Clinical trial NCT03129360
Conditions: Psychosis Schizophrenia Schizo Affective Disorder Schizophreniform
Keywords: Early Psychosis Levetiracetam
Sponsor: NYU Langone Health
Start date: 2017-08-18; Completion date: 2021-11-03
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In order to establish target engagement and identify an effective dose the investigators will conduct a placebo-controlled single-dose parallel group trial of levetiracetam 185 mg and 500 mg in 24 medication-naïve early psychosis (EP) patients, measuring hippocampal activity by pulsed arterial spin labelling (ASL) pre-dose and 2 hours post-dose. The lower dose is calculated to achieve blood levels within the range that were associated with reduced hippocampal activity and improved cognition in patients with mild cognitive impairment; the higher dose is a typical antiepileptic dose. Successful demonstration of target engagement will be defined by an effect size of 0.5 or greater compared to placebo in reduction by levetiracetam of hippocampal blood flow measured by ASL. The optimal dose will be defined by maximal reduction of hippocampal perfusion in the absence of clinically-significant adverse effects. The investigators will also study 8 healthy control subjects to verify that baseline hippocampal blood flow is elevated in the sample of EP subjects.

Detailed description:

Arms: arm 1: A single dose of 185mg of levetiracetam administered orally to participants. Participants undergo a 15-minute MRI scan using arterial spin labeling (ASL) before dosing and two hours post-dosing. arm 2: A single dose of 500mg of levetiracetam administered orally to participants. Participants undergo a 15-minute MRI scan using arterial spin labeling (ASL) before dosing and two hours post-dosing. arm 3: A single dose of placebo administered orally to participants. Participants undergo a 15-minute MRI scan using arterial spin labeling (ASL) before dosing and two hours post-dosing.
Interventions: intervention 1: Levetiracetam intervention 2: Placebo
Intervention descriptions: intervention 1: Levetiracetam is an atypical anticonvulsant that is frequently used in children and adults due to its superior tolerability, ease of use and excellent safety profile. intervention 2: Prepared in capsules to appear identical to levetiracetam.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL 
INVESTIGATING THE EFFECTS OF LEVETIRACETAM IN EARLY 
PSYCHOSIS 
NCT Number: 
NCT03129360 
Study Number: 
17-00266 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
8/4/2020  
 
 


  
CONFIDENTIAL 
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authorized in writing by the study sponsor 
 
 
 
 
 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL INVESTIGATING THE EFFECTS 
OF LEVETIRACETAM IN EARLY PSYCHOSIS 
 
 
 
 
 
Abbreviated Title:  
 
 
Version #: 
Version Date: 
 
 
 
Regulatory Sponsor: 
Levetiracetam in Early Psychosis 
 
 
1.19 
07/28/2020 
 
 
 
Donald Goff, MD 
Department of Psychiatry, NYU Langone Medical Center 
One Park Avenue, 8th Floor 
New York, NY 10016  
 
 
Protocol Number: 
S17-00266 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Research 


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Table of Contents 
 
STUDY SUMMARY ................................................................................................................. 1 
1 INTRODUCTION................................................................................................................ 2 
1.1 BACKGROUND .............................................................................................................................. 2 
1.2 INVESTIGATIONAL AGENT ............................................................................................................... 3 
1.3 CLINICAL DATA TO DATE ................................................................................................................ 4 
1.4 STUDY/DOSE RATIONALE ............................................................................................................... 7 
1.5 RESEARCH RISKS & BENEFITS .......................................................................................................... 8 
1.5.1 Risk of Study Drug ............................................................................................................. 8 
1.5.2 Other Risks of Study Participation ................................................................................... 8 
1.5.3 Potential benefits.............................................................................................................. 9 
2 STUDY OBJECTIVES ........................................................................................................... 9 
3 STUDY DESIGN ................................................................................................................. 9 
3.1 GENERAL DESIGN .......................................................................................................................... 9 
3.2 PRIMARY STUDY ENDPOINTS........................................................................................................... 9 
3.3    PRIMARY 
SAFETY 
ENDPOINTS
 
9 
4 SUBJECT SELECTION AND WITHDRAWAL .......................................................................... 9 
4.1 INCLUSION CRITERIA ...................................................................................................................... 9 
4.2 EXCLUSION CRITERIA ..................................................................................................................... 9 
4.3 SUBJECT RECRUITMENT AND SCREENING ........................................................................................ 10 
4.4 EARLY WITHDRAWAL OF SUBJECTS ................................................................................................ 10 
5 STUDY DRUG.................................................................................................................. 10 
5.1 DESCRIPTION .............................................................................................................................. 10 
5.2 TREATMENT REGIMEN ................................................................................................................. 10 
5.3 METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................................ 10 
5.4 PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 11 
5.5 PRIOR AND CONCOMITANT THERAPY……………………………………………………………………..11 
5.6 PACKAGING ................................................................................................................................ 11 
5.7 BLINDING OF STUDY DRUG ........................................................................................................... 11 
5.8 RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................. 11 
5.8.1 Receipt of Drug Supplies................................................................................................. 11 
5.8.2 Storage ............................................................................................................................ 11 
5.8.3 Dispensing of Study Drug ............................................................................................... 11 
5.8.4 Return or Destruction of Study Drug ............................................................................. 12 
6 STUDY PROCEDURES ...................................................................................................... 12 


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6.1 SCREENING- VISIT 1..................................................................................................................... 12 
6.2 BASELINE- VISIT 2 ....................................................................................................................... 12 
6.3 FOLLOW-UP PHONE CALL. ............................................................................................................ 12 
7 STATISTICAL PLAN .......................................................................................................... 12 
7.1 SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 STATISTICAL METHODS ................................................................................................................ 13 
7.3 SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 13 
8 SAFETY AND ADVERSE EVENTS ....................................................................................... 14 
8.1 DEFINITIONS ............................................................................................................................... 14 
8.2 RECORDING OF ADVERSE EVENTS .................................................................................................. 14 
8.3 REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ........................................ 15 
8.3.1 Investigator reporting: notifying the IRB ...................................................................... 15 
8.3.2 Sponsor reporting: Notifying the FDA ........................................................................... 16 
8.4 UNBLINDING PROCEDURES ........................................................................................................... 17 
8.5 MEDICAL MONITORING………………………………………………………………………………….....17 
8.6.1 Data Monitoring Committee.......................................................................................... 17 
9 DATA HANDLING AND RECORD KEEPING ........................................................................ 17 
9.1 CONFIDENTIALITY ........................................................................................................................ 17 
9.2 CONFIDENTIALITY AND HIPAA ...................................................................................................... 18 
9.3 SOURCE DOCUMENTS .................................................................................................................. 18 
9.4 CASE REPORT FORMS .................................................................................................................. 18 
9.5 RECORDS RETENTION................................................................................................................... 18 
10 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................... 18 
10.1 STUDY MONITORING PLAN ......................................................................................................... 18 
10.2 AUDITING AND INSPECTING ........................................................................................................ 19 
11 ETHICAL CONSIDERATIONS ........................................................................................... 19 
12 STUDY FINANCES .......................................................................................................... 19 
12.1 FUNDING SOURCE ..................................................................................................................... 19 
12.2 CONFLICT OF INTEREST ............................................................................................................... 19 
12.3 SUBJECT STIPENDS OR PAYMENTS ................................................................................................ 19 
13 PUBLICATION PLAN ...................................................................................................... 20 
14 REFERENCES ................................................................................................................. 21 
15 ATTACHMENTS ............................................................................................................. 26 
 
 
 


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List of Abbreviations 
 
AD: Alzheimer’s disease 
ASL: arterial spin labeling 
BPRS: Brief Psychiatric Rating Scale 
CAARMS: Comprehensive Assessment of At-Risk Mental States 
CBF: cerebral blood flow 
CSF: cerebrospinal fluid 
CSSRS: Columbia Suicide Severity Rating Scale 
EP: early psychosis 
HVI: hippocampal volumetric integrity 
MCI: mild cognitive impairment 
MRI: magnetic resonance imaging 
MRS: magnetic resonance spectroscopy 
SAFTEE: Systematic Assessment for Treatment Emergent Side Effects 
SCID: Structured Clinical Interview for DSMIV TR 
SIPS: Structured Interview for Prodromal Syndromes 
TLE: temporal lobe epilepsy 
UHR: ultra-high risk 
VTA: ventral tegmental area 
 
 
 
 
 
 
 
 


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Study Summary 
Title 
A randomized, double-blind, placebo-controlled trial investigating the 
effects of levetiracetam in early psychosis 
Protocol Number 
S17-00266   
Study Duration 
Months 1-2: Complete all staff training and regulatory requirements for 
levetiracetam administration. 
 
Months 3-24: Enroll 46 EP subjects to meet randomization target of at 
least 8 eligible FEP completers in each treatment group (placebo, low- 
and high-dose levetiracetam). Randomize 1.5 medication-naïve EP 
subjects each month and perform a single-dose placebo-controlled 
levetiracetam trial with ASL and spectroscopy. Enroll 12 healthy 
controls to meet randomization target of 10 healthy controls and study 
with ASL and spectroscopy. 
 
Months 24-28: Complete analysis of R61 data to determine if target 
engagement and tolerability goals have been achieved.  If achieved, 
select levetiracetam dose and begin preparations for the R33 trial. 
Study Center(s) 
Single-center 
Objectives 
A placebo-controlled single-dose parallel group trial of levetiracetam 
185 mg and 500 mg in medication-naïve EP patients will be conducted 
to establish target engagement and identify an effective dose. 
Hippocampal activity by pulsed arterial spin labeling (ASL) pre-dose and 
2 hours post-dose will also be measured and compared to the 
hippocampal activity of 10 healthy controls.  If this pilot trial is 
successful, we will proceed to the R33 placebo-controlled 12 week add-
on trial of levetiracetam in 84 EP subjects using a dose selected on the 
basis of the results of this study.  We are not requesting approval of the 
R33 trial. 


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Number of Subjects 
We aim to enroll a total of 58 participants: 46 EP participants, 12 
healthy controls. In anticipation of screen failures or study drop outs 
enrollment of 58 will allow us to reach our target goal of at least 8 EP 
completers in each treatment group (placebo, low- and high-dose 
levetiracetam) and 10 healthy controls. 
 
Due to drop-outs and participants who are disqualified from data 
analysis due to diagnostic ineligibility or technical problems with the 
MRI arterial spin labelling scan, recruitment will continue until all three 
EP treatment groups have 8 eligible completers. 
 


