The Effects of Kynurenine Aminotransferase Inhibition in People With Schizophrenia
Phase: PHASE1
Conditions: Schizophrenia, Schizoaffective Disorder, Schizophreniform Disorder
Sponsor: University of Maryland, Baltimore

The Effects of Kynurenine Aminotransferase Inhibition in People with Schizophrenia 
February 7, 2024
NCT04013555  
V.9
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Background: There is converging evidence to suggest that kynurenine pathway disturbances may be related 
to the pathophysiology of schizophrenia. In particular, clinical, genetic, and post-mortem studies suggest that 
the disruption of key regulatory pathway enzymes results in increased CNS production of kynurenic acid 
(KYNA) (1-10); a known antagonist of α-7 nicotinic and N-Methyl-D-aspartate (NMDA) glutamate receptors 
(11,12). The KYNA antagonism of these receptors is hypothesized to be a critical mechanism in the 
development of the cognitive impairments observed in schizophrenia. In our previous work, we demonstrated 
that increased KYNA (following tryptophan (TRYP) challenge) impaired learning on verbal and visual memory 
tests in healthy controls. In addition, we found that increased KYNA decreased whole brain and frontal cortical 
gray matter cerebral blood flow (CBF) in people with schizophrenia. Previous studies have also shown reduced 
resting frontal CBF, assessed with ASL, in schizophrenia (13-16); importantly lower resting CBF is related to 
poorer cognitive function in schizophrenia (17,18). Furthermore, we identified a subgroup of people with 
schizophrenia with elevated serum KYNA levels, who were characterized by higher BPRS total, positive 
symptom, and thought disorder factor scores; and who exhibited a significant worsening on their performance 
of a sustained attention task following TRYP, but not placebo, administration. Finally, we recently reported that 
higher circulating KYNA correlates with lower brain glutamate in humans (19) and present preliminary evidence 
that higher brain KYNA is associated with lower white matter fractional anisotropy. The convergence of these 
results provides further support for the hypothesis that increased KYNA may be related to the pathophysiology 
of cognitive impairments in schizophrenia.  
Of particular interest to the current project, we have recently demonstrated that high dose N-
acetylcysteine (NAC) inhibits kynurenine aminotransferase (KAT) II activity, the enzyme that converts 
kynurenine to KYNA. Specifically, we have shown that NAC reduces basal extracellular KYNA levels, 
measured by microdialysis, in the prefrontal cortex of freely moving rats; and the de novo production of KYNA 
from its precursor. In addition, we have shown that the IC50 of NAC on KAT II activity in liver and brain tissue 
homogenates from mice, rats, pigs and humans is in the high µM to the low mM range. Finally, we tested the 
effect of NAC on pure human recombinant KAT II protein and found that NAC inhibits enzyme activity with a 
IC50 of ~500 µM. Taken together, these results indicate that NAC can reduce cerebral KYNA levels via KAT II 
inhibition.  
Specific Aim: The purpose of the current study is to examine whether high dose N-acetylcysteine (NAC) 
blocks the adverse effects of increased kynurenic acid (KYNA) on selected measures of brain chemistry, 
function and behavior, through the inhibition of kynurenine aminotransferase (KAT) II, which converts 
kynurenine to KYNA. The study will be a double-blind, placebo-controlled, randomized cross-over challenge 
study, in which people with schizophrenia are pretreated with either high-dose NAC, 140 mg/kg up to a 
maximum of 15 g, or placebo, then receive tryptophan (TRYP), 6 gms. The tryptophan challenge method 
robustly increases peripheral measures of kynurenine and KYNA in humans and putatively increases brain 
KYNA levels, through the CNS conversion of kynurenine to KYNA; a process that is observed in both rodents 
and nonhuman primates. We will evaluate the ability of NAC to inhibit the conversion of kynurenine to KYNA 
with the following primary outcome measures: 1) we will measure serum kynurenine and KYNA before and 
after NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo 
blocks the peripheral conversion of kynurenine to KYNA; 2) we will use the arterial spin labeling (ASL) 
technique to measure whole brain and frontal gray matter cerebral blood flow (CBF) before and after 
NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo 
attenuates the effects of TRYP on ASL CBF measures; 3) we will use magnetic resonance spectroscopy 
(MRS) to measure glutamate and glutathione levels in the medial prefrontal cortex (mPFC) before and after 
NAC/placebo pre-treatment and TRYP administration and examine whether NAC compared to placebo 
increases MRS glutathione and glutamate measures; and 4) we will use diffusion tensor imaging (DTI) to 
measure white matter fractional anisotropy (FA) before and after NAC/placebo pre-treatment and TRYP 
administration and examine whether NAC compared to placebo increases white matter FA. 
We will have two secondary endpoints. First, if we observe that NAC attenuates the effects of TRYP on 
ASL and/or increases mPFC glutamate levels or white matter DTI FA, then we will examine whether these 
effects are related to changes in cognitive measures of attention, verbal and visual memory, and working 

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memory. Second, we will examine the relationship of serum KYNA levels and kynurenine 3-monooxygenase 
(KMO) gene polymorphisms to the observed effects of NAC on our neuroimaging and cognitive outcome 
measures. 
We hypothesize that NAC will inhibit KAT II, which will be reflected in the: 1) decreased peripheral 
conversion of kynurenine to KYNA; and 2) increased CBF, glutamate, and white matter fractional anisotropy 
(FA). In addition, we hypothesize that the NAC effects on the neuroimaging measures will be related to 
improved performance on cognitive measures of attention, verbal and visual memory and working memory. 
These observed effects of NAC will be greater than those seen with placebo. We further hypothesize that the 
NAC effects on ASL CBF, glutamate, and FA measures will be independent of NAC-induced changes in MRS 
glutathione, i.e., not due to the NAC oxidative stress mechanism, but, rather, will be correlated with NAC-
induced reductions in the peripheral conversion of kynurenine to KYNA. Finally, we hypothesize that the 
observed effects of NAC on CBF, glutamate, and FA will be related to baseline serum KMO activity and KYNA 
levels. The demonstration that NAC reverses the adverse impact of increased KYNA levels will importantly 
support the development of KAT II inhibitors for the enhancement of cognition in schizophrenia. 
 
