Proof of Mechanism Study Using a Retinal Biomarker to Predict Treatment Response With Intravenous Sodium Nitroprusside in Symptomatic Early Course Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: Beth Israel Deaconess Medical Center

NCT Number:  
NCT04986072 
Official Title: 
Sodium Nitroprusside in Early Course Schizophrenia 
Document Type: 
Study Protocol and SAP 
Document Date: 
07/17/2023 

(CCI) Committee on Clinical Investigations
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
PART B
STUDY DESCRIPTION
B1.
PURPOSE OF PROTOCOL
B2.
SIGNIFICANCE AND BACKGROUND FOR THE STUDY
Title of Protocol
Proof of Mechanism Study using a Retinal Biomarker to Predict
Treatment Response with Intravenous Sodium Nitroprusside in
Symptomatic Early Course Schizophrenia
Principal Investigator
Paulo Lizano
1.
The main purpose of this proposal is to determine the effectiveness of a single intravenous
administration of sodium nitroprusside (SNP) (0.5 mcg/kg/min for 4 hours) on positive and
negative symptoms in symptomatic Early Course Schizophrenia (ECS). 
2.
To examine the effect of SNP on cognition and retinal imaging phenotypes in
ECS, and whether baseline retinal microvasculature or inflammation (CRP levels) correlate
with a change in psychosis symptoms or cognition.
We hypothesize that SNP will improve psychosis symptoms and cognition in symptomatic ECS and
that this change can be predicted by retinal vessel morphology or CRP levels. We predict that SNP
will improve oxygen supply and reduce inflammation, which will be evidenced by reductions in
retinal vessel phenotypes.
Background: Despite decades of research, little clarity exists regarding the pathogenic
mechanisms of schizophrenia (SZ). Since the microvascular environment is the chief interface for
systemic factors influencing the brain1, it is a logical focus for understanding SZ neurobiology.
Altered microvasculature is central to the pathophysiology of many CNS disorders1, but it has
received less attention in SZ2. However, our understanding of the immunological underpinnings of
SZ, and enhanced methodologies for detecting microvascular impairment, have led to increased
research in this area2. We showed that inflammatory subtypes exist in psychosis and that an
increased pattern of peripheral inflammation (including C-Reactive Protein, CRP) displayed worse
overall cognition and elevated subcortical and neocortical gray matter thickening compared to
those with low inflammation-mediated microvascular injury3. Since retinal and cerebral
microvessels share embryological origins and are homologous in structure/function, the former can
be used to gauge the condition of cerebral microvessels4, including the detrimental effects of
increased peripheral inflammation on retinal microvascular changes in psychiatric disorders5.
Retinal arteriolar and venular diameter are commonly studied in relation to cerebrovascular disease
and advances in retinal imaging and image analysis now allow for the accurate quantitative
assessment of the condition of retinal microvessels, including diameter, length, density, and
capillary network6.
In a population-based birth cohort study using fundus imaging to assess retinal arteriolar and
venular diameter, Meier et al, (2013) found that individuals who later developed SZ had significantly
wider retinal venules compared to other medical groups, and that wider venules were associated
with adult and childhood symptoms of psychosis7. Meier’s findings were replicated in a longitudinal
twin eye study where individuals with >1 symptom of psychosis had wider retinal venules than
controls, and unaffected co-twins had intermediate values4. These findings support the view that
retinal venular diameter could be used as a prognostic and/or endophenotypic biomarker that can
bridge the gap between underlying neurobiological mechanisms and phenotypic expression of
psychosis6,8,9. In a patient with 22q11 deletion syndrome, a genetic disorder associated with a 30x