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Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
1. Males and females 16 to 35 years of age, inclusive, at time of 
informed consent 
2. Must have experienced a first episode of non-affective psychosis 
within 5 years and exhibit current psychosis, as defined by a score of ≥ 
2 on one of the following psychosis items on the BPRS: conceptual 
disorganization, suspiciousness, hallucinations, unusual thought 
content, or grandiosity, for at least 4 days per week for at least 4 weeks 
3. Must have a diagnosis of either schizophrenia, schizoaffective 
disorder or schizophreniform disorder as established by a Structured 
Clinical Interview for DSMIV TR (SCID) 
4. Must not have taken an oral antipsychotic medication within the 
past 4 weeks prior to study enrollment or received a long acting 
injectable antipsychotic within 3 times the dosing interval. 
5. If female and of childbearing potential, patients must: 
a. Have a negative urine pregnancy test (all females regardless of 
childbearing potential will be required to submit a pregnancy 
test) 
b. Not be nursing or planning a pregnancy for the duration of the 
study through 30 days after the last dosing visit 
c. Be abstinent or willing to use a reliable method of birth control 
from the screening visit and continue with the same method until 
termination from the study. 
 
Exclusion Criteria 
1. Current substance abuse or dependence for substances other than 
nicotine and THC (i.e. alcohol, amphetamines, barbiturates). 
a. A positive urine toxic screen (excluding THC, tricyclic 
antidepressants, or benzodiazepines (if prescribed)).  
b. Moderate or severe cannabis use disorder.  
c. use of marijuana within the 72 hours prior to MRI scanning by self 
report. 
2. Diagnosis of major mood disorder or other Axis I disorder other than 
Schizophrenia, Schizoaffective Disorder or Schizophreniform Disorder. 
3. Current suicidal ideation. Suicidal ideation with intent or plan 
(indicated by affirmative answers to items 4 or 5 of the suicidal 
ideation section of the baseline C-SSRS) in the 6 months prior to 
screening or subjects who represent a significant risk of suicide in the 
opinion of the Principal Investigator and/or PhD or MD level clinician 
completing screening visit. 
4. Pregnant, nursing or positive urine pregnancy test. 


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5. Significant medical or neurological illness by history or physical exam 
including seizure disorder, history of loss of consciousness related to 
head trauma or developmental disorder including mental retardation. 
6. Metal implants, pacemaker, or other metal in the body or medicinal 
patch.7. History of claustrophobia. 
8. Currently taking any antipsychotic medication (within 4 weeks).  
Study Product, Dose, 
Route, Regimen 
Non-affective early psychosis patients will be randomized to a single 
oral dose of levetiracetam 185 mg, 500 mg or placebo.  Subjects will 
have MRI brain imaging at baseline and 2 hours after administration of 
study drug. 10 healthy subjects will have brain imaging without being 
administered any medication. 
 


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1 
Introduction 
Title: A randomized, double-blind, placebo-controlled trial investigating the effects of levetiracetam 
in early psychosis 
1.1 
Background 
Pharmacologic treatment of schizophrenia has made little progress since clozapine was introduced 
25 years ago. Antipsychotics are only partially effective for psychosis in many patients and are 
generally ineffective for negative symptoms and cognitive deficits. It is increasingly clear that 
dopamine D2 receptor blockade does not target core deficits in most individuals with 
schizophrenia. In addition, our recent work suggests that antipsychotics may cause additional injury 
by increasing hippocampal dopamine release, which results in neurotoxic metabolites.  As will be 
outlined in this proposal, we are proposing to test a new approach based on converging animal and 
clinical evidence that targets a key dysregulation of hippocampal glutamate transmission in early 
psychosis. This approach is based on a specific mechanistic model for psychosis onset and 
progression of illness, involves a well-tolerated drug that targets a molecule that is genetically 
linked to schizophrenia, has highly specific and reliable imaging biomarkers for target engagement 
and clinical outcome and, if successful, could fundamentally alter the early course of illness. 
 
A model for illness onset and progression: It is well-established that individuals with schizophrenia 
display hippocampal hyperactivity at rest and fail to recruit hippocampal networks during cognitive 
activation (1-3). This increased hippocampal activity at rest has been associated with cognitive 
deficits, negative symptoms and psychosis (4, 5) and is believed to result from a deficit in 
GABAergic input from inhibitory interneurons (6, 7). The hippocampus is particularly vulnerable to 
hypoxia, stress and inflammation due to the low ratio of inhibitory interneurons to neurons (8); 
intrauterine exposure to inflammation, which is a risk factor for schizophrenia, has been 
demonstrated in mice to reduce hippocampal inhibitory interneuron density and disrupt CA1 
oscillatory activity (9). Furthermore, lesions of the ventral hippocampus in mice produce a 
neurodevelopmental model for schizophrenia that includes prefrontal cortical deficits and 
impairment of prepulse inhibition (10). Hippocampal hyperactivity, demonstrated by magnetic 
resonance imaging (MRI) with gadolinium measurement of blood volume in the CA1 subfield (11), 
or by arterial spin labeling (ASL) (12), is an early biomarker that correlates with psychosis, predicts 
progression from “ultra-high risk” (UHR) status to schizophrenia, predicts hippocampal volume loss, 
and differentiates individuals with schizophrenia from healthy controls (11).  Spontaneous 
improvement of psychotic symptoms in unmedicated UHR subjects was associated with a decrease 
in hippocampal perfusion measured by ASL (12). In addition, hippocampal glutamate 
concentrations measured by magnetic resonance spectroscopy (MRS) are elevated in EP and 
increased glutamate concentrations predict subsequent hippocampal volume loss (5) believed to 
result from excitotoxicity produced by excessive glutamatergic transmission.  A decrease in 
hippocampal volume in schizophrenia subjects is a strong predictor of poor outcome over a 5-7 
year follow-up (13, 14). Excessive activity of the CA1 subfield also results in increased excitatory 
input to  the ventral tegmental area (VTA) dopamine neurons which may drive psychosis via 
aberrant dopamine release in striatum and hippocampus (15).   
 


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While this model is now well-established by animal experiments and clinical imaging studies, no 
experimental therapeutic intervention has tested it. However, excessive glutamatergic transmission 
producing excitotoxic injury to the hippocampus is well established as a factor contributing to 
cognitive deficits and illness progression in mild cognitive impairment (MCI), Alzheimer’s disease 
(AD) and in temporal lobe epilepsy (TLE).  In MCI, elevated hippocampal activity and glutamate 
transmission are associated with hippocampal volume loss and progression to Alzheimer’s disease 
(16, 17).  In healthy elderly subjects, age-related increased hippocampal activity predicts cognitive 
decline at 3-8 year follow-up (18). 
 
In summary, hippocampal hyperactivity drives early psychosis and produces excitotoxic injury 
resulting in hippocampal volume loss which is associated with negative symptoms, cognitive 
deficits and poor outcome. 
Antipsychotic effects on hippocampus: D2 receptors are found in only two locations in the 
hippocampus: post-synaptic D2 receptors are located on mossy cells in the hilum (efferents from 
dentate gyrus to CA3) and presynaptic D2 autoreceptors are located on dopamine fibers in the CA1 
subfield (19). Antipsychotics decrease hippocampal activity (20), most likely via blockade of D2 
receptors on mossy cells. The reduction in hippocampal activity following a single dose of 
risperidone strongly predicted antipsychotic response at six weeks (21). In subjects treated with 
either haloperidol or olanzapine, a reduction of hippocampal activation after one week predicted 
antipsychotic response at 6 weeks (22).  A failure of D2 blockade to reduce hippocampal activity is 
associated with poor antipsychotic response (22).  Activity of the CA2 and CA3 subfields is not 
elevated in medicated patients with early psychosis, whereas CA1 activity remains elevated, but 
not to the degree reported in unmedicated EP patients (23); these findings are consistent with a 
primary antipsychotic effect “upstream” on mossy fibers. Blockade of D2 presynaptic autoreceptors 
in the CA1 subfield markedly increases the number of dopamine fibers and dopamine 
concentration in CA1 over a period of several weeks and is associated with memory impairment 
(19). Excessive dopamine release increases production of free radical dopamine metabolites (24) 
and of homocysteine, a neurotoxic by-product of dopamine metabolism by COMT in the 
hippocampus (25, 26).  A proteomic study of hippocampus in mice found that 28 days of 
haloperidol administration increased proteins associated with mitochondrial injury, consistent with 
oxidative stress (27). 
 
 In summary, antipsychotics may improve psychotic symptoms by reducing hippocampal 
hyperactivity via blockade of D2 receptors on mossy cells, but also produce neurotoxic metabolites 
via blockade of D2 autoreceptors in CA1. 
1.2 
Investigational Agent 
Levetiracetam is an atypical anticonvulsant that is frequently used in children and adults due to its 
superior tolerability, ease of use and excellent safety profile (28).  It is rapidly absorbed and rapidly 
crosses the blood-brain barrier.  Maximal blood levels, brain concentrations and antiepileptic 
efficacy occur approximately 1 hour after oral administration in rodents and in humans (29, 30).  
Levetiracetam exhibits linear pharmacokinetics, is not plasma bound, has approximately 100% 
absorption, and is not metabolized in the liver; it has no reported drug-drug interactions (29). The 
half-life of levetiracetam is 7 hours; clearance may be slowed in individuals with severe renal 


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impairment (29). The mechanism of action of levetiracetam is unlike any other anticonvulsant; it 
binds to synaptic vesicle glycoprotein 2A (SVP2A) (31) which modulates release of neurotransmitter 
vesicles under conditions of sustained high activation (32). SVP2A has been genetically linked to 
schizophrenia (33).  In the hippocampus, levitiracetam reduces neuronal glutamate and dopamine 
release and enhances GABA release from inhibitory interneurons (32, 34). Levetiracetam 
normalized hippocampal hyperactivity and improved hippocampus-dependent memory in aged 
rats at doses of 5 mg/kg and 10 mg/kg given 40 minutes before testing (35).  Higher doses typical of 
anticonvulsant activity were not effective (35). In patients with MCI, levetiracetam 62.5 mg bid and 
125 mg bid improved performance and normalized hippocampal BOLD hyperactivation during a 
pattern separation task (16). In addition, levetiracetam normalized left and right hippocampal 
activation patterns during verbal and visual memory tasks in patients with temporal lobe epilepsy 
(TLE) (36).  In a randomized, placebo-controlled cross-over trial in 20 healthy subjects (mean age 29 
years, range 20-49 years), levetiracetam 500 mg administered twice at an interval of 12 hours 
(consistent with anticonvulsant treatment) produced side effects in 50% of subjects compared to 
44% with placebo and 83% with lorazepam 2 mg. Unlike lorazepam, levetiracetam 500 mg did not 
adversely affect cognition but, compared to placebo, was associated with somnolence (40%), 
balance disorder (20%), dizziness (15%) but no psychiatric adverse effects.  Levetiracetam is 
approved at doses up to 3,000 mg/d administered twice-daily for epilepsy and oral loading doses of 
3,000 mg are well-tolerated (29).   
 
