do not have to answer any questions you do not feel comfortable 
answering.  
 
As a part of this visit, we will carefully evaluate you to determine if you have any metal in your body that 
could stop you from having the MRI. After we are sure that you are safe to complete the MRI, you will 
complete neuropsychological (memory) testing and the MRI scan.  
 
Neuropsychological Testing: We will ask you to complete a task that measures your memory abilities. 
This will be done on the computer. This task will take about 30 minutes.  
 
MRI: We will then continue the day 1 visit at the Vanderbilt University Institute of Imaging Science 
(VUIIS). A research team member will walk with you to and from the VUIIS. If you are unable to 
complete this walk, a research team member will instead accompany you on a Vanderbilt shuttle to and 
from the VUIIS. A MRI scan is taken in a large machine that is shaped like a tunnel. This scan does not 
use x-rays, but rather a strong magnet and radio waves to take pictures of your body. This will be a one-
hour long session, and you will be asked to complete one task during the MRI. The first task involves the 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
4 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
presentation of pictures of faces and scenes, while in the MRI scan, and then pushing a button in 
response to various directions. 
 
 
You may not be able to have this scan if you have a device in your body, such as aneurysm clips in your 
brain, heart pacemakers or defibrillators, or cochlear (inner ear) implants. Also, you may not be able to 
have this scan if you have iron-based tattoos or pieces of metal (bullet, BB, shrapnel) close to or in an 
important organ (such as the eye). If we determine that you cannot safely complete the MRI, we will 
withdraw you from the study. 
 
 
Certain metal objects like watches, hairpins, credit cards, writing pens, etc. may be damaged by the 
machine or may be pulled away from the body when you are getting the scan. Also, metal can 
sometimes cause poor pictures if it is close to the part of the body being scanned. For these reasons, 
you will be asked to remove these objects before going into the room for the scan. 
 
 
You will hear “hammering,” clicking, or squealing noises during the scan. You will be given earplugs to 
reduce the noise. You will also be told how to alert the staff if you need them. 
 
In this study, the MRI scan is for research only. However, if we see something that is not normal, you will 
be told and asked to consult your doctor. 
 
After the MRI is complete, you will receive LEV tablets. On this first day, we will ask that you take two 
250 mg tablets. A research team member will be present to monitor you when the study drug is 
administered. We will then wait for two hours. After two hours have passed, we will take another MRI 
scan. After this scan we will take another blood sample so we can check the LEV levels in your body. 
After the first day, you will take 250 mg tablets at two separate times in the day (in the morning and 
evening). 
 
Because somnolence (sleepiness, drowsiness) has been reported in people who take LEV, we will require 
that you a) have someone drive you to and from Vanderbilt Psychiatric Hospital or b) take a brief test 
before and after you take LEV. This test will make sure that LEV is not making it dangerous for you to 
drive. If the test shows that LEV has affected your ability to drive, we will purchase a car service 
(Uber/Lyft) to drive you home and back to Vanderbilt Psychiatric Hospital on another day that works for 
you to pick up your vehicle. 
 
This visit can last for the majority of a day. If needed we can spread the procedures out over two days. 
We will then schedule a follow up visit for about 14 days later. 
 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
5 
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Time between visits: It is very important that you take the medication we give you twice a day. You will 
take one 250 mg tablet in the morning and another 250 mg tablet in the evening. Over the 14 days, we 
may periodically contact you and ask how you are doing. We want to make sure you are not 
experiencing any side effects and are taking the medication. We will also be available to ask you any 
questions about the study. 
 
Day 14 Visit: You will be asked to complete the same neurocognitive and MRI tests. We also be asked to 
complete two additional surveys that will assess side effects and medication compliance. We will also 
take one final blood sample to check the levels of LEV in your body and make sure this medication has 
not changed any of your normal blood levels. We also ask that you bring any remaining LEV medication 
with you to this visit. 
 
Over the course of this study, we will ask women to take a urine pregnancy test. The medication we are 
giving, LEV, can cause pregnancy complications. If this test is positive, we will stop the study 
immediately. 
 
Payments for your time spent taking part in this study or expenses: 
You will be provided $25 for completion of the baseline 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 $475 at the 
completion of the testing visit. 
 
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 this 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. 
 
If you agree to take part in this research study, you and/or your insurance will not have to pay for the 
study medication or the tests and evaluations that are being done only for research. 
 
However, you are still responsible for paying for the usual care you would normally receive for the 
treatment of your illness. This includes treatments and tests you would need even if you were not in this 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
6 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
study. This will also include any antipsychotic medication you are already taking.  These costs will be 
billed to you and/or your insurance.  
 
You have the right to ask what it may cost you to take part in this study. If you would like assistance, 
financial counseling is available through the Vanderbilt Financial Assistance Program. The study staff can 
help you contact this program. You have the right to contact your insurance company to discuss the 
costs of your routine care (non-research) further before choosing to be in the study. You may choose 
not to be in this study if your insurance does not pay for your routine care (non-research) costs and your 
doctor will discuss other treatment plans with you. 
 
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 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 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 the study coordinator, Maxwell Roeske, at (615) 875-1896, 
or the study doctor, Dr. Stephan Heckers, at (615) 322-2665. 
 
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 Vanderbilt University 
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:  
Your study doctor may withdraw you from study participation if he or she determines that, based on the 
initial study interview, you are not eligible to continue the study. He or she may also withdraw you if you 
are having difficulty completing study procedures, if you need an immediate referral for clinical care, or 
if he/she decides that it is not in your best interest to continue in the study. If you are taken out of the 
study, you will be told the reason. 
 
What will happen if you decide to stop being in this study? 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
7 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
If you decide to stop being part of the study, you should tell your study doctor. We may ask you to come 
in for a final study visit. Because you are receiving study medication, it is important to discuss a safe and 
effective plan for continuing, altering, or stopping the medication. All participation in the study is 
voluntary, and there is no penalty for refusing to participate or for early withdrawal.  
 
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 reasonable efforts will be made to keep the personal information in your research record private and 
confidential, but absolute confidentiality cannot be guaranteed. Your records will be kept in locked filing 
cabinets within locked rooms, and only the research team will have access. Your information may be 
shared with institutional and/or governmental authorities, such as the Vanderbilt University Institutional 
Review Board, if you or someone else is in danger or if we are required to do so by law. 
 
During the research, if we learn you are having thoughts about suicide or hurting yourself or others, the 
research staff will ask you more questions about your thoughts. Based on your response, the staff may 
provide you with help to get treatment. This may include working with you to contact a doctor, 
contacting a trusted family member or therapist to discuss your thoughts, or working with you on a plan 
that may include getting you to a hospital for safety. 
 
Vanderbilt may share your information, without identifiers, to others or use it for other research 
projects not listed in this form. Vanderbilt, Dr. Heckers, and his staff will comply with any and all laws 
regarding the privacy of such information.  There are no plans to pay you for the use or transfer of this 
de-identified information. 
 
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: 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
8 
This box is for 
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Do not edit or delete 
 
Your individual study results will not be shared with you. The final results of the study will be made 
available through www.clinicaltrails.gov and potentially through publication in the scientific literature. 
 
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: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
9 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Pharmacologic Modulation of Hippocampal Activity in Psychosis 
Version Date: 
PI: 
02/29/2020 
Stephan Heckers, MD 
  
 
 
 
 
10 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
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