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
increase SZ risk, ocular examination identified bilateral retinal vascular tortuosity10. In a cross-
sectional study, Appaji et al, (2019) demonstrated that patients with SZ had significantly increased
retinal venules11, tortuosity12, capillary network13, and vessel trajectory14 compared to controls, with
retinal vessel diameter being associated with cognitive deficits in SZ15. While these findings have
laid the foundation for understanding retinal pathology in SZ, there are several limitations
associated with fundus imaging, including reduced image resolution and absence of retinal depth
determination. Advances in retinal imaging, such as swept-source optical coherence tomography
angiography (SS-OCTA), provide greater microvascular clarity to visualize the retina non-invasively,
in a more detailed, quicker, and cost-effective manner. In a pilot study using SS-OCTA, we
identified greater vessel length (SD), density (VD), capillary network (FD), and diameter (VDI) in the
superficial layer of patients with chronic psychosis compared to HC5.
The pathophysiological mechanisms underlying these retinal microvascular changes are not
entirely understood, but they have been associated with inflammation (including CRP), endothelial
dysfunction, reactive oxygen species and hypoxia/ischemia, which have also been consistently
observed in SZ. While it is currently unclear whether venular diameter plays a causal role in the
development of SZ, it has been hypothesized that smaller retinal arterioles and wider venules may
reflect cumulative structural damage to the microvasculature from inflammation/endothelial
dysfunction and indicate problems with the oxygen supply to the brain.
Nitric oxide (NO) signaling is a potential mechanism for protecting the microvasculature against
oxidative stress, inflammation and endothelial dysfunction16. NO-donors (NOD) can protect nerve
tissue from injury and preserve the integrity of the blood brain barrier, suggesting that cerebral
vascular endothelium is essential in the control of vascular inflammatory and oxidative responses,
leukocyte migration, and the production of inflammatory mediators1. In addition to reducing
oxidative stress and inflammation, NOD can increase cerebral and retinal blood flow16. In healthy
volunteers, SNP dose dependently increases retinal arteriolar/venular diameter, and leukocyte
flow17. However, in pathologic states such as ischemia, SNP can enhance neuroprotection by
increasing arteriolar diameter and reducing venular leukocyte adhesion (i.e., reduced venular
diameter), which together facilitate blood flow16. Preclinical and clinical evidence have shown that
SNP may have an antipsychotic profile. In preclinical studies, SNP has been used to prevent SZ-
related behaviors in a spontaneously hypertensive rat model18. Five clinical studies to date have
examined the effects of SNP on psychosis symptom improvement with mixed results. In one study,
a single infusion of SNP resulted in an immediate improvement in overall psychosis and negative
symptoms in an antipsychotic medicated ECS group with <5 years illness duration, an effect that
persisted for 4 weeks19. However, four studies performed in chronic SZ did not find any evidence of
symptomatic improvements, with two of these studies providing repeated infusions of SNP20–23.
There were several limitations with these negative studies: older patient population, longer
durations of illness (8-17 years), and the absence of a treatment biomarkers. These studies
neglected to consider an alternative mechanism of action for SNP, which would include the
protection against inflammatory mediated microvascular dysfunction. Another important factor to
consider is that while ~70 randomized control trials to date have examined adjunctive anti-
inflammatory drugs on psychosis symptoms or cognition in SZ24, six of these have performed post
hoc analyses of participants with elevated levels of individual inflammatory markers (such as CRP),
and their findings strongly suggest that ECS individuals with elevated peripheral inflammation have
the greatest benefit with anti-inflammatory drugs24. Thus, it is conceivable that treatment effects
could be stronger in participants with elevated markers of inflammation or disruptions in related
pathways. As a result, in order to SNP to be effective it should be administered to patients with
ECS. Thus, further work is needed to determine whether the effect of SNP treatment is dependent
on a patient’s illness duration and whether a retinal biomarker for microvascular
dysfunction/inflammation can predict treatment response to SNP. 
There is a growing literature on how increased peripheral inflammation and
microvascular dysfunction are central to the pathophysiology of SZ. Advances in retinal imaging

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
now allow for the accurate quantitative assessment of the condition of retinal microvessels, and
early studies implicate microvascular dysfunction in SZ, but the specific pathophysiological
mechanisms underlying greater length, density, capillary network, and diameter are not yet
entirely understood. A potential target is NO signaling, which is involved in vessel protection
from oxidative stress, inflammation and endothelial dysfunction, and treatment with NOD have
been shown to reduce oxidative stress/inflammation and to increase cerebral blood flow in
cerebrovascular disorders. Anti-inflammatory drug trials in SZ suggest that ECS individuals with
elevated peripheral inflammation show the greatest benefit to adjunctive anti-inflammatory
treatments. Also, there is a growing interest in the use of SNP in SZ and studies to date have
been mixed. Hallak et al (2013) demonstrated that a single infusion of SNP in patients with ECS
was both safe and associated with immediate and longer-term clinical outcome. While three
other studies demonstrated that SNP was well-tolerated in patient with multi-episode SZ, they
were not able to replicate Hallak’s finding, which was likely due to the disease heterogeneity, the
inclusion of an older population with a longer duration or multi-episodes of illness, and the lack
of treatment biomarkers. Thus, the principal goal in the field of SZ is to identify biomarker-based
targets for early intervention, evidence of engaging this target by selective interventions and
assessing therapeutic efficacy25.  
References:
1. Abbott, N. J. Anatomy and Physiology of the Blood–Brain Barriers. in Drug Delivery to the Brain
(eds. Hammarlund-Udenaes, M., de Lange, E. C. M. & Thorne, R. G.)  vol. 10 3–21 (Springer
New York, 2014). 
2. Pong, S., Karmacharya, R., Sofman, M., Bishop, J. R. & Lizano, P. The Role of Brain
Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia.
Complex Psychiatry 6, 30–46 (2020). 
3. Lizano, P. et al. Multivariate relationships between peripheral inflammatory marker subtypes
and cognitive and brain structural measures in psychosis. Mol.  Psychiatry (2020)
doi:10.1038/s41380-020-00914-0. 
4. Meier, M. H. et al. Retinal microvessels reflect familial vulnerability to psychotic symptoms: A
comparison of twins discordant for psychotic symptoms and controls.  Schizophr. Res. 164, 47–
52 (2015). 
5. Sekeryapan Gediz, B., Ozturk, M., Kilinc Hekimsoy, H., Yuksel, E. G. & Ozdamar Erol, Y.
Choroidal Vascularity Index as a Potential Inflammatory Biomarker for Obsessive
Compulsive Disorder. Ocul. Immunol. Inflamm. 1–5 (2020)
doi:10.1080/09273948.2020.1800052. 
6. Adhan, I., Bannai, D. & Lizano, P. Commentary: Can retinal imaging biomarkers
inform psychosis pathophysiology? Schizophr. Res. 215, 3–5 (2020).
7. Meier, M. H. et al. Microvascular Abnormality in Schizophrenia as Shown by Retinal
Imaging. Am. J. Psychiatry 170, 1451–1459 (2013).
8. Bannai, D. & Lizano, P. Identifying retinal layer endophenotypes for schizophrenia.
Schizophr. Res. 220, 25–26 (2020). 
9. Lizano, P. et al. A Meta-analysis of Retinal Cytoarchitectural Abnormalities in Schizophrenia and
Bipolar Disorder. Schizophr. Bull. 46, 43–53 (2020).
10. De Niro, J. E., Randhawa, S. & McDonald, H. R. RETINAL VASCULAR TORTUOSITY IN
DIGEORGE SYNDROME COMPLICATED BY SOLAR RETINOPATHY: Retin. Cases Brief Rep.
1 (2013) doi: 10.1097/ICB.0b013e3182919cb2. 
11. Appaji, A. et al. Retinal vascular abnormalities in schizophrenia and bipolar disorder:
A window to the brain. Bipolar Disord. 21, 634–641 (2019).
12. Appaji, A. Et al. Retinal vascular tortuosity in schizophrenia and bipolar disorder.
Schizophr. Res. 212, 26–32 (2019). 