Whereas levetiracetam is now generic, the manufacturer, UCB, has recently received FDA approval 
for a levetiracetam analogue, brivarecitam, which is more potent and more rapidly crosses the 
blood brain barrier (20 minutes vs 1 hour).  The rapidity of CNS penetrance is an advantage for 
status epilepticus; however, because brivaracetam is less selective for SVP2A than levetiracetam 
(37) and because data on dosing for neuroprotection of hippocampus is only available for 
levetiracetam, we will study levetiracetam rather than brivaracetam, although it is a potential 
option for future studies. 
1.3 
Clinical Data to Date 
There are compelling reasons to study levetiracetam in early schizophrenia, since it is expected to 
decrease the neurotoxic excessive release of glutamate associated with psychosis and the 
neurotoxic excessive dopamine release associated with early antipsychotic treatment. However, 
the only studies of levetiracetam in schizophrenia were in later-stage patients for the treatment of 
tardive dyskinesia-- levetiracetam significantly reduced tardive dyskinesia compared to placebo, 
producing response rates of 44% vs 19%. A total of 58 patients with psychotic disorders received 
levetiracetam in placebo-controlled (38) and open-label trials (39) in subjects with tardive 
dyskinesia and no adverse effects were observed.  One reason for the relative lack of experience 
with levetiracetam in schizophrenia is the warning against using it in patients with psychiatric 
illness due to reports of aggression and hostility. However, adverse behavioral effects have been 
largely limited to patients with epilepsy (40) and affective disorders (41) but have not been 
observed in patients with cognitive or anxiety disorders (40). 
 
Antipsychotic-associated excitotoxicity and oxidative stress: Twenty years ago we found that 
treatment with first generation antipsychotics elevated cerebrospinal fluid (CSF) concentrations of 


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alanine, consistent with free radical injury to mitochondrial function (42). Using tardive dyskinesia 
as a model of antipsychotic toxicity, we also found elevated CSF levels of aspartate and products of 
oxidative stress (43).  Aspartate crosses the blood brain barrier more readily than glutamate and 
preferentially binds to extra-synaptic NMDA receptors which mediate excitotoxicity (44). Hence, 
our results were consistent with antipsychotic toxicity mediated via excitotoxicity and oxidative 
stress resulting in injury to mitochondria. 
 
Hippocampal volume loss in early psychosis: With our collaborators in Shanghai (Dr. Jijun Wang, 
M.D.), we recently completed a biomarker study of 64 medication-naïve EP patients and 58 healthy 
matched controls; 24 patients were subsequently treated with second generation antipsychotics 
and both the treated patients and 32 matched controls were re-examined after 8 weeks by MRI 
measurement of hippocampal volumetric integrity (defined below).  At baseline there was a 
significant elevation of serum aspartate levels (Cohen’s d=0.43, p=0.02) and significantly decreased 
hippocampal volumetric integrity bilaterally (Right: Cohen’s d= 0.57, p=.001; Left: Cohen’s d= 0.91, 
p=.0001) with the left side significantly more affected than the right (p=.005) in medication-naïve 
patients compared to age and gender-matched controls.  From baseline to week 8, hippocampal 
volumetric integrity was significantly reduced in patients bilaterally compared to controls (Right: 
Cohen’s d=1.3, p=.05; Left: Cohen’s d= 1.1, p <.01); left hippocampal volume loss occurred at a 
mean annualized rate of 6.5% and significantly correlated with duration of untreated psychosis 
(DUP) (r= -.61,p=.002), with baseline concentration of S100B (a marker of glial injury) (r= -.50, 
p=.01), and with a treatment-related increase in thioredoxin (a marker of oxidative stress) (r=-.54, 
p=.01).  Right hippocampal volume decreased at a rate of 4.8% per year and did not significantly 
correlate with serum biomarkers (p>0.1).   Left hippocampal volume at baseline correlated with 
symptom severity at baseline (BPRS total, r=-.34, p=.01) and the change in left hippocampal volume 
correlated inversely with response of negative symptoms at week 8 ( r=.-.41, p=.05).  In addition, 
concentrations of homocysteine increased with treatment (Cohen’s d=0.52, p=.01). The increase in 
homocysteine concentration was predicted by COMT genotype (p<.05) and correlated with an 
increase in S100B (r= .54, p=.01), consistent with the hypothesis that COMT metabolism of 
dopamine produces homocysteine, which is toxic to glia. Overall, these results are consistent with a 
model of glutamatergic excitotoxicity associated with early psychosis, early hippocampal injury and 
with an interaction between DUP, illness-related glial injury, and antipsychotic-related oxidative 
injury producing hippocampal volume loss during the early phase of treatment. The treatment-
related oxidative injury may result from dopamine metabolism which produces free radical 
metabolites and homocysteine. This process appears to be clinically significant since hippocampal 
volume correlated with psychotic symptoms at baseline and hippocampal volume loss during the 
first 8 weeks of treatment was associated with negative symptom severity at week 8, consistent 
with previous reports that hippocampal volume loss was associated with severity of psychosis and 
cognitive impairment across psychotic diagnostic groups (45). The rapid rate of volume loss that we 
observed could not be sustained long-term, given the absence of evidence for volume loss greater 
than 10% in post-mortem studies. The rapid volume loss resulting from excessive dopamine release 
may be time-limited, since antipsychotics produce “depolarization blockade” of VTA dopamine 
neurons after 2-3 months (46), and so hippocampal exposure to high levels of treatment-related 
oxidative stress may be time-limited, potentially making it critically important to treat 
prophylactically with levetiracetam early in the course of antipsychotic treatment.  


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Hippocampal volumetric integrity measurement: Our collaborator, Dr. Babak Ardekani, has 
developed an automated measure of hippocampal volumetric integrity expressed as the fraction of 
the volume of a region that is expected to encompass the hippocampus in a normal brain that is 
occupied by tissue (rather than CSF) (47). The fully automated, fast, reliable and robust process is 
based on 3D T1-weighted structural MRI and involves identification of the mid-sagittal plane (48) 
and the anterior and posterior commissures (49) on the MRI scan, from which a rigid-body 
transformation is performed to a standard orientation.  Once in standard space, based on a priori 
training, 230 landmarks in the vicinity of the hippocampi are detected by template matching from 
which two (one for each hemisphere) 12-parameters affine transformations are computed.  The 
composite (rigid-body + affine) transformations are applied to probabilistic left and right 
hippocampi labels determined based on manual tracings of hippocampi on scans from 65 normal 
subjects. Thus, a volume is determined (separately for each hemisphere) that is expected to 
encompass the hippocampus in a normal brain. Finally, an automated histogram analysis method 
using the expectation maximization (EM) algorithm is used to determine the partial fraction of this 
region that is occupied by brain tissue (rather than CSF). The ratio is termed the hippocampal 
volumetric integrity (HVI). This procedure has been well-validated and has demonstrated excellent 
test-retest reliability of ICC=0.998 using two independent structural MRI scans acquired on the 
same day on multiple subjects (figure 1) (50) and demonstrated superior discrimination of 
Alzheimer’s disease subjects from healthy controls (figure 2) with significantly greater accuracy 
than achieved by using the FreeSurfer measure of hippocampal volume. This approach requires no 
pre-processing of the MRI scan, is very simple to apply, and volumetric analysis requires less than 
one minute per scan—making this a biomarker with wide potential clinical applicability. Due to the 
affine transformation step, the HVI is a scale-invariant measure which, unlike the absolute 
hippocampal volume, does not require correction for intra-cranial volume and can be used across 
3T imaging platforms. 
 
  


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Figure 1. Hippocampal volumetric integrity measurement. ICC = 0.998 
 
 
 
Figure 2. Hippocampal volumetric integrity, Alzheimers subjects and healthy controls. 
 
Measurement of hippocampal perfusion using ASL: Our collaborator, Dr. Henry Rusinek, has 
developed an approach for measurement of hippocampal perfusion using a pulsed arterial spin 
labeling sequence with excellent spatial resolution, sensitivity and test-retest reliability (ICC = 0.90; 
figure 3) (51). This approach is based on multi-shot true fast imaging in steady precession and is 
calibrated by subtraction of cerebral blood flow (CBF) in cortical white matter, which is 
approximately 3 times lower than CBF in gray matter.  A co-registered 3D MPRAGE is used to 
eliminate all voxels with less than 75% gray matter and all large blood vessels.  This method will 
allow us to measure a change in hippocampal blood flow with sufficient sensitivity and reliability to 
detect changes with levetiracetam. A similar approach has been used successfully to measure 
region-specific changes in CBF after single-dose antipsychotic administration (52). 
 


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Figure 3. Measurement of hippocampal perfusion. ICC = 0.90 
In summary, levetiracetam at low, well-tolerated doses normalizes hippocampal hyperactivity by 
decreasing excessive glutamatergic and dopaminergic transmission, thereby making it an ideal 
agent to enhance treatment of early psychosis and to prevent antipsychotic toxicity. 
 
Measurement of glutamatergic transmission using proton MR spectroscopy:  
 
1H MRS is the study of compounds other than water whose 1H signal is high enough to be reliably 
detected. A brain 1H MRS spectrum is usually dominated by three major singlets: the N-acetyl 
groups of N-acetyl-aspartate (NAA) at 2.01 ppm; creatine and phosphocreatine (Cr) at 3.03 ppm; 
and the tetra methylamines of choline-containing compounds (Cho) at 3.19 ppm. At short echo 
time (TE), also observable are the pseudo-singlets of myo-inositol (mI) at 3.56 ppm, glutamate (Glu) 
at 2.35 ppm and glutamine (Gln) at 2.43 ppm (74, 75) 
(figure 4). These metabolites are widely used as surrogate 
markers for neuronal dysfunction (NAA); cellular 
energy/density (Cr); membrane turnover (Cho); glial 
activation (mI); and Glu+Gln, or Glx, for changes in the 
glutamate cycle between neurons and astrocytes (74). For 
this project, special emphasis is placed on Glx, since 
levetiracetam is thought to exert its effects through 
decrease of glutamate release. Because of the proximity of 
their major resonances around 2.4 ppm (figure 4), Glu and 
Gln are usually not reliably distinguished at clinical 
magnetic field strengths (≤ 3 T) (76). Their sum, however, referred to as Glx (76), can be quantified 
with high accuracy, especially when TE=108 ms, as employed in this study (figure 5). Importantly, 
abnormally high Glx has been previously found in the hippocampus of schizophrenia patients (77), 
likely reflecting excessive glutamatergic transmission. 
 