Methods:  The proposed study will be a double-blind, placebo-controlled, randomized cross-over challenge 
study, in which people with schizophrenia are pretreated with either high-dose NAC, 140 mg/kg up to a 
maximum of 15 g, or placebo, then receive TRYP, 6 gms. We will collect baseline and post-treatment KYNA 
and kynurenine; clinical; neuroimaging; and cognitive measures. Participants (n=100) will be of either sex and 
any race, between 18 - 55 years old, with a Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 
(20) diagnosis of schizophrenia or schizophreniform or schizoaffective disorder. A best estimate diagnostic 
approach will be utilized in which information from the Structured Clinical Interview for DSM-5 (SCID; 21) is 
supplemented by information from family informants and medical records to generate a diagnosis. Participants 
will be judged by their clinician to be clinically stable. We will not restrict the type of antipsychotic with which 
the participant is treated or the use of concomitant medications; there is little evidence of a differential effect of 
first and second generation antipsychotics on KYNA levels (22). The inclusion and exclusion criteria are: 
 
Inclusion Criteria: 
1) Males and females 
2) Age: 18 to 55 years 
3) DSM-5 Criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder (documented 
by SCID) 
4) Prescription of antipsychotic medication for at least 60 days and constant dose for 7 days prior to study 
entry (either first or second generation antipsychotics permitted) 
5) Female participants must agree to use a medically accepted means of contraception 
 
Exclusion Criteria: 
1) DSM-5 alcohol or substance use disorder in the last 3 months, other than nicotine and cannabis 
(documented by SCID). Only participants meeting a moderate to severe cannabis use disorder will be 
excluded. 
2) History of an organic brain disorder; intellectual disability; or a medical condition, whose pathology or 
treatment could alter cognition or increase their safety risk of protocol participation 
3) Active disorders that have been reported to affect tryptophan metabolism or interfere with absorption 
will be excluded (Acute Intermittent Porphyria, Celiac Disease, Crohn’s Disease, Irritable Bowel 
Syndrome). 
4) Excessive self-reported daily caffeine intake, defined as intake exceeding 1000mg or the equivalent of 
10 cups of coffee 
5) Pregnancy or lactation secondary to pregnancy 
6) Presence of MRI contraindications (e.g. pacemakers) 
7) Regularly scheduled use of monoamine oxidase inhibitors, migraine headache medications (triptans) 
and dextromethorphan. Excludes only daily use, prn permitted. 

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Participant Recruitment: Potential participants with SRDs will be recruited from three sources: the Maryland 
Psychiatric Research Center (MPRC) clinical programs: the Outpatient Research Program (ORP), the 
Treatment Research Program (TRP), and the First Episode Clinic (FEC); local outpatient mental health 
centers; and a standing recruitment database, from which we have enrolled participants in previous MPRC 
clinical trials. Potential MPRC and community participants will be identified primarily through chart review or 
nomination by their primary clinicians who are aware of study entry criteria and demands, and have been 
asked to identify clinically stable patients who may be interested in research participation. MPRC and 
community participants may also be self- or peer-referred for this study. Participants may also be recruited 
from internet based advertising (HP-00061828) that will refer interested participants to the MPRC web site 
 
Study Assessments: 
 
Clinical Assessments: The following rating scales will be used to characterize the baseline clinical 
state of the study sample and to assess whether there any changes in the clinical state of the study 
participants during their participation in each of the Challenge Phase visits: the Brief Psychiatric Rating Scale 
(BPRS; 23) total score will be used to measure global psychopathology. The four BPRS positive symptom 
items - conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content - will 
be used to measure positive psychotic symptoms. The Scale for the Assessment of Negative Symptoms 
(SANS; 24) total score will be used to measure negative symptoms; Calgary Depression Scale (CDS; 25) total 
score will be used to measure depressive symptoms; and Clinical Global Impression Scale (CGI; 26) severity 
of illness item will be used to confirm clinical stability prior to entry into the Challenge Phase and assess global 
changes during the Challenge Phase. 
 
Cognitive Assessments: The following cognitive assessments will be used to assess the effects of 
NAC-induced KAT II inhibition on neuropsychological test performance.  We will use the following 7 tests from  
the MATRICS Consensus Cognitive Battery (27): Brief Assessment of Cognition in Schizophrenia (BACS), 
Symbol-Coding, Hopkins Verbal Learning Test–Revised (HVLT-R), Brief Visuospatial Memory Test–Revised 
(BVMT-R), Continuous Performance Test-Identical Pairs (CPT-IP), Maryland Letter-Number Sequencing 
(LNS), and WMS®-III Spatial Span.  
 