(CCI) Committee on Clinical Investigations
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B3.
DESCRIPTION OF RESEARCH PROTOCOL
A.
Study Design – Overview, Methods, Procedures
13. Appaji, A. Et al. Retinal vascular fractal dimension in bipolar disorder and schizophrenia. J.
Affect. Disord. 259, 98–103 (2019).
14. Appaji, A. et al. Examination of retinal vascular trajectory in schizophrenia and bipolar disorder.
Psychiatry Clin. Neurosci. 73, 738–744 (2019).
15. Appaji, A. et al. Relation between retinal vascular abnormalities and working memory
impairment in patients with schizophrenia and bipolar disorder. Asian J.  Psychiatry 49, 101942
(2020). 
16. Donati, G., Pournaras, C. J. & Tsacopoulos, M. Effect of nitroprusside on arteriolar constriction
after retinal branch vein occlusion. Invest. Ophthalmol. Vis. Sci. 39, 1910–1917 (1998). 
17. Polak, K. Evaluation of the Zeiss retinal vessel analyser. Br. J. Ophthalmol. 84, 1285–1290
(2000). 
18. Diana, M. C. et al. Sodium nitroprusside is effective in preventing and/or reversing the
development of schizophrenia-related behaviors in an animal model: The SHR strain. CNS
Neurosci. Ther. 24, 624–632 (2018). 
19. Hallak, J. E. C. et al. Rapid Improvement of Acute Schizophrenia Symptoms After
Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo Controlled Trial.
JAMA Psychiatry 70, 668 (2013). 
20. Stone, J. M. et al. The effect of sodium nitroprusside on psychotic symptoms and spatial
working memory in patients with schizophrenia: a randomized, double blind, placebo-controlled
trial. Psychol. Med. 46, 3443–3450 (2016). 
21. Wang, X. et al. Sodium nitroprusside treatment for psychotic symptoms and cognitive deficits of
schizophrenia: A randomized, double-blind, placebo-controlled trial. Psychiatry Res. 269, 271–
277 (2018). 
22. Brown, H. E. et al. Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside
Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry
76, 691 (2019). 
23. Adelino MPM, Nunes MV, Nunes MFQ, Costa ER Jr, Ajub E, Mitrovitch MPB, Ushirohira JM,
Quarantini LC, Hallak JCE, Lacerda ALT. Treatment-resistant schizophrenia - A RCT on the
effectiveness of repeated-dose sodium nitroprusside. Schizophr Res. 2021 May; 231:70-72.
24. Kroken, R. A., Sommer, I. E., Steen, V. M., Dieset, I. & Johnsen, E. Constructing the
Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review
Translating Descriptives into Diagnostics. Front. Psychiatry 9, 753 (2019). 
25. Insel, T. R. The NIMH experimental medicine initiative. World Psychiatry 14, 151–153 (2015).
Study Design
This is a 4-week, single-center, double-blind, randomized, parallel-group, placebo-controlled
pilot trial of SNP in symptomatic ECS patients.
Participants who meet eligibility criteria and are taking antipsychotics for 8 weeks with a stable dose
of 4 weeks, will be randomized using a block design to either the SNP or placebo arm. A
randomization identifier taking into account gender and race will be generated for each participant
and this identifier will be accessible to the site pharmacy to prepare the corresponding infusion
treatment.
Follow up visits (1st week, 2nd week, 4th week)
Patients will be observed for 28 days. All participants should complete their follow-up study visits,
including efficacy assessments, safety assessments, vital sign assessments, and blood collection.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
Clinical evaluation: A detailed medical history will be obtained by the PI (Dr. Lizano) or Co-I (Dr.
Berg). This will include information regarding the subjects’ full history of medical and psychiatric
conditions, diagnoses, procedures, treatments, demographic information, and any other noteworthy
medical information, including suicidality, with dates of start and finish. This information will be
collected either in person or virtually. Any updates to medical history information that the PI or
designee becomes aware of will be captured throughout the study. The PI’s will perform the
physical examinations (PEs) as indicated in the Schedule of Events (SOE). A complete PE,
including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, heart,
abdomen, lymph nodes, extremities, and general appearance. The physical examination will not
include a pelvic, breast, or rectal examination. A neurological examination will also be performed,
which includes mental status, cranial nerves, strength, sensation, deep tendon reflexes, and
coordination.
Vital Signs: Evaluation of vital signs will be performed by qualified site personnel after the subject
has been supine for 5 minutes and will include a measurement of systolic and diastolic blood
pressure, pulse rate, oral temperature, and respiratory rate. Systolic and diastolic blood pressure
should be then measured from supine to standing to assess orthostatic hypotension. Subjects will
be asked about lightheaded or dizzy, blurry vision, weakness, syncope, confusion, or nausea why
performing orthostatic vital signs. Vital sign measurements will be obtained at the time points
indicated in the study flow chart and following the supine ECG assessments, if taken at the same
time. Blood pressure should be taken on the same arm throughout the study.
Anthropometric Measurements: Weight (kg) (assessed in ordinary indoor clothing with shoes off)
will be recorded at the time points indicated in the flow chart. Height (cm) will be recorded at Visit 1
(screening) only. Body Mass Index (BMI) will be calculated at all visits in which anthropometrics are
collected. Waist circumference will be measured to the nearest 0.1 cm.
Laboratory Procedures: Screening blood work will be fasting, and blood work taken as part of the
study treatment monitoring process will be non-fasting as a precautionary measure to reduce the
risk of a hypotensive episode.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
Routine laboratory panels will include (see Section C below for exclusionary laboratory criteria):
•
Hematology (absolute and percentage): White blood cell (WBC) count with differential
(absolute neutrophil count, lymphocytes, monocytes, basophils, and eosinophils), red blood
cell (RBC) count, hemoglobin (Hgb), hematocrit (Hct), and platelet count.
•
Comprehensive Metabolic Panel: Glucose, sodium, potassium, calcium, chloride, carbon
dioxide, blood urea nitrogen (BUN), creatinine, calculated glomerular filtration rate, uric acid,
phosphorus, magnesium, total protein, albumin, lipid panel (triglycerides, total cholesterol,
HDL-cholesterol, calculated LDL-cholesterol) aspartate amino transferase (AST), alanine
amino transferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase
(GGT), total bilirubin, creatine phosphokinase (CPK), creatine kinase (CK) thyroid
stimulating hormone (TSH) and uric Acid, and C-Reactive Protein (CRP).
•
Serum Pregnancy: Serum beta human chorionic gonadotropin (Beta- hCG).
•
Urinalysis: color, appearance, specific gravity, pH, ketones, protein, glucose, nitrite,
leukocyte esterase, and occult blood; microscopic examination of sediment will be
performed only if the results of the urinalysis evaluation are positive (microscopic
examination may include but is not limited to WBC count, red blood cell (RBC) count, casts,
and crystals).
•
Urine drug screen: cannabis, opioids, cocaine, amphetamines, methadone, cannabinoids,
barbiturates, benzodiazepines, methamphetamine, and phencyclidine.
•
Urine Pregnancy Test: urine pregnancy test will be performed in female subjects of
childbearing potential using a dipstick urine test.
12-Lead Electrocardiogram (ECG): A 12-lead ECG will be taken at following a supine rest for 5
minutes. ECG parameters including the QT interval, Bazett’s corrected QT interval (QTcB), and
QTcF Fridericia’s corrected QT interval (QTcF), pulse rate (PR), and QRS intervals, and heart rate
will be recorded. The ECGs will be reviewed by the Co-I to assess any immediate abnormalities.
Efficacy Measures: Symptoms will be assessed with the Positive and Negative Syndrome Scale
and antipsychotic use with chlorpromazine (CPZ) equivalents. Global severity of illness will be
assessed using the Clinician Global Impression severity scale (CGI-S). Clinical information will be
collected using electronic forms when possible and they will be de-identified and maintained on
Beth Israel Deaconess Medical Center (BIDMC) servers. IQ will be estimated with the Wechsler
Abbreviated Scale of Intelligence. Cognition will be assessed with the Brief Assessment of
Cognition in Schizophrenia (BACS). BACS is available electronically and can be performed on a
tablet to assess cognition and a participant’s information will remain de-identified on BIDMC
servers. Social functioning will be assessed with the global and social functioning scales, and
nicotine dependence with the Fagerstrom Test for Nicotine Dependence.
Safety Measures:
The Systematic Assessment for Treatment Emergent Effects–Systematic Inquiry
(SAFTEE-SI) is a self-rated questionnaire assessing possible adverse events during the course of
the trial. The time frame is the past 7 days. The abnormal Involuntary Movement Scale (AIMS) is a
12-item scoring tool that is commonly used to monitor the occurrence and severity of tardive
dyskinesia for patients receiving neuroleptic medications. In this study, the highest severity
observed for each item on the AIMS scoring sheet will be recorded. For movements that occur
upon activation, one severity grade less than the spontaneously observed movement will be
selected for the item. The Columbia Suicide Severity Rating Scale (C-SSRS) is a low-burden
measure of the spectrum of suicidal ideation and behavior that was developed in the National
Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and
track suicidal events through any treatment. It is a clinical interview providing a summary of both