 
Figure 4. 1H MRS. Short TE, brain in vivo spectrum 
showing the major resonances in healthy tissue and 
their general specificities. 


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Single voxel 1H MRS. Prior to the 1H MRS, scanner manufacturer’s “advanced shimming” procedure 
will be employed to adjust the first- and second-order currents, reducing the full-width-at-half 
maximum water linewidth to ~20 Hz. Next, a 1H MRS single voxel with the following parameters will 
be placed on the left hippocampus: 3×1.5 ×1.5 cm3, TR=1800 ms, TE=105 ms, 192 averages, (figure 
5). The duration of the 1H MRS sequence will be around 7 minutes. Finally, a reference scan (< 1 
min) with the water suppression turned off, will be obtained for quantification purposes. Absolute 
quantification of metabolite levels will be done off-line using in-house software, as previously 
described (78).  
 
 
 
Measurement of corneal temperature and hand temperature. (Optional Procedure) 
Evidence suggests that unmedicated patients with schizophrenia may have elevated body (core) 
temperature [79], accompanied by decreased peripheral (hand) temperature [80]. In addition, 
medications used to treat schizophrenia may reduce temperature [81-82]. Given neuronal activity 
is known to be strongly influenced by temperature [83], changes in brain temperature that 
accompany disease states or medication effects may interact with brain activity relevant to this 
study and inform outcomes. Measurement of corneal and hand temperature by infrared, using a 
portable infrared camera, is non-invasive, with no known risks to patient safety. Measurement of 
core temperature with a temporal artery forehead scan takes seconds and is routinely used in 
outpatient clinical settings. 
 
 
1.4 
Study/Dose Rationale 
 
We are proposing a 2-year R61 
project in which we will examine 
the effects of a placebo-
controlled trial of single dose 
administration of levetiracetam 
185 mg and 500 mg on 
hippocampal CBF measured by 
ASL in up to 48 EP participants in 
order to collect data in at least 8 
eligible completers per 
treatment group ((placebo, low-
dose levetiracetam and high-dose levetiracetam) 
 to establish target engagement, assess tolerability, and guide dose selection. Due to drop-outs and 
participants who are disqualified from data analysis due to diagnostic ineligibility or technical 
problems with the MRI arterial spin labelling scan, recruitment will continue until all three EP 
treatment groups have 8 eligible completers. 
 
Figure 5. Single voxel 1H MRS of the hippocampus.  
MP-RAGE superimposed with the 3×1.5×1.5 cm3 PRESS VOI placed on the left 
hippocampus and the corresponding spectrum obtained at TE=105 ms. Note: (1) the choice of 
TE, at which the Glx multiplet (e.g. Fig. 4) appears as a pseudo-singlet, enabling easier 
quantification; (2) the excellent SNR consequent to the large size voxel, which enables the 
quantification of mI even at this intermediate TE; (3) the additional resonance of Cr, at 3.9 
ppm, which would be included in the modelling algorithm used for quantification.  
 


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We will verify the elevation of hippocampal CBF at baseline in our sample by also studying 10 
healthy controls group-matched on age and gender. Healthy controls will not be randomized to 
receive study drug or placebo, but will only have brain imaging. 
 
The evidence for hippocampal dysfunction in schizophrenia is quite strong and the model of CA1 
hyperactivity in early psychosis is supported by imaging studies using multiple modalities (PET, 
fMRI, MRI with gadolinium contrast, ASL).  Evidence for early hippocampal volume loss is also 
consistent across studies; our finding of hippocampal volume loss during the first 8 weeks of 
antipsychotic treatment was a large effect size and was highly statistically significant. 
Levetiracetam is clearly the best agent to test this model since it is well-established that 
levetiracetam targets SVP2A, reduces excessive glutamatergic and dopaminergic 
neurotransmission, and is neuroprotective.  Furthermore, studies similar to our proposed approach 
have been successful in MCI and in temporal lobe epilepsy. 
 
The neurodevelopmental model for early schizophrenia upon which this proposal is based, the 
pharmacologic agent and its target, and the imaging biomarkers are all well-validated. However, 
this proposed study is highly innovative in several ways. It is the first intervention study to directly 
test the model of hippocampal hyperactivity and neurodegeneration in early psychosis.  It also is 
the first to study levetiracetam and the SVP2A target in early psychosis. This study is also the first 
to employ ASL and an MRI measure of hippocampal volumetric integrity as biomarkers for target 
engagement and clinical outcome.  Our collaborators developed and validated new methods for 
both of these imaging biomarkers that are far more sensitive and reliable than prior approaches. 
The automated measurement of hippocampal volumetric integrity is user-friendly, fast and 
potentially could become widely employed for monitoring of illness progression.  
 
In the study of hippocampal CBF measured by ASL in UHR and EP subjects by Allen and colleagues 
(12), the elevation in left hippocampal CBF compared to healthy controls was a very large effect (Z 
statistic = 4.35). In addition, repeated measurements of hippocampal CBF in subjects who remained 
psychotic were highly reliable (12).  Bakker and colleagues (58) found that levetiracetam decreased 
elevated hippocampal activation in patients with MCI to levels below those observed in healthy 
controls (from 0.8 to -0.2 in MCI patients vs. 0.0 in healthy controls). The magnitude of reduction of 
hippocampal hyperactivation with levetiracetam was highly consistent between trials involving two 
patient samples (58).  Furthermore, the method of ASL that we will use to measure hippocampal 
CBF has very high reliability (ICC=0.90) (51). Therefore, based on previous studies, the elevation of 
hippocampal activation in our sample should be large, the reduction by levetiracetam should also 
be large, and our method for measurement is highly reliable, so we are confident that our 
proposed approach for verifying target engagement is quite valid and feasible. In addition, two 
hours post-dose should be sufficient to measure levetiracetam effects with ASL since maximal 
blood levels are achieved within one hour and, within one hour of oral levetiracetam 
administration, abolishment of seizures has been demonstrated in humans with photosensitive 
epilepsy {Kasteleijn-Nolst Trenite, 1996 #6357} and within one hour a reduction of corticospinal 
excitability measured by transcranial magnetic stimulation (TMS) has been demonstrated in 
healthy human subjects {Kasteleijn-Nolst Trenite, 1996 #6357}.  Because a single dose can treat 
epilepsy within the two hour time frame of our R61 study and because perfusion as measured by 


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ASL should reflect hippocampal activation acutely, we believe that a single dose will provide us 
valid information about the range of levetiracetam concentrations that will correct hyper-perfusion 
associated with first episode psychosis.  If we fail to observe a reduction in hippocampal perfusion 
with either of the two doses, we would recommend repeating the R61 study with a two-week 
repeated dosing trial in FEP subjects who have been stabilized on medication but remain 
symptomatic.  We would make this decision in consultation with NIMH staff.  
 
We will use a method developed and validated by our collaborator, Henry Rusinek (51) and 
recently adopted by our imaging team (Rusinek & Convit) in the study of insulin resistance on brain 
CBF (60).  This is a 3T ASL method with balanced steady-state free precession (bSSFP) readout. 
bSSFP is chosen instead of the more conventional echo planar sequence to reduce susceptibility 
artifacts and to allow for higher spatial resolution without image distortion. The 64 channel 
Siemens Prisma head coil yields excellent S/N and tagging efficiency. The slice-selective FAIR 
inversion pulse is applied in a slab encompassing the imaging slice, but 2.5 times thicker. The 1.2 s 
inversion time allows for blood outside the slab to flow into the imaging slice and to estimate tissue 
perfusion. Data are acquired in a single shot using parallel imaging, with an acceleration factor of 2 
to reduce the echo train duration. Other parameters are: TE=1.4 ms, flip angle = 360O, receiver 
bandwidth = 977 Hz/pixel, slice thickness = 6 mm, 320 x 210 matrix, voxel size 0.9 x 0.9 mm (fine 
enough to resolve small blood vessels). 48 repetitions are performed, alternating between 
nonselective and slice-selective inversions. The repetition time (TR) between successive inversion 
pulses is 3 s. Since this is not long enough to ensure complete recovery of magnetization, the first 4 
repetitions are excluded.  
 
We will use the signal difference in healthy white matter (WM) as reference. This approach, 
justified by animal evidence, exploits the fact that cerebral blood flow (CBF) is ~3x lower in WM 
compared to gray matter (GM). Deviations from this assumption introduce a relatively minor bias 
on cerebral GM flow (51). Our measurements of the resting cortical CBF agree with CBF measured 
using O15 PET. However, the precision of our technique is double that of competing methods (51), 
likely due to the use of WM as reference. The tissue perfusion computation uses a general kinetic 
model (61). WM and GM segmentation is done directly from bSSFP images. To avoid blood vessel 
contamination, we use only cortical voxels with CBF values < 150 mL/(100 g min). Although this will 
exclude only the largest blood vessels, smaller vessels likely do not to contribute to the “through 
flow” artifact (51). 
 
In a two-week trial, levetiracetam doses of 62.5 mg bid and 125 mg bid reduced hippocampal 
activation and improved cognition in a sample of MCI patients with a mean age of 70 years 
whereas a dose of 250 mg bid was not effective {Bakker, 2015 #6213}.  Due to an estimated 30% 
reduction in renal clearance in the elderly {Contin,  #6359}, these effective doses would be 
equivalent to 84 mg bid and 167 mg bid in young EP patients.  We selected an intermediate value 
of 125 mg bid (half-way between 84 mg and 167 mg); a single dose of 185 mg is calculated to 
produce blood levels equivalent to blood levels achieved at steady state following repeated dosing 
of 125 mg bid.  Therefore, we will administer a single levetiracetam dose of 185 mg to achieve 
blood levels within the range of steady state blood levels that were effective in elderly patients 
with MCI. The 500 mg levetiracetam dose is a standard antiepileptic dose for partial (temporal 


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lobe) epilepsy. We expect that both doses of levetiracetam will be well-tolerated; in the treatment 
of epilepsy, levetiracetam doses up to 3 g are routinely administered without serious side effects. 
 
It is possible that a low dose of levetiracetam “optimizes” synaptic transmission and is preferable to 
a higher antiepileptic dose in MCI, but we cannot be certain that this will also hold true for first 
episode psychosis. We thus selected two doses: a dose that achieves blood levels within the range 
that was effective for MCI (correcting for age and calculating a single dose that will produce blood 
levels equivalent to steady state concentrations achieved by repeated dosing) and a typical 
anticonvulsant dose for which we can be confident of full target engagement.  Since it is a trade-off 
between the number of doses examined and the sample size in each dose group, we believe it is 
better to perform a definitive test of these two doses than to risk having an under-powered test of 
multiple doses.   
 