Clinical and Cognitive Assessment Training and Reliability: The MPRC provides resources for the 
conduct of training and interrater reliability procedures for the BPRS, SANS, CDS, and CGI. The clinical rater 
will be appropriately trained and meet required inter-rater reliability standards (ICC ≥ 0.80), before assignment 
as a rater. During the course of the study, interrater sessions for these assessments will be held every three 
months to maintain rater reliability and minimize rater drift. Dr. Gold will train the neuropsychological rater in 
the administration of the cognitive assessments. 
 
Laboratory Assessments: The following laboratory assessments will be collected:  
   a) Kynurenine pathway metabolites: We will collect the following kynurenine pathway metabolites: 
kynurenine and KYNA. We will use high performance liquid chromatography to measure serum kynurenine and 
kynurenic acid levels. Perfusate samples will be diluted 1:2 for determination of both molecules. Plasma 
samples will be diluted 1:2 for kynurenine and 1:10 for KYNA determination. Twenty μL will then be subjected 
to HPLC analyses and analytes will be detected fluorimetrically.  
   b) We will collect ~8mL of whole blood which will be transferred into a 10mL Cryovial cryogenic tube 
and placed in -80 freezer until time of analysis. Single-Nucleotide Polymorphism (SNP) genotyping will be 
performed on gDNA isolated from blood with QIAamp DNA Maxi Kit (Qiagen) using TaqMan polymerase chain 
reaction (PCR) technology.c)  Two aliquots of blood will be stored at -80 until analyzed for inflammatory 
markers, oxidative stress, and other related markers.  
 

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Neuroimaging Assessments and Procedures: All participants will undergo pre- and post-treatment 
structural, ASL, and MRS studies. MRI data will be acquired using a 3-T Siemens Prisma scanner equipped 
with a 64 channel head coil at the University of Maryland Center for Brain Imaging Research (CBIR), located at 
the MPRC. A T1-weighted structural image (MP-RAGE: 0.8 mm isotropic voxels, 256X256 mm FOV, TR/TE/TI 
= 2400/ 2.22/ 1000ms) will be acquired for spectroscopic voxel prescription and segmentation and anatomical 
reference.  
 
    Arterial Spin Labeling (ASL): We will use a Pseudo-continuous Arterial Spin Labeling (pCASL) 
sequence that provides full brain coverage with high spatial resolution and excellent WM signal-to-noise ratio 
(SNR) (SNR>15). Specifically, we will use a pCASL EPI with TE/TR = 16/4000ms, labeling duration = 2100ms, 
24 contiguous slices with 5 mm thickness, matrix = 64 x 64, 3.4 x 3.4 x 5 mm resolution (FOV = 220 mm), 
labeling gradient of 0.6 G/cm, bandwidth=1594 Hz/pixel, labeling offset = 90 mm (32). A total of 68 alternating 
labeled and unlabeled image pairs will be collected. Equilibrium magnetization (M0) images will be collected 
using a long TR=10s protocol (33). ASL data will be processed using the pipeline described elsewhere 
(http://www.mccauslandcenter.sc.edu/CRNL/tools/asl). Absolute gray and white matter cerebral blood flow 
quantification will be calculated in native space from the mean perfusion images. Voxel-wise perfusion, in ml 
per 100 g per minute, will be calculated under the assumption that the post label delay is longer than the 
arterial arrival time (32), with labeling efficiency set at 0.85, and the mean transit time set to 0.7s, based on 
empirical data (34). 
 
    Magnetic Resonance Spectroscopy (MRS): Glutamate will be detected using very short TE phase 
rotation stimulated echo acquisition mode (STEAM: TR/TM/TE= 2000/10/6.5 ms, NEX=128, 2500-Hz spectral 
width, 2048 complex points, and Δφ1=135°, Δφ2=22.5°, Δφ3=112.5°, and ΔφADC=0°) (35). Water 
suppression will be automated using a water suppression enhanced through T1 effects sequence (WET). 
Spectra will be analyzed using the fully automated, standard curve-fitting software, LCModel. Metabolites will 
be referenced to water and only metabolites of good fits (CRLBs< 20) will be included. Voxel will be 
segmented into CSF, gray, and white matter tissue using SPM8 and in house Matlab code; metabolites will be 
corrected according to Gasparovic et al (36). We will use the gold standard MEGA-PRESS sequence for GSH 
detection and quantification (TR/TE: 2000/120ms (37), NEX=256 (128 “on” and 128 “off”, on editing pulse 
frequency = 4.56ppm, refocusing pulse bandwidth=kHz) (38). GSH data will be analyzed using Gannet 3.0 and 
GSH/Water ratios with fit errors above15%, will be excluded. We have shown these sequences to be optimal 
for glutamate and GSH detection through rigorous phantom and simulation studies, and highly reproducible 
through test-retest studies in healthy control and schizophrenia samples (38-41). 
 
Diffusion Tensor Imaging (DTI): Diffusion weighted data will be collected used a homologized DWI 
protocol, based on our on-going Amish Connectome Study, which consists of fifteen b-shells distributed 
equally between b=0-3500 s/mm2 with 32-directions/shell. The same analysis protocol is used in pigs and 
humans and combines diffusion tensor imaging (DTI), White Matter Tract Integrity (WMTI) and Permeability-
Diffusivity (PD) modeling. DTI is a commonly used DWI approach, which describes the Gaussian properties of 
the diffusion displacement distribution of water in the brain by fitting a mono-exponential function to the 
weighted diffusion signal decay at a low “diffusion weighting” (b-value ≤ 1000 s/mm2). The choice of a lower b-
value range makes DTI sensitive to water molecules with high diffusivities. DTI FA is a simple and empirical 
parameter; however, at higher b-values, DTI fails to approximate the non-mono-exponential decay of diffusion 
signal that is caused by the restriction of diffusion by cellular membranes. WMTI and PD models overcome DTI 
limitations; characterize the sources of the non-Gaussian distribution of diffusion signals; and provide 
additional characterization of WM integrity, which are sensitive to slow-diffusive water pool: Kurtosis Anisotropy 
(KA) and Permeability-Diffusivity Index (PDI). These two measures are sensitive to exchange between axonal 
and extra axonal water-pools and thus are sensitive to the functional component of axonal diffusivity (42-44). 
 