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Study Description – Part B
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PI Revision Date:7/17/23
ideation and behavior that can be administered during any evaluation or risk assessment to identify
the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor
for clinical worsening. The C-SSRS will be performed to assess suicidal ideation and behavior.
SS-OCTA: Images will be obtained using the Zeiss PLEX Elite 9000, which is a quick, inexpensive,
and non-invasive method for acquiring retinal images with an axial resolution of ~5μm and a scan
depth of 3.0mm. Automated layer segmentation provides four horizontal depth-resolved retinal
slabs: superficial (SRL), deep (DRL), outer retinal layer (ORL) and the choriocapillaris. Participant
images will be excluded for low signal strength (≤6), blink artifacts, doubling artifacts, media opacity
obscuring visualization of the vasculature, and/or segmentation errors. Manual segmentation
editing will be conducted to ensure proper layer assessment. Microvessels for the SRL, DRL, and
choriocapillaris slab will be processed using a custom semiautomated algorithm we developed to
rapidly quantify several vessel parameters including vessel density, length, diameter, and capillary
network. All images will be independently analyzed and compared among study subjects by two
graders blinded to the group assignment.
Outcome: Primary outcomes include the change in PANSS positive and negative scores (2hrs,
5hrs, 1wk, 2wk, and 4wks) in the SNP group compared to placebo. The secondary outcomes
include the change in overall cognition (0hr, 1wk, 2wk, and 4wks) and retinal microvascular
measures (0hr, 5hrs), as well as examining the relationship between baseline or change in retinal
vessel measures or CRP and the change in psychosis symptoms and cognition after SNP
treatment compared to placebo.
SNP Treatment Protocol
The BIDMC IV DRUG ADMINISTRATION GUIDELINE for clinical use of Nitroprusside Sodium
(Nipride®) recommends use of this drug in the ICU setting. We are proposing the use of
intravenous (IV) SNP for a research study in stable (not hospitalized) patients with early course
schizophrenia (Clinical Trials.gov registry: NCT04986072; IND Exemption approved on 8/31/2021).
Per our discussions with Critical Care leadership (Drs. Molly Hayes and Michael Cocchi), there are
limited intensive care unit (ICU) beds available for research subjects who aren’t already admitted to
the ICU. It is important to note that five prior clinical trials of SNP in similar populations have also
been conducted in non-ICU settings with no adverse effects reported1–5. For these reasons, we are
proposing that the SNP study in early course schizophrenia take place in the Clinical Research
Center (CRC) at BIDMC. We have received approval from the Critical Care Executive and Critical
Care Practice Committees for execution of the protocol in the CRC at BIDMC (please see
attached approval letters).
Paulo Lizano, MD, PhD (Neuropsychiatrist, clinical investigator, and Assistant Professor of
Psychiatry at BIDMC/HMS) is the PI for this study. Dr. Lizano will conduct efficacy and safety
assessments, perform medical reviews, recommend medical clearance for study inclusion, and
conduct assessments prior to discharge. Dr. Lizano will be available at the CRC through the study
visit.
Katherine Berg MD, (Pulmonary and Critical Care Physician, clinical investigator, and Assistant
Professor of Medicine at BIDMC/HMS) is the co-investigator, has prior experience with
administering SNP, and will be the physician of record for the study. Dr. Berg will provide oversight
of medical clearance, ordering the study drug, and responding to clinical issues during the study
visit. Dr. Berg will be available before, during, and after the SNP infusion. Specifically, Dr. Berg will
be present in the CRC 30 minutes prior to SNP infusion and 30 minutes after the initiation of SNP.
Dr. Berg will be available on the East Campus of BIDMC after stable titration of SNP, in close to
proximity to the CRC.
The BIDMC CRC is prepared to support this study and has the appropriate resources to conduct
the study, including 1:1 ACLS/BLS certified nursing. CRC nursing staff involved with the study will