1.5 Research Risks & Benefits 
1.5.1   Risk of Study Drug 
The most common side effects reported with levetiracetam are drowsiness, weakness, dizziness 
and infection.  Mood and behavioral problems have also been reported, including aggression, 
anxiety, anger, depression, apathy and hostility—these responses appear to be most common in 
patients with epilepsy and pre-existing mood disorders.  Rare cases of suicidality and of serious 
dermatologic reactions have also been reported. 
 
Drug Interactions  
There are no known interactions between tetrahydrocannabinol (THC), cannabidiol (CBD) or other 
phytocannabinoids and levetiracetam. Levetiractam is not metabolized by the hepatic cytochrome 
P450 system, so pharmacokinetic interactions are unlikely. THC may transiently worsen psychosis 
in some patients and CBD may improve psychosis; whether THC-associated worsening of psychosis 
responds to antipsychotics is unclear—the data are inconsistent. Similarly, it is not known whether 
THC-associated worsening of psychosis will improve with levetiracetam.  1.5.2   Other Risks of 
Study Participation 
 
Phlebotomy 
Phlebotomy may cause soreness, bruising, bleeding and rarely, infection. 
 
Privacy 
Loss of confidentiality regarding psychiatric or medical information is a possible risk for which 
precautions will be taken. Participants will be assigned a study identification code that will be used 
for all study documents. All identifiers will be redacted from records from this study. Study 
documents collected in this study will be kept in a locked cabinet. Only research staff who are 
directly involved in this study will have access to that file. 
 
Several measures have been taken to protect subjects against risks incurred by participation in this 
protocol. We will screen out potential subjects with medical vulnerabilities, including epilepsy or 


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unstable medical illness and will exclude individuals with a history of suicidality or violence.  During 
the Baseline scan, we will monitor adverse effects for 3 hours after administration of levetiracetam; 
subjects will be psychiatrically cleared by a psychiatrist prior to release from the imaging center. 
Subjects will be contacted the following day to assess safety. 
1.5.3   Potential benefits 
All subjects will receive a comprehensive psychiatric and medical evaluation and optimal clinical 
treatment as part of participation. 
 
Incidental Findings: 
Study participants will be informed at the time of screening if urine tests are positive for pregnancy 
or drugs of abuse since either is exclusionary.  No other laboratory tests will be performed. MRI 
scans will be reviewed by a neuroradiologist at the Center for Brain Imaging (CBI) and the results 
reviewed by Dr. Goff. If clinical readings of MRI scans show unanticipated abnormalities that 
require medical follow-up Dr. Goff will contact participants via telephone and study staff will send a 
follow up letter signed by the study PI via mail to advise participants that scans findings require 
medical follow up. The MRI and/or laboratory reports and a copy of the letter, if applicable, will be 
maintained with source documents. Otherwise, no research information will be shared with 
subjects. 
 
2 
Study Objectives 
The objectives of this study are to evaluate the tolerability and efficacy of two different doses of 
levetiracetam (185 or 500 mg) in medication-naïve EP patients.  
3 
Study Design 
3.1 
General Design 
This is a Phase 2, single-center, randomized, double-blind, placebo-controlled study to assess the 
tolerability and efficacy of levetiracetam. The study consists of an up to 4-week Screening period, 
one Baseline visit, and a follow-up telephone call the day after, as shown below. The Screening visit 
and Baseline visit may occur on the same day.  
 
Sequence 
Screening 
Baseline 
Telephone Follow-
Up 
Duration 
Day -28 to Day 0 
Day 1 
Day 2 
 
3.2 
Primary Study Endpoints 
The primary efficacy outcome measure for the R61 clinical trial is the change from baseline in 
hippocampal CBF measured by ASL; the Go/NoGo signal will be based on the effect size magnitude 
rather than formal hypothesis testing. 
 


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3.3 
Inclusion of Subjects using Marijuana 
THC use is very common among early psychosis patients (similar to cigarette smoking) most studies 
of early psychosis patients in the US and in Australia have found greater than 50% of patients use 
cannabis.  Hence, for a treatment intervention to be generalizable to typical clinical populations, 
the intervention must be safe and effective in individuals who use THC. There is no reason to 
expect a negative interaction between cannabis and levetiracetam (no pharmacokinetic or 
pharmacodynamics interaction). Because treatment is randomized, the two treatment groups 
should be balanced in terms of cannabis use.  We will record past use of cannabis and urine toxic 
screen results for cannabis at screening in addition to self-report of cannabis during the trial and 
will include this as a factor in our analysis to assess whether cannabis use influences response to 
levetiracetam.    
4 
Subject Selection and Withdrawal 
4.1 
Inclusion Criteria for EP Patients 
1. Males and females 16 to 35 years of age, inclusive, at time of informed consent 
2. Must have experienced a first episode of nonaffective psychosis within 5 years and exhibit 
current psychosis, as defined by a score of > 2 on one of the following psychosis items on the 
BPRS: conceptual disorganization, suspiciousness, hallucinations, unusual thought content, 
or grandiosity, for at least 4 days per week for at least 4 weeks. 
3. Must have a diagnosis of either schizophrenia, schizoaffective disorder or schizophreniform 
disorder as established by a Structured Clinical Interview for DSM-IV TR (SCID for DSM-IV-TR) 
4. Must not have taken an oral antipsychotic medication within 4 weeks prior to study 
enrollment or received a long-acting injectable antipsychotic within 3x the dosing interval.   
5. If female of childbearing potential, patients must 
a) have a negative urine pregnancy test (all females regardless of childbearing potential 
will be required to submit a pregnancy test), and 
b) not be nursing or planning a pregnancy for the duration of the study through 30 days 
after the last dosing visit, and  
c) be abstinent or willing to use a reliable method of birth control from the Screening 
Visit, and continue with the same method until termination from the study. 
4.2 
Exclusion Criteria for EP Patients 
1. Current substance abuse / dependence for substances other than nicotine and THC, (i.e. 
alcohol, amphetamines, barbiturates, etc.)  
a. A positive urine toxic screen (excluding THC, tricyclic antidepressants, or benzodiazepines 
(if prescribed)). 
b. Moderate or severe cannabis use disorder.  
c. use of marijuana within the 72 hours prior to MRI scanning by self report. 
2. Diagnosis of major mood disorder or other Axis I disorder other than schizophrenia, 
schizoaffective disorder or schizophreniform disorder. 


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3. Current or recent suicidal ideation-- suicidal ideation with intent or plan (indicated by 
affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in 
the 6 months prior to screening or subjects who represent a significant risk of suicide in the 
opinion of the investigator.  
4. Pregnant or nursing or positive urine pregnancy test. 
5. Significant medical or neurological illness by history or physical exam, including seizure 
disorder, history of loss of consciousness related to head trauma or developmental disorder 
including mental retardation. 
6.   Metal implants, pacemaker, or other metal in the body or medicinal patch. 
7. History of claustrophobia. 
8. Currently taking any antipsychotic medication (within 4 weeks).  
 
4.3    Inclusion Criteria for Healthy Controls 
1. Males and females 16 to 35 years of age, inclusive, at time of informed consent 
2. No prior history or current diagnosis of either schizophrenia, , schizoaffective disorder or 
schizophreniform disorder as established by a Non Patient version of the Structured Clinical 
Interview for DSMIV TR (SCID-NP) 
3. Medically healthy as assessed by study physician. 
4. If female of childbearing potential, participants must 
a) have a negative urine pregnancy test (all females regardless of childbearing potential 
will be required to submit a pregnancy test), and 
b) not be nursing or planning a pregnancy for the duration of the study through 30 
days after the last dosing visit, and 
c) be abstinent or willing to use a reliable method of birth control from the Screening 
Visit, and continue with the same method until termination from the study1. Males 
and females 16 to 35 years of age, inclusive, at time of informed consent 
4.4    Exclusion Criteria for Healthy Controls. 
1. Current substance abuse or positive urine toxic screen. 
2. Current or past Axis I psychiatric history (including Substance Use Disorder/Alcohol Use 
Disorder, with the exception of nicotine use disorder). 
3. Current or recent suicidal ideation-- suicidal ideation with intent or plan (indicated by 
affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in 
the 6 months prior to screening or subjects who represent a significant risk of suicide in the 
opinion of the investigator.  
4. Pregnant or nursing or positive urine pregnancy test. 


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5. Significant medical or neurological illness by history or physical exam, including seizure 
disorder, history of loss of consciousness related to head trauma or developmental disorder 
including mental retardation. 
6. Metal implants, pacemaker, or other metal in the body or medicinal patch. 
7. History of claustrophobia. 
8. History of or current treatment with any antipsychotic medication.  
 
4.5 Vulnerable Populations 
The inclusion of children for this research is necessary as early psychosis often affects individuals 
under the age of 18. For underage individuals, the treating clinicians will ask the potential subjects 
and their guardians if they would like to speak to a researcher and both will be required to 
complete the consenting process. Patients and/or their guardians will have an opportunity to 
discuss involvement in the study with their treating clinician prior to enrollment. The clinician or 
trained research coordinator obtaining the informed consent will take steps to ensure that the 
participant and his/her guardian are capable of consenting and participating in the study. The 
clinician or trained coordinator will ensure that the individual understands the content and 
procedures of the study, their rights as a participant, and their right to discontinue participation at 
any time. Individuals who are not able to demonstrate this level of comprehension will be excluded 
from participation. As described previously, the potential subject must also achieve a perfect score 
on a ten-item true/false quiz that asks questions about the study procedure and potential risks. 
Those who are deemed to lack the capacity to consent will not be enrolled in the study. 
 
Students will be informed that if they elect to participate in this study, they can choose to/not to 
participate or withdraw at any time without any impact on their grades or academic standing.  
 