Medical and Safety Assessments:  In the 2-week Evaluation Phase, all participants will receive a 
complete medical history and physical examination, including vital signs (blood pressure, heart and respiratory 

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rates, height and weight), and a nicotine use questionnaire. We will also collect baseline EKG; CBC; complete 
metabolic panel, (including electrolytes, BUN/Creatinine, LFTs, lipid panel, and TSH); U/A; expired CO, and 
Toxicology screen assessments. Female participants will have a pregnancy test during the Evaluation Phase 
and on each challenge test day. The Side Effect Checklist (SEC) is designed to assess medication side effects 
commonly associated with pharmacological treatments. The SEC version for the proposed study rates 32 
potential side effects, and comprehensively covers the side effects that have been previously reported with 
NAC and TRYP administration, i.e., nausea, vomiting, diarrhea, abdominal pain, dizziness, dysgeusia, rash 
with or without fever, and sedation. In addition, there are three “other” spaces for idiosyncratic participant 
complaints, which are not usually associated with medication treatment. We will use the self-rated Stanford 
Sleepiness Scale (SSS) to supplement our assessment of sedation (45). The SSS is a 7-point Likert scale.  
 
Study Procedures: Study Visit 1 will last about 3 hours, Study Visit 2 will last about 2 hours, and Visits 3 and 
4 each will each last about 7.75 hours for a total study participation time of 20.5 hours.  
Evaluation Phase (Visits 1 and 2): There will be a 2-week Evaluation Phase, during which potential 
participants will undergo baseline assessments to determine whether they meet inclusion criteria. Participants 
will be clinically stable, with clinical stability defined as two consecutive CGI ratings with no change in score.  
Challenge Phase (Visits 3 and 4): The Challenge Phase will utilize a double-blind, placebo-controlled, 
randomized cross-over design. A permuted block randomization system (block sizes 2 or 4) will be used to 
randomly assign participants to NAC, 140 mg/kg up to a maximum of 15 g, or placebo. There will be two 
Challenge Phase visits, which will be at least two weeks apart. On the day of each visit, participants will arrive 
at the MPRC Brief Stay Unit (BSU) at 7:15AM; all participants will have fasted since midnight. Participants are 
asked to avoid eating food of any kind after midnight the evening prior to visits 2 and 3. Participants are 
encouraged to drink water but to strictly avoid food, coffee, alcohol, and sodas. Participants who regularly use 
nicotine products will be given short breaks to use their products in order to avoid effects of nicotine 
withdrawal. The nicotine breaks will occur at least 60 minutes prior to the neuroimaging sessions in order to 
minimize the effect of nicotine on any of the neuroimaging measures. A heparin lock will be inserted for the 
repeated laboratory assessments and the initial clinical, cognitive, laboratory, and safety assessments will be 
conducted (including urine pregnancy test for female participants). Participants will then undergo their pre-
treatment imaging studies. Upon completion of the imaging studies, participants will receive NAC, 140 mg/kg 
up to a maximum of 15 g, or placebo. They will receive the other study medication on the second visit (i.e., 
placebo or NAC). The proposed NAC dose has been used extensively to treat acetaminophen poisoning. We 
selected this high dose based on our preclinical studies showing high doses inhibit KAT II. There is extensive 
safety data available with this dose. We selected the effervescent formulation to minimize gastrointestinal and 
other side effects. In addition, the effervescent formulation is flavored, which helps to increase the tolerability 
and to mask the smell typically associated with NAC (46). Thirty minutes after NAC/placebo administration 
participants will receive TRYP, 6 grams in oral slurry form. The dose was chosen based on previous work 
showing cognitive effects to be associated with doses above 5 grams (47) and our the preliminary data from 
our previous Conte Center project, in which we demonstrated that TRYP (6 grams) produces a robust increase 
in KYNA and kynurenine and reduction in the ASL measure of CBF in participants with schizophrenia and 
related disorders.  
Two hours after ingestion of NAC/placebo, participants will undergo the post-treatment imaging studies. 
We chose to begin scanning 120 minutes after NAC and 90 minutes after TRYP, because 1) our preclinical 
data show that NAC administered 30 minutes prior to TRYP administration attenuates KYNA production 
through KAT II inhibition; 2) our preliminary data suggests that peripheral kynurenine and KYNA levels are 
initially elevated 30 minutes after TRYP ingestion, and continue to increase over the next three hours and 
remain elevated for at least 3.5 hours; 3) NAC pharmacokinetic studies have demonstrated that peak serum 
levels occur within 90-150 minutes of administration and remain elevated for 4-6 hours (46,48); and 4) GSH, 
an indirect measure of NAC in the CNS, starts to elevate 50 minutes after NAC administration, reaches 
maximal elevation 90-110 minutes after oral NAC administration and remains elevated for at least 120 minutes 
(49). Thus, there should be sufficient time to complete the post-treatment MRI, clinical, laboratory, and 
cognitive assessments. A non-blind pharmacist will dispense all study medications. The blind will be broken 

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only if a medical emergency requires this information. If this occurs, the participant will be withdrawn from the 
study. The day after each challenge day, the RA will follow-up with the participant, via telephone, to evaluate 
whether there are any persistent effects from the receipt of the challenge medications. Any concerns of the 
participant will be reported immediately to the study physician. 
 