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Study Description – Part B
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PI Revision Date:7/17/23
undergo training by critical care nursing to be able to safely administer nitroprusside in the CRC.
The CRC is equipped with an Omnicell and can be stocked with rescue medications needed for the
study. The CRC has the capability to conduct continuous monitoring of heart rate, blood pressure,
pulse oximetry and telemetry (see attached support letter from the CRC).
The CRC and the PI and co-investigators are prepared to ensure that this study protocol is
conducted safely outside of an ICU setting, and an outline of the protocol, including procedures for
study drug administration and monitoring, is as follows:
Patient Selection
Medically Relevant Exclusion Criteria:
•
Presence of renal, hepatic, cardiac, hematologic, neurologic (seizures or elevated
intracranial pressure) impairments.
•
Pregnant or breastfeeding. Women of childbearing potential must have a negative
pregnancy test performed at the screening visit prior to the baseline assessment and
randomization.
•
Physical exam suggestive of an underlying disease state that may, in the opinion of the
investigators, confound the results of study, increase risk to the subject or lead to difficulty
complying with the protocol.
•
Baseline systolic BP <100mmHg or symptomatic orthostatic hypotension (systolic BP <90
mmHg or diastolic BP <60 mmHg with any of the following: lightheaded or dizzy, blurry
vision, weakness, syncope, confusion, nausea).
•
Abnormal laboratory testing (see appendix)
•
Medications that interfere with the metabolism or excretion of nitroprusside or are
associated with drug-drug interactions (see appendix below)
•
Medications that could pose a significant risk to the participants’ health
•
Hypersensitivity to SNP
•
Currently taking clozapine or chlorpromazine
•
Subjects with a current (within the last 3 months) DSM-V diagnosis of alcohol or substance
use disorder or dependence (excluding nicotine) at the screening visit
•
Has tested positive for any of the following: cannabis, opioids, cocaine, amphetamines,
barbiturates methadone, methamphetamine and phencyclidine at the screening or baseline
visits.
•
Subjects at imminent risk of suicide or injury to self or others or history of significant suicide
attempt within the last 12 months.
Screening Pre-infusion Visit
Visits will consist of informed consent signing, inclusion/exclusion criteria review, medical record
review, and psychiatric diagnostic assessments. Some of these assessments will be performed
virtually. Medical clearance will also be performed and includes a review of concomitant
medications, urine pregnancy and drug testing, blood collection for laboratory testing,
electrocardiogram, and vital sign monitoring. Safety measures will also be performed, and they
include the SAFTEE-SI, AIMS, and C-SSR.
Protocol for Nitroprusside Infusion
Protocol created with reference to BIDMCs Nitroprusside IV Drug Administration Guideline
(Approved by Critical Care Practice, Critical Care Exec, Pharmacy and Therapeutics Committee on
December 2005 and revised in February 2019) with amendments from the CRC and Dr. Berg, as
well as from the Critical Care Practice and Critical Care Executive Committees.
Scheduling:
•
Participants will be scheduled for the single SNP infusion when CRC staff and PIs (Dr. Berg
and Dr. Lizano) are all available on site