4.6 Subject Recruitment and Screening 
Participants will be antipsychotic-free (i.e. no antipsychotic medication within 4 weeks of study 
enrollment) help-seeking right-handed males or females, ages 16-35, with early psychosis within 5 
years of onset, meeting diagnostic criteria for schizophrenia, schizoaffective disorder or 
schizophreniform disorder and currently exhibiting at least mild psychotic symptoms defined by a 
score of 2 or greater on at least one psychosis item of the BPRS (conceptual disorganization, 
suspiciousness, hallucinations, unusual thought content, grandiosity) with persistence of at least 4 
days per week for at least 4 weeks in the absence of psychotomimetic substance use or other 
potential organic etiologies, or major mood disorder, and in the absence of suicidal ideation, 
pregnancy, or significant medical illness (including epilepsy). For this study, subjects will be 
recruited from our network of NYU-affiliated institutions, including the NYU Medical Center 
Emergency Psychiatric Service and Adult Inpatient Psychiatry Unit (which have documented 1-3 EP 
unique patient visits monthly over the past 12 months), Bellevue Hospital Emergency Psychiatry 
Service, Walk-in Clinic and Inpatient Units (8-12 EP visits monthly), NYU Student Health Clinic (1-2 


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EP visits monthly) and NYU-Lutheran Hospital Emergency Service and Outpatient Psychiatry Clinics 
(4-8 EP unique EP patient visits monthly).  
 
At the Bellevue Inpatient Psychiatry Unit, the staff will identify patients who are refusing 
medication and will introduce the research study to these patients. If the patients are interested in 
participating, Dr. Leonardo Lopez, the Director of the Inpatient Unit, will assess the clinical 
appropriateness of the individual to participate in research and will assess the individual’s capacity 
to consent. Dr. Goff, a study MD/PhD or the nurse practitioner will also perform an assessment of 
clinical appropriateness and capacity to consent for any individuals interested in participating. After 
a potential study participant agrees to sign consent, the remaining screening procedures will take 
place on the inpatient unit at Bellevue. Following the screening procedures, individuals who qualify 
to participate will be transported to the NYU CBI for the Baseline procedures via ambulance as per 
the existing protocol at the Inpatient Unit to transport patients within NYU and Bellevue facilities 
for clinical procedures.  
 
Additionally, patients will also be recruited at the Nathan Kline Institute/Rockland Psychiatric 
Center and Gouverneur Health. All potential study participants will be referred by clinicians – 
clinicians will be asked to only refer individuals who they believe are appropriate for the study, can 
safely delay treatment for 24 hours and who are capable of deciding to participate. Once referrals 
are given, the study team will access EPIC to determine the participant’s initial eligibility. Subjects 
will also be recruited through advertisements in local newspapers. Additionally, the study team will 
use NYU’s DataCore service to gather information from EPIC for current NYU patients who may be 
eligible. Fliers and brochures will be distributed by clinicians to potentially interested participants. 
Dr. Goff and the study coordinator will maintain relationships with clinicians at these institutions in 
order to generate referrals. 
 
We will also be recruiting Spanish speaking subjects for our study. In order to recruit for Spanish 
speaking patients, our team will receive referrals from clinicians from our network of NYU-affiliated 
institutions. Clinicians who refer Spanish speaking patients will initially determine if the subject will 
be eligible to participate our study. If the patient qualifies and agrees to participate in our study, 
our team will provide a native Spanish speaking interpreter with training and understanding in 
medical terminology during the study visits.  
 
Our goal is to recruit and randomize 1.5 subjects per month out of 14-25 potential subjects who are 
identified in our referral network monthly.  In addition, we will study 10 healthy controls meeting 
the same exclusionary criteria as EP participants and group-matched on age and gender.  To recruit 
healthy controls, the study team will utilize an existing study database that is locked and password 
protected. The study database contains contact information of well-screened healthy volunteers 
who can be selected based on relevant demographic and medical information meeting study 
inclusion criteria; this approach is the preferred approach since subjects have been pre-screened by 
trained study staff and a representative sample can be selected based on demographic 
information. Additional healthy control study participants will be recruited through advertisements 
in local newspapers, on research websites such as ResearchMatch, or on sites such as Craigslist. 
“Umbrella” approaches, such as listing this study on ClinicalTrials.gov, will also be used. All 


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recruitment materials will be approved by the IRB prior to distribution. Initial recruitment 
procedures via telephone will be performed by trained study staff. 
 
The incidence of cannabis use in early psychosis patients in the US is estimated at 40% to 60% and 
a serious concern has been raised that excluding individuals who use cannabis may bias samples 
and make results less generalizable to clinical populations (Manseau & Goff, 2015) In addition, a 
recent study found that effects of cannabis on cognition are small and after 72 hours are essentially 
nondetectable, whereas urine toxic screens may remain positive for 2 weeks due to THC absorption 
in adipose tissue.(Scott et al., 2018) Most studies of THC effects in healthy individuals and 
individuals with early psychosis have found transient increases of paranoia and memory 
impairment that return to normal within 6 hours.  We selected a 72 hour period of cannabis 
abstinence based on self-report because in our experience self-report of research subjects has 
been quite reliable and confirmed by urine toxic screen, 72 hours is a conservative threshold to 
ensure that cognitive effects are unlikely to persist, and reliance on urine toxic screen is not reliable 
since it can remain positive for weeks after brain effects are no longer detectable.  We sought 
consultation from other investigators working in the area of early psychosis and from our DSMB 
and have adopted exclusionary criteria for cannabis use consistent with their recommendations. 
These new criteria are based on the  Diagnostic and Statistical Manual (DSM) 5 which revised the 
classification for cannabis use from abuse & dependence to cannabis use disorder, mild, moderate 
or severe. Criteria are provided for each category.  We would like to adopt these criteria for the 
current study and future studies: 
1. Exclude individuals with moderate or severe cannabis use disorder. 
2. Exclude individuals who report having used cannabis within 72 hours of the MRI scan.  
3. Include individuals with mild cannabis use disorder who have not used cannabis within 72 
hours prior to the MRI scan. 
4.7 
Remote Study Visits  
4.7.1 Screening and Baseline Procedures 
In light of the coronavirus pandemic, we have outlined a plan to protect patients and staff during 
study visits.  
 
The NYU Langone study team will minimize in-person contact with study participants. All 
assessments that can be completed remotely will, optionally, take place via WebEx, a secure video 
conferencing platform. Participants without access to a computer or stable internet will be able to 
come to One Park for screening visits, and all department outlined precautions for in-person visits 
will be followed. 
 
If consent can take place remotely, study staff will review the electronic consent form and consent 
quiz with the participant over WebEx. Participants will be provided an electronic consent form to 
sign (in REDCap), and a copy will be sent to their email. 
 
For outpatients, all screening assessments that can be conducted remotely will be completed via 
WebEx.  If participants meet eligibility criteria according to those assessments, participants will be 


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scheduled for an in-person visit at One Park Avenue / the Center for Brain Imaging at 660 1st 
Avenue, with careful adherence to all institutional safety precautions and social distancing. The 
screening assessments that must be completed in-person include the following: vital signs, 
anthropometrics, physical exam, and collection of a urine specimen for toxicology 
analysis/pregnancy screening.  
 
 
At the in-person Baseline visit, study staff will first complete the in-person assessments from the 
screening visits. Once these assessments have been reviewed by a Study MD/NP, and it has been 
determined that participants meet all IEC for the study, study staff will proceed with the baseline 
visit procedures.   
4.7.2 Physical Exams / Laboratory Tests 
Physical exams that were performed within the last 6 months and are documented in the medical 
record will be used to replace the in-person physical exam for patients unless medical history 
obtained by the research NP or MD suggests the possibility of a new medical condition with onset 
after the most recent physical exam.  
 
A rapid urine drug screen and (for individuals assigned female at birth or with childbearing 
potential of childbearing age) a urine pregnancy test will be conducted by the research coordinator 
/ research assistant or by clinical staff during the screening visit or prior to the baseline visit if the 
screening visit was conducted remotely. These results will be reviewed at the time of the visit with 
the study MD or NP. These results will be confirmed by also submitting urine samples to outpatient 
labs.  
 
 
 
4.8 Subject Consent and Assent 
 
All subjects will be evaluated by trained research coordinator or the nurse practitioner for capacity 
to consent and will be further evaluated by a licensed psychiatrist for safety and appropriateness to 
participate. Consent and assent will be completed by a trained coordinator or study clinician at One 
Park Avenue. In order to further ensure protection of privacy for this patient population, patients 
will not be contacted by any member of the research team unless they have agreed to hear about 
the research process beforehand from the initial treating clinician. Clinicians in the NYU Medical 
Center Emergency Psychiatric Service and Adult Inpatient Psychiatry Unit, Bellevue Hospital 
Emergency Psychiatry Service, Walk-in Clinic and Inpatient Units, NYU Student Health Clinic, NYU-
Lutheran Hospital Emergency Service and Outpatient Psychiatry Clinics Outpatient Psychiatry Clinic, 
Inpatient Psychiatry Units and the Comprehensive Psychiatry Emergency Program at Bellevue 
Hospital will be provided with study information as well as a document listing the 
inclusion/exclusion criteria in order to facilitate recruitment. This will allow the initial treating 
clinicians to help identify potential subjects as well as provide interested individuals with basic 
study-related information. Potential subjects identified by the initial treating clinicians will be asked 
whether they would like to speak to a researcher. If the patient agrees, the initial treating clinician 


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will then contact the study psychologist or trained study team member and they will determine 
whether the study clinician (psychologist or psychiatrist) will go and meet with the patient at that 
time or whether the patient will be scheduled for a screening visit at One Park Avenue. During this 
meeting, the study will be explained to the potential participant and in the event that the individual 
is interested in participating, s/he will then be given the consent form to read and review.  
 
Bellevue Psychiatry Inpatient Unit only: Dr. Leonardo Lopez, the Director of the Inpatient Unit, will 
assess the clinical appropriateness of the individual to participate in research and will assess the 
individual’s capacity to consent. Dr. Goff or the MD/PhD level clinician / nurse practitioner will also 
perform an assessment of clinical appropriateness and capacity to consent for any individuals 
interested in participating. After a potential study participant agrees to sign consent, the remaining 
screening procedures, including the informed consent process (as outlined below), will take place 
on the inpatient unit at Bellevue. 
 
Process of Consent: Patients who are interested in participating in the study will meet with a 
trained research coordinator, an MD/PhD level clinician, or the nurse practitioner, who will review 
the consent form and assess the patient's capacity for participation in research in accordance with 
our standardized research procedures. After signing consent, participants will be assessed for 
eligibility. Subjects’ capacity for participation in research will be reviewed by the coordinators in 
addition to an MD/PhD level clinician or a nurse practitioner during the screening process. The 
study team member obtaining the informed consent will take steps to ensure that the participant is 
capable of consenting and participating in the study. The study team member will ensure that the 
individual understands the content and procedures of the study, their rights as a participant, and 
their right to discontinue participation at any time. Individuals who are not able to demonstrate 
this level of comprehension will be excluded from participation. In addition, the potential subject 
must also achieve a perfect score on a ten-item true/false quiz that asks questions about the study 
procedure and potential risks. After the consent form has been signed, the subject will be provided 
with a letter detailing study-related information and contact information for key study staff. 
 