 
Procedures/Assessments 
Evaluation 
Phase 
(2 weeks) 
Challenge Visit 
#1: 
  
Challenge visit 
#2:  
Initials 
Informed Consent, Evaluation to Sign 
Consent 
X 
 
 
 
Medical Screening: 
Medical History, physical exam, blood 
draw, urinalysis, toxicology screen, 
pregnancy test (females), EKG, 
medication use screening, caffeine use 
screening, Birth Control Selection 
(females) 
X 
 
 
 
MRI screening 
X 
 
 
 
Clinical Stability Determination (for 
participants with schizophrenia or a 
related disorder only): 2 unchanged 
CGIs  
X 
 
 
 
Scheduling of challenge day visits  
X 
 
 
 
Participant arrival at Brief Stay Unit 
(BSU) 
Review of Study Procedures 
 
7:15 am 
7:15 am 
 
Urine pregnancy (females); expired 
CO**; urine toxicology and breath 
alcohol testing 
 
7:30 am 
7:30 am 
 
Insertion of heparin lock  
 
7:40 am 
7:40 am 
 
Vital signs, SEC, SSS; 
 
7:50 am 
7:50 am 
 

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Laboratory Assessments (1): kynurenine 
pathway metabolites, inflammatory 
markers, oxidative stress and other 
related markers  
Nicotine Break (1)* 
Protein Free Snack 
 
7:55 am 
7:55 am 
 
Cognitive Measures (1): MCCB 
measures: HVLT-R, BACS Symbol 
Coding, BVMT, CPT-IP, WMS®-III, LNS;  
 
8:00 am 
8:00 am 
 
Clinical Assessments (1): BPRS, SANS, 
CDS, CGI 
 
8:45 am 
8:45 am 
 
Neuroimaging Studies (1) 
 
9:15 am 
9:15 am 
 
Nicotine Break (2) 
 
10:30 am 
10:30 am 
 
Oral Administration of  
N-acetylcysteine (NAC) 140 mg/kg up to 
a maximum of 15gm or placebo 
 
10:35 am 
10:35 am 
 
Oral Administration of Tryptophan 6 
grams 
 
11:05 am 
11:05 am 
 
Lunch 
 
11:25 pm 
11:25 pm 
 
Vital signs, SEC, SSS  
Laboratory Assessments (2) 
 
12:05 pm 
12:05 pm 
 
Neuroimaging Studies (2) 
 
12:20 pm 
12:20 pm 
 
Laboratory Assessments (3) 
 
1:35pm 
1:35pm 
 
Protein Free Snack 
Nicotine break (3) 
 
 
 1:40 pm 
 1:40 pm 
 
Cognitive Measures (2) 
 
1:55 pm 
1:55 pm 
 

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*Nicotine breaks are optional and subject to occur at different times as long as they do not occur within 60 
minutes prior to the neuroimaging studies. 
 
**Due to the COVID-19 pandemic, the expired CO breathalyzer assessment is an optional procedure. 
 
 
Randomization and Blinding: This will be a double-blind, placebo-controlled, randomized cross-over 
challenge study. Participant randomization will use a permuted block randomization system (block sizes 2 or 
4), in which treatment assignment order is random within each block, with an equal number of participants 
assigned to each treatment, to generate a list of treatment assignments. Thus, it will be difficult to ascertain the 
next treatment assignment, even if a participant becomes unblinded, while any imbalance in the number of 
participants between the treatment groups will be kept within tight limits. All raters, investigators and other staff 
will be blind to treatment assignment except for the research pharmacist. The research pharmacist does not 
participate in assessing any of the primary symptom or side effect dependent variables and conveys no 
information about treatment assignment to participants or staff except in a medical emergency. 
 
Adherence: The NAC and placebo will be administered as dissolving tablets in a glass of 300 mL of water and 
the tryptophan will be given as a powder mixed with 150 mL of water. The participants will drink both mixtures 
in the presence of research staff.  
 
Participant Payment: Participants will receive $20 per hour and $100 for the completion of each challenge 
day, for a total of approximately $620. Participants will be paid by check, which may take up to 4-6 weeks to 
receive payment. 
 
Management of Data: Data collected for this study will be entered into the MPRC research data base using 
the usual procedures developed for MPRC clinical trials. This study will be reviewed UMB IRB and by a Data 
Safety Monitoring Board (DSMB).  
 