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Study Description – Part B
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PI Revision Date:7/17/23
•
We will follow BIDMC guidelines, as well as our study staff and CRC recommendations for
decision on pausing the study due to COVID19 restrictions
Infusion Monitoring:
•
Pre-infusion orders
•
Semi-recumbent position, IV-line placement, Volumetric pump with a carrier line
•
nicotine patch [if appropriate, see cigarettes per day (cpd) break down below]
•
if 15 cpd: 21 mg patch
•
if 8-15 cpd: 14 mg patch
•
if 5-8 cpd: 7 mg patch
•
if <5 cpd: PRN nicotine gum or lozenges 2 mg (1 piece every 3-4 hours)
•
12-lead EKG
•
Pre-infusion (60 mins before)
•
During (30 mins after start of infusion)
•
Post-infusion (60 after end of infusion)
•
VS (BP, HR, O2 sat)
•
Pre-infusion (baseline)
•
During
•
Phase I (q5 Xs 10 mins)
•
Phase II (q5min Xs 10 mins, then q10min Xs 40 mins, then q20min Xs 3
hours)
•
Post-infusion (q20mins Xs 60 mins)
•
Study Investigators
•
Co-I: Dr. Berg will be present 30 minutes prior to SNP infusion
•
PI: Dr. Lizano will be present during the entire study visit
Phase I Infusion Protocol
•
Co-I (Dr. Berg) will be present during Phase I (10 mins)
•
A 10-minute run-in period at 0.25 mcg/kg/min using a carrier line and infusion pump
•
If SBP < 89 and/or if SBP decreased by >20% PAUSE infusion. Lie flat, feet up, call PIs
•
If HR > 120 bpm and/or >20 bpm over baseline HR, PAUSE infusion. Lie flat, feet up, call
PIs Continue to check BP.
•
If SpO2 <92%, PAUSE infusion. Lie flat, feet up, call PIs
•
If patient reports headache, ask: “do you feel this headache is tolerable?”
•
If patient says “yes,” continue dose
•
If patient says “no,” PAUSE infusion. Call PIs
•
If patient experiences symptomatic hypotension (nausea, dizziness) PAUSE infusion. Call
PIs
•
If Phase I is tolerated per the above guidelines after the 10-minute run-in period, then start
Phase II
Phase II Infusion Protocol
•
Co-I (Dr. Berg) will be present for the first 20 mins of Phase II to ensure safe up titration of
SNP
•
Increase to max dose of 0.5 mcg/kg/min with the following parameters
•
If SBP between 81 and 89 and/or if SBP decreased by >20%, lower dose to Phase I dose
for 15 min. Monitor with CRC Nurse.
•
If SBP rises to >89mm Hg continue Phase I dose
•
If SBP remains between 81 and 89mm Hg PAUSE and call PIs
•
If SBP <80, PAUSE infusion, lie flat, feet up & call PIs

(CCI) Committee on Clinical Investigations
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
•
If HR >120 bpm and/or >20 bpm over baseline HR, lower dose to Phase I dose for 15 min.
Continue to check BP
•
If SpO2 < 92% PAUSE infusion and call PIs
•
If patient reports headache, ask, “Do you feel this headache is tolerable?”
•
If patient says “yes”, continue dose
•
If patient says “no”, lower dose to Phase I dose for 15 min
•
If better, continue Phase I dose
•
If still intolerable, PAUSE infusion. Lie flat, feet up, call PIs
•
If patient experiences symptomatic hypotension (nausea, dizziness) lower dose to Phase I
dose for 15 min
•
If better, continue Phase I dose
•
If not, PAUSE infusion and call PIs
PRN Rescue Medications
•
In consultation with CRC Nurse and study PIs
•
Omnicell automated medication dispensing cabinet system available for dispensing rescue
medication
•
For SBP <80 mmHg, may give 250 ml 0.9% NS IV bolus via Sigma pump @999 ml/hr over
15 min X 2
•
For rash may give Diphenhydramine 25 mg by mouth X 1
•
The need for additional potential rescue medications to be available in the Omnicell will be
discussed between study staff and pharmacy
Infusion Considerations
•
IV line will be left in place for at least 1 hour.
•
If additional IV medication is necessary, Dr. Berg and the CRC nurse will start the infusion
and a medical team will be present during the entire infusion period.
•
A study PI or Co-I will release the subject at the conclusion of the visit.
•
A trained RA, research nurse, and study PI (Dr. Lizano) will be present during the entire
infusion and monitoring period.
•
The psychiatry research staff member will administer rating scales.
•
All side effects and vital parameters will be recorded during the infusion and 2 hours
following the infusion by CRC nursing.
•
Any abnormal, clinically significant vital signs will be recorded as adverse events.
Discharge Procedure
•
Gross motor and cognitive function, ataxia, reflexes/clonus will be evaluated and
documented by a study PI (Dr. Lizano) prior to discharge.
•
Before being discharged patients should be awake and alert, feeling well, with no nausea,
vertigo, or dizziness.
•
There should be no significant change in vital signs from prior to infusion.
•
They will be given a small meal before discharge from the CRC.
•
Patients will be instructed not to drive. If necessary, the study nurse will release them to the
care of an adult family member or caregiver, who will accompany the patient home. If
needed, a trained Research Assistant will contact the participants support system to ensure
transportation is coordinated.
Study Drug Handling