For Spanish Speaking Subjects: Spanish speaking subjects will be provided with certified translated 
consent forms and assent forms accompanied by a native Spanish speaking interpreter with 
training and understanding in medical terminology during study visits. 
 
 
Consent Forms: Consent forms will be stored in a locked file cabinet in folders labeled with the 
patients study identification number. This file will be separate from any of the subject’s study data 
in order to separate their data from any identifying information. 
 
4.9    Early Withdrawal of Subjects 
Participants will be advised verbally and in the ICF that they have the right to withdraw from the 
study at any time without prejudice or loss of benefits to which they are otherwise entitled. 
Participants may withdraw from the study at any time and for any reason, and are not obligated to 
provide the reason. 


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The Investigator or Sponsor may discontinue a patient from the study in the event of an inter-
current illness, AE, other reasons concerning the health or well-being of the patient, or in the case 
of lack of cooperation, non-compliance, protocol violation, or other administrative reasons. If a 
patient does not return for a scheduled visit, every effort should be made to contact the patient. In 
any circumstance, every effort should be made to document patient outcome, if possible. The 
Investigator should inquire about the reason for withdrawal and follow-up with the patient 
regarding any unresolved AEs. 
 
Any reason for withdrawal given (or the failure to provide a reason) must be recorded in the source 
documentation and on the patient’s electronic case report form (eCRF). 
5 
Study Drug  
5.1 
Description 
The study drug (Levetiracetam 185mg, 500mg, or placebo) will be supplied in a blinded and pre-
labeled package.   
5.2 
Treatment Regimen 
At least 24 and maximum of 46 early psychosis patients will be randomized to a single oral dose of 
levetiracetam 185 mg, 500 mg or placebo, which will be administered at Baseline (Visit 2). 
5.3 
Method for Assigning Subjects to Treatment Groups 
Randomization will be in a 1:1:1 ratio in blocks of random size (3 or 6), stratified by diagnosis 
(schizoaffective vs. schizophreniform/schizophrenia). 
5.4 
Preparation and Administration of Study Drug 
Study drug dispensation will take place at the NYU Langone Investigational Pharmacy. In order to 
ensure blinding, the 185mg, 500mg and placebo will be prepared in identical capsules. Once a 
participant passes the screening procedures, the Investigator, study physician, or nurse practitioner 
will enter the prescription information into EPIC or write a prescription order to be submitted 
physically to the pharmacy. The study drug will be prepared in accordance with the randomization 
list which will be kept by the pharmacy. Study staff will retrieve the study drug from the pharmacy 
and a study physician or nurse practitioner will administer the drug.  
5.5 
Prior and Concomitant Therapy 
Concomitant medications that are permitted during the study include Benadryl for sleep. 
Antipsychotics  are not permitted due to interactions with neurotransmitters affected by 
levetiracetam. 
5.6 
Packaging 
All capsules of the study drug will be received in one bulk shipment from Sentrix Pharmacy and 
Discount and will be stored at room temperature in a marked bottle at the NYU Langone 
Investigational Pharmacy.  


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5.7 
Blinding of Study Drug 
The NYU Investigational Pharmacy will maintain a randomization list for study participants. All 
other study staff, aside from one designated unblinded study team member, will be blinded to the 
treatment groups. All study drug doses and placebo will be prepared in identical capsules in order 
to maintain blinding.  
5.8 
Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment at the NYU Langone 
Investigational Pharmacy.  It is important that the designated study staff counts and verifies that 
the shipment contains all the items noted in the shipment inventory.  Any damaged or unusable 
study drug in a given shipment (active drug or comparator) will be documented in the study files.  
The investigator must notify study sponsor of any damaged or unusable study treatments that 
were supplied to the investigator’s site. 
5.8.2 Storage 
All study drug will be kept at the NYU Langone Investigational Pharmacy at room temperature. No 
special handling or storage requirements are indicated.  
5.8.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed by the study’s unblinded pharmacist to 
document drug assigned, drug consumed, and drug remaining. This reconciliation will be logged on 
the drug reconciliation form, and signed and dated by the pharmacist. Administration of study drug 
during Baseline (Visit 2) will be logged by study clinician or delegated site staff.   
5.8.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, 
and drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and 
dated.  Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug.  Drug destroyed on site will be documented in the study files. 
6 
Study Procedures 
Study Participants will be seen in the clinic for a Screening Visit within 28 days of Baseline (Visit 2 – 
Day 1) to assess eligibility for the study. EP participants will be randomized after eligibility is 
confirmed during Screening. During the screening visit, healthy controls will complete the non-
patient version of the SCID while EP participants will complete the patient version of the SCID for 
DSM-IV-TR. In addition, EP participants will complete the BPRS rating scale per inclusion criteria 
and both EP participants and health controls will complete the C-SSRS. During the baseline visit, EP 
participants will complete all procedures. Healthy controls will receive the second ASL scan but will 
not receive levetiracetam, and will not have blood drawn for levetiracetam levels.  


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6.1 
Screening (Visit 1 – Days -28 to 0) 
The following procedures will be performed at Screening: 
1. The Investigator, Study MD, trained research coordinator, or the nurse practitioner will 
provide the participants with informed consent documents and will explain the rationale for 
the study. 
2. Participants will be assessed for inclusion and exclusion criteria. 
3. Medical history, including patient demographics, and any concomitant medications use 
(including over-the-counter medications, vitamins, and supplements) will be reviewed and 
recorded. 
4. Psychiatric history will be recorded and a SCID will be conducted by the study MD or nurse 
practitioner. The SCID for the DSM-IV (Modules A-D) will be used to assess the primary 
psychiatric diagnosis for patients. Module E of the SCID for the DSM-IV will be used to assess 
alcohol and substance dependence/abuse (except for cannabis). Cannabis use disorder will 
be assessed using Module E from the SCID for the DSM-5. The other modules for the SCID will 
not be performed as they do not relate to the inclusion/exclusion criteria. Healthy controls 
will complete the non-patient version of the SCID; EP participants will complete the patient 
version of the SCID for DSM-IV-TR. 
5. Physical examination will be completed by study MD or health nurse practitioner. Vital signs 
will also be completed by a trained study team member.  
6. A urine pregnancy test will be performed on all females of childbearing potential. 
7. A urine drug screen test will be performed. 
8. In addition, the following rating scales will be completed: 
a. Brief Psychiatric Rating Scale (BPRS) – EP Participants only. 
b. Columbia Suicide Severity Rating Scale (CSSR-S) 
Participants who are excluded from the study either due to high scores on suicidal severity 
screening or a cannabis use disorder will be referred to appropriate care by the study team.  
6.2 
Baseline (Visit 2 – Day 1) 
The following procedures will be performed at Baseline: 
1. A trained research assistant will complete the BPRS (EP participants only), SAFTEE and MRI 
safety questionnaire. 
2. Optional: EP participants may decide to complete the Matrics Consensus Cognitive Battery 
(MCCB) to evaluate cognition.  
3. Study participants will undergo a 15-minute ASL imaging scan to measure blood flow in the 
brain. If time permits, study participants will undergo additional ASL imaging, up to 30 
minutes total, and a spectroscopy scan, up to 30 minutes, to measure chemical activity in 
the brain.  
4. Study medication will be administered by study MD or nurse practitioner (EP participants 
only). 
5. HC participants will also complete an additional 15-minute ASL imaging scan, and an 
additional spectroscopy scan, up to 30 minutes. 2 hours after the first scan is completed. 
1. All participants will have their corneal, hand and temporal artery (forehead) temperature 
measured while seated in a chair (1 minute procedure). (optional) 
 


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Two hours after administration of study medication, the following procedures will be performed in 
EP participants only: 
2. A trained research assistant will complete the BPRS and SAFTEE. 
3. Blood will be drawn (1 milliliter, or 0.25 teaspoons) for assay of levetiracetam levels.  
4. Participants will complete a second 15-minute ASL imaging scan. If time permits, study 
participants will undergo additional ASL imaging, up to 30 minutes total, and an additional 
spectroscopy scan, up to 30 minutes. 
5. Safety evaluation will be completed by study psychiatrist or nurse practitioner prior to 
discharge. 
6. Participants will have their corneal, hand and temporal artery (forehead) temperature 
measured while seated in a chair (1 minute procedure). (optional)  
 
 
Participants will be allowed to smoke cigarettes ad lib prior to and after imaging. 
6.3 
Follow-up Telephone Call (Day 2) 
A study clinician or trained research assistant will contact the participant via telephone the 
following day to assess safety.  
 
6.4 
Optional follow up procedure: 
Participants may undergo a second session of imaging and study drug administration following 
approximately 8 weeks of exposure to antipsychotic medication. They will receive the same study 
drug (placebo, low dose levetiracetam or higher dose levetiracetam) that they received at their first 
session.  This follow-up imaging may provide important information about possible changes in 
brain activation following medication compared to healthy controls and whether levetiracetam is 
likely to benefit individuals when added to antipsychotic medication.  If subjects elect to remain 
medication-free, after a delay of at least 2 weeks they may return for a second session of imaging 
and administration of levetiracetam or placebo.  They will also receive the same study drug 
(placebo, low dose levetiracetam or higher dose levetiracetam) that they received at their first 
session.  This will provide important information about whether hippocampal ASL changes with 
severity of psychosis and whether the effect of levetiracetam on hippocampal ASL changes with 
severity of psychosis.  Individuals will receive the same remuneration for all three sessions (initial 
session, session following initiation of antipsychotic medication and session following a progression 
of psychotic symptom severity off-medication).  Thus, participants are not incentivized to remain 
medication free—they will have an opportunity to repeat the procedure regardless of their 
decision about medication. 
The follow-up procedure will include the following assessments:  
1. Medical history, including patient demographics, and any concomitant medications use 
(including over-the-counter medications, vitamins, and supplements) will be reviewed and 
recorded. 


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2. Physical examination will be completed by study MD or nurse practitioner. Vital signs will also 
be completed by a trained study team member.  
3. A urine pregnancy test will be performed on all females of childbearing potential. 
4. A urine drug screen test will be performed. 
5. In addition, the following rating scales  will be completed: 
a. Columbia Suicide Severity Rating Scale (CSSR-S) 
6. Subsequently, participants will complete the imaging section of the visit, which will include 
all procedures outlined above under Baseline (Visit 2 – Day 1) 
 
7 
Statistical Plan 
7.1 
Sample Size Determination 
We are not testing for statistical significance and are not powering the study based on estimates of 
statistical significance.  This is a pilot study to determine whether we have an adequate signal to 
proceed to a fully-powered clinical trial (R33). In keeping with the NIMH “fast fail” guidelines, we 
are selecting a threshold which will provide reasonable evidence to support continuing to the next 
phase of development.  The decision to proceed to the R33 trial will be based on the 
demonstration of target engagement, defined by an effect size (Cohen’s d) of .5 or greater in the 
mean reduction by levetiracetam of hippocampal perfusion measured by ASL compared to placebo, 
plus the demonstration of adequate tolerability defined by the absence of serious adverse events 
and confirmed by review of safety and tolerability data with the DSMB and NIMH staff.  The 
decision whether to proceed and the selection of the optimal dose will be made in conjunction 
with NIMH staff.   
 