Data Analysis: Statistical analyses will be conducted using intent-to-treat analytic strategies. The overarching 
goal of our statistical approach is to identify the NAC versus placebo effects on measurements collected from 
 
Clinical Assessments (2) 
 
 
2:40 pm 
2:40 pm 
 
Vitals, SEC, SSS 
Laboratory Assessments (4) 
 
3:05 pm 
3:05 pm 
 
Participant discharged.  
If participant has not returned to pre- 
challenge baseline, they will be 
reassessed every 30 minutes until ready 
 
3:15 pm 
3:15 pm 
 

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various biomedical assays, including peripheral KYNA (Specific Aim #1), ASL-CBF (Specific Aim #2), DTI FA 
and MRS measures (Specific Aim #3). The multilevel mixed effect model will be used to examine the NAC 
effects, while accounting for the hierarchical random effects that 1) each participant will have two Challenge 
Phase visit days; and 2) on each day longitudinal and/or multivariate measurements will be recorded (e.g. 
KYNA will be measured at different time points); the multilevel mixed model is compatible with unbalanced 
measurements. Taking Specific Aim #1 for example, the model will be KYNA ~ Treatment + covariates + 
randomEff-day/time. Adjustments for multiple testing will be performed when necessary. When the variance 
and covariance matrix is difficult to compute, the hierarchical Bayesian model will be implemented for 
parameter estimation via Markov Chain Monte Carlo (MCMC) sampling. With a sample size of 100 participants 
and 20% attrition rate (i.e., 60 participants will complete the study), we will achieve power > 80% for all three 
specific aims. In Exploratory Aim 1, we will perform mediation analysis to examine the NAC effects on cognitive 
measures via the changes in the central nervous system (neuroimaging measures as mediators). In 
Exploratory Aim 2, we will evaluate whether the baseline KMO and/or KYNA levels can moderate the NAC 
effects on the measures described in Specific Aims 1-3 (50).  
    Specific Aim #1: Peripheral KYNA will be measured prior and after treatment on both Challenge 
Phase visit days (i.e., N-acetylcysteine (NAC) and placebo). We will denote the Challenge Phase visit day as 
d=1,2, and the multiple measurement times on each day by t=1,…, T for each participant i (i=1,…, 100). To 
test the hypothesis whether NAC compared to placebo blocks the peripheral conversion of kynurenine to 
KYNA, we will apply the multilevel mixed model to compare the changes of KYNA levels from baseline 
between the two treatment groups. The hierarchical random effects will include day and time points within a 
day. With a sample size of 100 participants and 20% attrition rate (i.e., 60 participants will complete the study), 
we will achieve power 80% to detect a small-medium effect size of Cohen’s d 0.37 at the alpha level 0.05. In 
our previous study, the effect size of peripheral KYNA change (tryptophan vs. placebo) is d= 4.77. Thus, we 
will have ample power to detect the difference. The covariates including age, sex, and others will be examined 
and adjusted when necessary.   
    Specific Aim #2: To examine whether NAC compared to placebo attenuates the effects of tryptophan 
on ASL CBF measures, we will apply the mixed model to compare the changes of ASL CBF levels from 
baseline between treatment and placebo. The primary ASL outcome measure will be whole brain gray matter 
CBF. If significant, then we will perform additional analyses to examine whether specific cortical regions show 
group differences. The multiple comparison correction will be performed for the voxel level and cluster level 
inference using permutation test-based strategy (51). With a sample size of 100 participants and 20% attrition 
rate (i.e., 60 participants will complete the study), we will achieve power 80% to detect a small-medium effect 
size of 0.37 at the alpha level 0.05. In our previous study, the effect size of ASL whole brain gray matter CBF 
(tryptophan vs. placebo) was Cohen’s d=0.48. Thus, we should have sufficient power to detect the difference. 
The covariates including age, sex, and others will be examined and adjusted when necessary. 
    Specific Aim #3: To examine whether NAC compared to placebo increases the whole brain white 
matter Kurtosis Anisotropy (KA) and Permeability-Diffusivity Index (PDI) and ERP interhemispheric transfer 
and MRS glutamate measures, we will apply the mixed model to compare the changes of FA, ERP 
interhemispheric transfer, and MRS glutamate levels from the baseline between treatment and placebo. With a 
sample size of size of 100 participants and 20% attrition rate (i.e., 60 participants will complete the study), we 
will achieve power 80% to detect a small-medium effect size of Cohen’s d 0.44 at the alpha level 0.0125 with 
the Bonferroni correction. If the whole brain white matter KA and PDI are significant, we will perform follow-up 
analyses to examine whether specific cortical white matter regions show group difference. The multiple 
comparison correction will be performed for the voxel level and cluster level inference using permutation test-
based strategy (51). 
To synchronize all aims, we will perform mediation and moderation analysis and causal inference to 
systematically investigate i) whether the attenuation of the effects of elevated KYNA can alter performance on 
the cognitive measures via changing the function, chemistry and/or structure of the central nervous system 
(CNS); and ii) whether the complete or partial mediation pathways can be modified by the baseline KMO and 
KYNA levels. Importantly, the carefully designed challenge study will provide a unique opportunity to construct 

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the causal relationship that changing the dynamics of kynurenine-related pathways by NAC and TRYP 
=>changes in CNS=>altered cognitive functions in people with schizophrenia (52).  
    In Exploratory Aim 1, we will perform mediation analysis to examine the NAC effects on cognitive 
measures via the changes in the central nervous system (i.e., neuroimaging measures as mediators). The 
mediation analysis will be performed using the procedures in VanderWeele (50), since multiple mediators will 
be analyzed. The multiplicity will be adjusted, and variable selection steps will be performed to construct the 
most parsimonious mediation models. In addition, the multivariate CNS measurements may be correlated and 
the covariance/dependence structure will be taken into account for statistical inference (53). The model 
validation (e.g. bootstrap procedure) will be performed to ensure the robustness and stability of the mediation 
model.  
    In Exploratory Aim 2, we will evaluate whether the baseline KYNA and/or KMO activity levels can 
moderate the NAC effects in the Specific Aims 1-3 and Exploratory Aim 1. For the measurements in the 
Specific Aims 1-3, the interaction term between baseline KYNA and/or KMO activity and NAC treatment will be 
tested for the moderation effect. To examine whether baseline KYNA and/or KMO activity moderate the 
mediation pathways in Exploratory Aim 1, the nonparametric statistical inference (e.g. permutation tests and 
bootstrap inference) will be used due to relatively small sample size for the complex mediation and moderation 
model. 
 