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B.
Statistical Considerations
C.
Subject Selection
•
Nitroprusside will be compounded by research pharmacy in 5% dextrose
•
5% dextrose will be used as placebo
•
Study drug will be stored at room temperature and the required amount will be released
from the pharmacy to the CRC at the time a patient is scheduled for the protocol.
•
Study drug will be provided in light-blocked bags with labeling to ensure blinding of study
staff.
Nitroprusside standard concentration is 50mg/250mL of D5W and the concentrated version
is 100mg/250mL.
Institutional Approvals
Critical Care Executive – Todd Sarge and Jane Foley – Approval granted on 9/8/21
Critical Care Practice – Joanna Anderson and John Whitlock – Approval granted on 9/8/21
Power calculation: With 16 ECS individuals in the SNP group and 16 in the placebo group we will
have >80% power to detect a 10-point PANSS difference between the placebo and treatment
groups, with a SD of 6, alpha of 0.05, 2-sided alternative hypothesis, 2-sample t-test, based on the
sample size suggested by the retinal vessel differences in our pilot data. The above-mentioned
sample size was determined based on our pilot SS-OCTA data, which suggests that we will have
>70% power to detect group differences of at least 0.007 (estimated standard deviations of skeletal
density =0.008, significance level=0.05, two-sided t-tests).
Baseline demographic details will be compared between the SNP and placebo groups using
independent-samples t tests or Mann-Whitney U tests where appropriate using R software.
Categorical data will be compared using chi-square tests. Effect sizes will be provided using
Cohen’s d. The primary outcome (PANSS) will be analyzed using a 2 (treatment group) × 5 (time
point) mixed analysis of variance (ANOVA). Analyses of secondary outcome measures will be
compared using a 2-group x 4 time point mixed ANOVA for cognition and a 2 x 2 for retinal
measures. The relationship between baseline or change in retinal vessel measures or CRP and
change in PANSS scores or cognition will be performed using Pearson’s (parametric) or
Spearman’s (non-parametric) correlation.
Population: Men and women, 18-60 years of age, from diverse background, symptomatic, with early
course schizophrenia, and meet all study inclusion and exclusion criteria.
Inclusion criteria for ECS patients are: a DSM-V diagnosis of SZ or schizoaffective disorder with
<5 years from the onset of psychosis and up to 2 years of lifetime exposure to antipsychotics, total
score of >55 on the PANSS with a score of >3 on 1 or more PANSS Positive Scale items
(delusions, conceptual disorganization,  hallucinatory behavior, suspiciousness, or unusual thought
content) and/or score of >3 on the CGI-S scale, taking antipsychotic for 8 weeks with a stable dose
of 4 weeks (no medication change will be allowed during the trial), English proficiency, understands
and is able, competent and willing to give informed consent in accordance with the International
Conference on Harmonization Good Clinical Practice Guidelines.
Exclusion criteria are:

Presence of renal, hepatic, cardiac, hematologic, neurologic impairments or abnormal
physical exam.

Presence of retinal disease (myopia >4.0 diopters)

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23

Baseline systolic BP <100mmHg or symptomatic orthostatic hypotension (systolic BP <90
mmHg or diastolic BP <60 mmHg) with any of the following: lightheaded or dizzy, blurry
vision, weakness, syncope, confusion, nausea.

Pregnant or breastfeeding (pregnancy test at screening visit and prior to randomization).

Abnormal laboratory testing (see appendix)

Treatment with medications that may interfere with the metabolism or excretion of SNP or
are associated with drug-drug interactions (see list of medications below).

Prior history of intolerance to SNP

Currently taking clozapine or chlorpromazine

Treatment with anti-inflammatory drugs, hormones or immunosuppressant agents in the 6
months before study entry

Subjects with a current DSM-V diagnosis of alcohol or substance use disorder or
dependence (excluding nicotine)

Urine drug screen tested positive for any of the following: cannabis, opioids, cocaine,
amphetamines, barbiturates methadone, methamphetamine and phencyclidine at the
screening or baseline visits

Subjects at imminent risk of suicide or injury to self or others or history of significant suicide
attempt within the last 12 months as measured by the C-SSRS together with the opinion of
the trial investigator.

Subjects that have taken an investigational drug or taken part in a clinical trial within 30
days prior to screening.

Participation for any reason would compromise patient safety or integrity of the study in the
opinion of the investigator.
Exclusionary Safety Values of Potential Clinical Concern
Complete Blood Counts
Leukocytes
<2 or >17.5 x 103/mm3
Platelets
<75 or >700 x 103/mm3
Comprehensive Metabolic Panel
Sodium
<1.1 times the lower limit or >1.1 times
upper limit of the reference range
Potassium
<1.1 times the lower limit or >1.1 times
upper limit of the reference range
Chloride
<1.1 times the lower limit or >1.1 times
upper limit of the reference range
Glucose
>2 times the limits of the reference range
Blood Urea Nitrogen (BUN)
>1.3 times upper limit of the reference range
Creatinine
>1.3 times upper limit of the reference range
Calculated Glomerular Filtration
<60
Total bilirubin
>2 times the upper limit of the reference
range
Aspartate amino transferase (AST)
>3 times upper limit of the reference range
Alanine amino transferase (ALT)
>3 times upper limit of the reference range

(CCI) Committee on Clinical Investigations
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
Drug-Drug Interactions:
-Risk X: Avoid combination
Bromperidol
Phosphodiesterase 5 Inhibitors
Riociguat
-Risk D: Consider therapy modification
Amifostine
Obinutuzumab
-Risk C: Monitor therapy
Alkaline phosphatase (ALP)
>3 times upper limit of the reference range
Creatine phosphokinase (CPK)
>3 times upper limit of the reference range
Creatine kinase (CK)
>3 times upper limit of the reference range
Thyroid Stimulating Hormone (TSH)
>3 times upper limit of the reference range
Uric acid
>3 times upper limit of the reference range
Lipid panel (triglycerides, total cholesterol
(C), HDL-C, calculated LDL-C)
>3 times the upper limit of the reference
range
Serum beta human chorionic gonadotropin
(Beta- hCG)
< 6 IU/L negative