7.2 
Subject Population(s) for Analysis 
Both the incidence of adverse effects and ASL evidence of hippocampal target engagement will be 
analyzed in all participants who receive study drug. The primary efficacy outcome measure for this 
trial are described above in section 3.2.  
 
8 
Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there 
is a reasonable possibility that the incident experience, or outcome may have been caused 
by the procedures involved in the research) 


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• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, the study treatment follow-up is defined as 30 days following the last administration of 
study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 


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General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 
visit, the investigator should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation in 
this study.  The investigator should notify the study sponsor of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol.  Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition.  Surgery should not be reported as an outcome of an adverse event 
if the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 


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Procedures to minimize additional risks: 
As described, a psychiatrist will provide a psychiatric and medical evaluation as part of screening.  A 
study MD or nurse practitioner will be present at the imaging center during the procedure and will 
evaluate the participant after completion of the scanning procedure to affirm that the participant is 
safe to leave after completing the study.  Subjects will also be contacted by telephone the following 
day to affirm that they are stable.  We will follow the same emergency procedures that are 
followed at the imaging center in the event of adverse reactions to contrast agents or other 
medical complications—the study physician (Dr. Goff or Urban) will respond to the event along 
with other CBI staff (including a nurse) and 911 will be called if needed.  We are studying a low 
dose and an extremely low dose of levetiracetam.  The low dose is the standard starting dose which 
has been approved for almost 20 years and is not associated with medical complications.  
Psychiatric reactions occur but usually only after 1 week of daily dosing—we will be monitoring 
closely for psychiatric reactions to the single dose, even though this is highly unlikely to occur. 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events should 
be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.  Serious adverse events that are still ongoing at 
the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a minimum 
those events that must be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 


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• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study treatment 
8.3.1 Investigator reporting: notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated 
problems posing risks to subjects or others.  The following describes the NYULMC IRB reporting 
requirements, though Investigators at participating sites are responsible for meeting the specific 
requirements of their IRB of record.  
 
Report promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 
working days from the time the investigator becomes aware of the event: 
• Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and 
package inserts.  
– Related to the research procedures: An event is related to the research procedures if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working 
days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional 
deviations from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 


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• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study. 
• New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or 
a more severe or frequent side effect; Other research finds arm of study has no therapeutic 
value; FDA labeling change or withdrawal from market) 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable Event 
Form” or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent 
form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
8.3.2 Sponsor reporting: Notifying the FDA 
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports. The following 
describes the safety reporting requirements by timeline for reporting and associated type of event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit 
the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
Additional reporting requirements 


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Sponsors are also required to identify in IND safety reports all previous reports concerning similar 
adverse events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form; see Attachment XXXX), 
or in a narrative format. If supplied as in a narrative format, the minimum information to be 
supplied is noted above at the beginning of section 8.3. The contact information for submitting IND 
safety reports is noted below: 
 
[Include the FDA Division, contact person, telephone number and fax number here] 
8.4 
Unblinding Procedures 
If the study psychiatrist determines that unblinding is necessary for a subject’s safety, the study 
psychiatrist will contact the NYUMC Research Pharmacy and the study code will be unblinded and 
shared with clinicians as appropriate. 
8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as 
noted above, as well as the construction and implementation of a site data and safety-monitoring 
plan (see section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 
8.5.1 Data Monitoring Committee 
Our existing data safety and monitoring board (DSMB) will monitor this study.  The DSMB has 
monitored five clinical studies over the past 7 years and is comprised of a statistician and two 
psychiatrists with extensive experience conducting clinical trials and in participating on DSMBs. If 
specific risks emerge additional members with expertise in the area of the potential safety issue 
will be added to the DSMB. The DSMB will approve the protocol prior to initiation of the study. The 
DSMB will review site performance, including recruitment, subject retention, protocol violations, 
and data quality reports. The DSMB will receive an unblinded report of all safety data after 
completion of the first 4 subjects in addition to reports for bi-annual meetings.  The DSMB will also 
be provided copies of all communications with the IRB. The DSMB will meet prior to initiation of 
the study and a minimum of every six months and will be provided data regarding enrollment and 
side effects and a study summary prior to each meeting. The DSMB may request additional 
meetings as necessary to monitor safety or site performance. The study will be halted by the PI if 
any serious safety issues arise pending review by the DSMB.   Dose selection and titration schedule 
can be adjusted by the DSMB. Dr. Goff will not attend meetings of the DSMB. Throughout the 
study, notification of any Serious Adverse Events (SAEs) as well as any proposed investigator 
initiated changes in the protocol will be submitted to the DSMB. Based on its review of the revised 
protocol , the DSMB will identify the data parameters and format of the information to be regularly 
reported.  All SAEs and adverse events will be tabulated and submitted to the IRB and DSMB in the 
quarterly data reports or at the time of continuing review. AEs will be reported to the IRB annually.  


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9 
Data Handling and Record Keeping 
9.1 
Confidentiality 
Subjects will be assigned a study identification code that will be used for all study documents. All 
patient identifiers will be redacted and subjects will not be identified in any presentations that are 
given of the results of this study. Study documents collected in this study will be kept in a locked 
cabinet in a locked office belonging to the study staff. Only research staff who are directly involved 
in this study will have access to that file. 
9.2 
Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
9.3 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
9.4 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF 
is left blank because the procedure was not done or the question was not asked, write “N/D”.  If 
the item is not applicable to the individual case, write “N/A”.  All entries should be printed legibly in 
black ink.  If any entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it.  All such changes must be initialed 
and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 


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9.5 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Section 8.5 and 8.5.1. The 
investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the 
above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups of 
all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review 
Board (IRB) in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB/EC concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before commencement of 
this study.  The investigator should provide a list of IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  See Attachment [include attachment number here] for a copy of the Subject Informed 
Consent Form.  This consent form will be submitted with the protocol for review and approval by 


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the IRB for the study.  The formal consent of a subject, using the IRB-approved consent form, must 
be obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or subject’s parent/guardian (if under 18), and the investigator-designated research 
professional obtaining the consent.  
 
12 Study Finances 
12.1 Funding Source 
This study is financed through a grant from the US National Institute of Health. Upon request of 
study participants, referrals for treatment may be provided. Study participants will be informed 
that they are responsible for any costs associated with referrals. 
 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All NYULMC investigators will follow the applicable University conflict of 
interest policies. 
12.3 Subject Payments 
There is no cost to subjects for participating. Round trip metro cards will be provided for each study 
visit.    
 
EP participants will receive $200.00 for completion of the study and up to $150 for completion of 
optional study procedures.  
• $50 for Screening (Visit 1) 
• $150 for Baseline (Visit 2) 
• Optional: $150 for follow-up imaging sessions 
• Optional: $25 for MCCB at Baseline 
 
Healthy controls will receive $100.00 for completion of the study and up to $175.00 for completion 
of the optional study procedures.  
• $25 for Screening (Visit 1) 
• $100 for Baseline (Visit 2) 
• Optional: $75 for follow-up imaging 
 
Subjects will not receive remuneration for the follow-up phone call. 
13 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 


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investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 
 
 
 
 
 
 
 
 
 
 
 
14 References 
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writing by the study sponsor 
56.  Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, 
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writing by the study sponsor 
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writing by the study sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


[Levetiracetam in Early Psychosis] 
 
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writing by the study sponsor 
15 Attachments 
Schedule of Events – EP Participants 
 
 
Screening, 
Visit 1 
Baseline, 
Visit 2 
Follow-up  
Phone Call 
Follow-up, 
Visit 3 
(Optional) 
Follow-up 
Phone Call 
(Optional) 
 
Days -28 to 
0 
Day 1 
Day 2 
Day 3 (Week 
8) 
Day 4 
Consent 
X 
 
 
 
 
Authorization Form 
X 
 
 
 
 
Inclusion/Exclusion 
Checklist 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Concomitant 
Medications 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
Anthropometrics 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Study drug 
dispensation 
 
X 
 
 
 
SCID for DSM-IV-TR 
X 
 
 
 
 
BPRS 
X 
X 
 
 
 
C-SSRS 
X 
 
 
 
 
SAFTEE 
 
X 
 
X 
 
MCCB (optional) 
 
X 
 
 
 
ASL Imaging 
 
X 
 
X 
 
Spectroscopy 
Imaging 
 
X 
 
X 
 
Levetiracetam blood 
levels 
 
X 
 
 
 
Safety evaluation 
 
X 
 
X 
 
Adverse Event Form 
 
X 
X 
X 
X 
Phone Call 
 
 
X 
 
X 
Study Completion 
Form 
 
 
X 
 
 
 


[Levetiracetam in Early Psychosis] 
 
Page 46 
Version: 1.19 
 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor 
Schedule of Events – Healthy Controls 
 
 
Screening, 
Visit 1 
Baseline, 
Visit 2 
Follow-up  
Phone Call 
Follow-up, 
Visit 3 
(Optional) 
Follow-up 
Phone Call 
(Optional) 
 
Days -28 to 
0 
Day 1 
Day 2 
Day 3 (Week 
8) 
Day 4 
Consent 
X 
 
 
 
 
Authorization Form 
X 
 
 
 
 
Inclusion/Exclusion 
Checklist 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
Psychiatric History 
 
 
 
 
 
Demographics 
X 
 
 
 
 
Concomitant 
Medications 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
Anthropometrics 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Study drug 
dispensation 
 
 
 
 
 
SCID-NP 
X 
 
 
 
 
BPRS 
 
 
 
 
 
C-SSRS 
X 
 
 
 
 
SAFTEE 
 
X 
 
X 
 
MCCB (optional) 
 
 
 
 
 
ASL Imaging 
 
X 
 
X 
 
Spectroscopy 
Imaging 
 
X 
 
X 
 
Levetiracetam blood 
levels 
 
 
 
 
 
Safety evaluation 
 
X 
 
X 
 
Adverse Event Form 
 
X 
X 
X 
X 
Phone Call 
 
 
X 
 
X 
Study Completion 
Form 
 
 
X