Potential Risks to the Participants:  
Risks Related to N-acetylcysteine: 
• 
Diarrhea. Somewhat likely and seriousness varies. If participants experience diarrhea they are free to 
end participation and may remain at the Research Center until they feel well enough to drive or 
someone can take them home. They will be instructed to drink fluids to remain hydrated.  
 
• 
Flatulence. Somewhat likely and not serious. If participants experience flatulence they are free to end 
participation and may remain at the Research Center until they feel well enough to drive or someone 
can take them home.  
 
• 
Nausea. Somewhat likely and not serious. If participants experience nausea they are free to end 
participation and may remain at the Research Center until they feel well enough to drive or someone 
can take them home.  
  
• 
Vomiting. Somewhat likely and seriousness varies. If participants experience vomiting they are free to 
end participation and may remain at the Research Center until they feel well enough to drive or 
someone can take them home. They will be instructed to drink fluids to remain hydrated.  
 
• 
Abdominal discomfort. Somewhat likely and not serious. If participants experience abdominal 
discomfort they are free to end participation and may remain at the Research Center until they feel well 
enough to drive or someone can take them home. 
 
• 
Dysguesia. Not likely and not serious. If participants experience a change in their sense of taste they 
are free to end participation in the study and stop taking the study medication.   
 
• 
Dizziness. Not likely and not serious. If participants experience dizziness they are free to end 
participation and may remain at the Research Center until they feel well enough to drive or someone 
can take them home. 
 

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• 
Rash (with or without fever). Not likely and not serious. If participants experience a rash, with or without 
fever, they are free to end participation and may remain at the Research Center until they feel well 
enough to drive or someone can take them home. 
 
Risks Related to Tryptophan: 
• 
Nausea, dyspepsia. Somewhat likely but not serious. In our previous experience with tryptophan, 
nausea was seen in 1 of 11 participants exposed to tryptophan. The participant vomited and then felt 
relief. If participants experience nausea they are free to end participation and may remain at the 
Research Center until they feel well enough to drive or someone can take them home.  
 
• 
Vomiting. Somewhat likely and seriousness varies. If participants experience vomiting they are free to 
end participation and may remain at the Research Center until they feel well enough to drive or 
someone can take them home. They will be instructed to drink fluids to remain hydrated.  
 
• 
Sleepiness. Somewhat likely and not serious. If participants experience sleepiness they are free to end 
participation and may remain at the Research Center until they feel well enough to drive or someone 
can take them home.  
 
• 
Transient exacerbation of cognitive impairment and/or exacerbation of schizophrenia symptoms. 
Expected, not serious. We hypothesize a small, transient decrease in cognitive testing scores or 
worsening of schizophrenia after participants receive tryptophan. This impairment is on the order of 
magnitude one would expect when sleepy or distracted and will not impact any routine functioning. All 
participants are evaluated by trained medical staff prior to discharge to confirm a return to baseline. Any 
persisting symptoms or abnormal vitals will be reported to the study physician who will determine 
whether the participant is safe to be discharged. A return to baseline before discharge will be recorded 
in the participant’s study documents.  
 
Blood Draw: 
• 
Infection or bruising at the blood draw site. Not likely, seriousness varied. The blood draw and IV 
catheter placement will be done by experienced nursing staff using universal precautions. 
 
MR Scanning: 
• 
Claustrophobia. Not likely, not serious. Participants will be screened prior to scanning. They can also 
abort the scanning procedure by squeezing a rubber signal ball. Research staff will be in 
communication with participants throughout the scanning. 
 
• 
Thermal injury. Not likely, possibly serious. Participants will be screened prior to scanning for MR-
incompatable materials.  
 
• 
Backache. Somewhat likely, not serious. Participants who experience backache while lying in the 
scanner may abort the scanning procedure at any time.  
 
• 
Temporary decrease in hearing after MRI. Not likely, not serious. The loud noises of the MRI machine 
may be loud enough to damage one’s hearing. Participants will be fitted with ear plugs and/or 
headphones to reduce this risk. Participants may abort the scanning procedure at any time if they feel 
uncomfortable with the noise level.  
 

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• 
Nausea and vomiting. There may be a slight risk from taking the study compounds. If vomiting occurs 
inside the scanner, there is a risk of choking and that can be dangerous. Participants will be instructed 
to inform research staff if they feel nauseous before the scanning or anytime during the scan. 
 
 
 Miscellaneous: 
• 
Boredom, Frustration. Somewhat likely, not serious. Participants may become bored or frustrated with 
interviews or testing. Participants may take breaks or end interviews/testing at any time- however, 
doing so may interfere with completion of the study and lead to early termination of participation. 
 
• 
Loss of Confidentiality. Unlikely, potentially serious. All research participation carries the risk of loss of 
confidentiality. This is minimized by the research protocol's protections for participant data.  
 
Adequacy of Protection against Risks: We will make every attempt to minimize all study-related risks. We 
will carefully monitor patients and psychiatric symptoms throughout the study 
 
Confidentiality: Careful procedures will be used to protect the privacy of participants and the confidentiality of 
the data.  Names will only appear on consent forms and on a master list that links them with study ID numbers 
(different from medical record numbers). This list will be stored in locked files in a separate location from the 
data.  At the conclusion of the project, the list will be destroyed, unless continuation is planned and approved 
by the Institutional Review Board. All data (whether on forms or electronic data files) will be collected, 
analyzed, and reported according to the study ID number and will contain no names or other personal 
identifiers. Paper-based data will be stored in locked files. Electronic data files reside on desktop computers 
and are password protected. 
 
 
Consenting: Potential participants will be identified through chart review or nomination by the treatment team. 
No participant will be approached for recruitment without approval of a primary clinician, who will determine 
suitability of the person for the protocol. A chart review will be completed for all nominated potential 
participants to reduce the likelihood that participants will be found ineligible after participating in more extensive 
assessment. The study interviewer will verify with the primary clinician that a potential participant is sufficiently 
stabilized to consider participation and has capacity to provide consent. This is done prior to the study 
interviewer approaching a potential participant. The study interviewer will be introduced to the potential 
participant and provide a brief overview of the project.  
Research staff members are trained to recognize symptoms of severe mental illness and cognitive 
impairment that could undermine an individual's ability to provide informed consent. Interested participants will 
be provided study information and an informed consent form that contains all pertinent details of participation. 
As some potential participants will have poor reading skills, the consent form will be read aloud in tandem with 
their own silent reading of the document. Our research staff are carefully trained on obtaining consent from and 
interacting with people with seriously mentally illness and supervised by senior staff members. The individual 
securing consent will review any points about which the participant is unclear, and the participant will be invited 
to ask questions as needed. All participants who express willingness to provide consent will be queried about 
each paragraph of the agreement in order to ensure that they have adequate understanding of what they are 
agreeing to. Research staff are trained in strategies for interacting with people with severe mental illness, 
including speaking slowly and clearly, stopping to summarize frequently, and providing time for questions.  
After reading the consent, and before obtaining a signature, a brief questionnaire, the Evaluation to 
Sign Consent (ESC), is administered to verify that the subject is competent to provide consent and has 
demonstrated comprehension of the consent document. The recruiter will also make a clinical judgment and 
not recruit participants who appear unable to grasp key aspects of the procedure. This approach, which 
requires a proactive demonstration on the part of the participant that they understand what is being requested, 

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has been used extensively at our sites. Per IRB regulations, a copy of the signed consent form is given to the 
participant, a copy is placed in the participant's medical record, and the original is kept in the laboratory. 
Research assistants obtaining informed consent will be experienced clinicians. They will receive detailed and 
standardized training as to how to obtain informed consent from people with severe mental illness. They will be 
observed obtaining informed consent from a potential participant by senior staff prior to being allowed to recruit 
on their own. Prior to signing the consent form, participants will be informed that participation in the study is 
contingent upon their meeting diagnostic criteria as determined in the clinical interview. All discussions with 
potential study participants will take place in a private room behind closed doors. 
 
Potential Benefits of the Proposed Research to Participants and Others: By participating in this study 
there is no direct benefit to the study for the participant. However, we may improve understanding of illnesses 
that affect thinking and memory, and help physicians care for patients with such problems. 
 
 
Importance of the Knowledge to be Gained: People with schizophrenia are characterized by marked 
cognitive impairments, which are major determinants of poor functional outcome in schizophrenia (54,55). 
Unfortunately, first and second generation antipsychotics have limited benefits for cognitive impairments 
(56,57), and studies of add-on pharmacological agents for the treatment of cognitive impairments have been 
largely disappointing to date (58-63). Cognitive remediation and other non-pharmacological strategies have 
shown some promise, but the observed beneficial effects rarely generalize beyond the measures included in 
the training exercises (64). In the absence of an effective treatment, cognitive impairments remain a critical 
unmet therapeutic need, and the demonstration that inhibition of KAT II leads to improved brain and cognitive 
function would represent a critically important development in the therapeutics of this disorder.  
Our project is uniquely based on an emerging body of evidence, which suggests that disturbances in 
the kynurenine pathway, especially those that lead to increased levels of KYNA, may be of critical importance 
in the pathophysiology of cognitive impairments in schizophrenia. Second, the proposed study is the first 
experimental test of brain and behavioral effects of KAT II inhibition in human subjects. The results from the 
study would provide unique insights into the mechanisms underlying the role of KYNA in the pathophysiology 
of schizophrenia. Third, although the use of NAC is not innovative, the hypotheses that: i) NAC may work 
through its ability to inhibit KAT II; ii) there may be large effects in a subgroup of people with schizophrenia, 
i.e., those characterized by high serum KYNA levels or low KMO activity; and iii) the use of high NAC doses 
(>5 times other clinical studies) are innovative. Fourth, in order to provide a comprehensive evaluation of the 
effects of NAC on various KYNA related manifestations of the illness, we will use a multi-dimensional 
evaluation of the effects of NAC on KYNA production in schizophrenia, which will include behavioral, 
biochemical, neuroimaging, and phenomenological assessments. Fifth, the parallel assessments across the 
two preclinical studies and two clinical studies will provide a framework to bi-directionally inform the 
interpretation of the results of these studies. The ability to translate the results across each of the proposed 
studies is critically important for the proposed Center. Finally, the demonstration that NAC blocks the impact of 
increased KYNA levels in people with schizophrenia will importantly support the development of KAT II 
inhibitors for the enhancement of cognition in schizophrenia.

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