(CCI) Committee on Clinical Investigations
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
Alfuzosin
Amphetamines
Clozapine and Chlorpromazine
Barbiturates
Benperidol
Blood Pressure Lowering Agents
Brigatinib
Brimonidine (Topical)
Dapsone (Topical)
Dexmethylphenidate
Diazoxide
DULoxetine
Herbs (Hypertensive Properties)
Herbs (Hypotensive Properties)
Local Anesthetics
Lormetazepam
Methylphenidate
Molsidomine
Naftopidil
Nicergoline
Nicorandil
Nitric Oxide
Pentoxifylline
Pholcodine
Prilocaine
Prostacyclin Analogues
Quinagolide
Sodium Nitrite
Sildenafil or Tadalafil
Yohimbine
References
1.
Brown, H. E. et al. Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside
Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry
76, 691 (2019). 
2.
Hallak, J. E. C. et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous
Sodium Nitroprusside: A Randomized, Double-blind, Placebo Controlled Trial. JAMA Psychiatry
70, 668 (2013).
3.
Stone J.M. et al. The effect of sodium nitroprusside on psychotic symptoms and spatial working
memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.
Psychological Medicine 46, 3443-3450 (2016).
4.
Wang X. et al. Sodium nitroprusside treatment for psychotic symptoms and cognitive T deficits
of schizophrenia: A randomized, double-blind, placebo-controlled trial. Psychiatry Research
269, 271-277 (2018).
5.
Adelino et al. Treatment-resistant schizophrenia - A RCT on the effectiveness of repeated-dose
sodium nitroprusside. Schizophr Res. 2021 May;231:70-72.

(CCI) Committee on Clinical Investigations
Page 15 of 20
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B4.
POSSIBLE BENEFITS
B5.
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO
There are no direct benefits to subjects. However, as shown by previous clinical studies, an
immediate improvement in overall psychosis and negative symptoms in participants with ESZ may be
achieved with SNP treatment.
Potential benefits to society include increased understanding of the pathophysiology of schizophrenia
and the personalization of treatment early in the course of schizophrenia illness. We are expecting to
have an impact on the growing consensus in immunopsychiatry and neuro-ophthalmology that the
retina provides a window into the brain that informs our understanding of brain pathophysiology and
identifies biomarkers of treatment response with this study.
Psychological Interview: There is a possibility that a patient may become distressed when being
asked about symptoms or personal information during the diagnostic evaluation or assessment
session. The primary risks to the patients are discomfort or anxiety. Subjects may also experience
some discomfort or anxiety from discussing personal information. Yet this anxiety is not expected to
be greater than that subjects already experience and subjects will be assured that they will be able to
withdraw from the study at any time. There is a possibility of suicidal ideation as a result of any
anxiety or distress associated with discussing personal information. This risk is largely reduced by
screening out patients with significant suicidal ideation or those who have enacted suicidal behaviors
within 6 months prior to intake.
Cognitive Tests: The cognitive tasks pose no risks to participants. The tasks will require sustained
attention and mental effort for a steady period of time. This could lead to minor temporary fatigue or
boredom, but otherwise there are no known risks. We will ensure that data remain as confidential as
possible. Also, these data generally are not considered to be of sensitive nature.
Confidentiality: Although every effort will be effort made to assure confidentiality, it is possible
someone could without permission gain access to study related data during the time they are being
used or stored for examination results.
Blood draw: Temporary irritation from the needle stick, the likelihood of pain or bruising at the site of
the blood draw, occasional symptoms of lightheadedness, and, in rare cases, infection at the site of
the blood draw are all risks and discomforts associated with the blood draw procedure.
SS-OCTA: OCTA is painless and safe techniques that will be used to investigate the structure and
function of the retina. Performing these imaging techniques in individuals with psychotic disorders
does not pose specific, additional unique challenges or risks to the participants. Participants will
have their pupils dilated for OCT/OCTA retinal imaging, as is done with all ophthalmology imaging
facilities, which may result in light sensitivity or acute angle-closure glaucoma. When possible, we
will forgo pupil dilation, especially when high quality retinal images can be obtained without the
need for pupillary dilation.
IV infusion of SNP:
IV treatment is relatively safe, there can be complications if not administered properly. The most
common complications include phlebitis, extravasation, air embolism, infection.
The single administration of IV Sodium nitroprusside has been reported to be safe and well
tolerated. The most important adverse reactions are the avoidable ones of hypotension and
cyanide toxicity and other side effects reported as; bradycardia, tachycardia, palpitations,
headache, increased intracranial pressure, skin rash and nausea. The potential for cyanide toxicity

(CCI) Committee on Clinical Investigations
Page 16 of 20
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
is greatest when more than 500 g/kg of sodium nitroprusside is administered faster than 2 g/kg/min,
as cyanide is generated faster than the unaided patient can eliminate. Cyanide toxicity will be
avoided in this study as the dose administered is very low, and individuals with renal impairment will
be excluded. Also, the study treatment will be infused within 3-12 hours of preparation as sodium
nitroprusside is only stable in solution for 24 hours. The infusion protocol will be 0.5mcg/kg/min
which is the minimum therapeutic dose and patients will be continuously monitored during the
infusion. The infusion procedure will take place at the Clinical Research Center at BIDMC, which is
a fully staffed center with nurses and physicians, as well as all the necessary monitoring and
personal protective equipment. In 4 other similar studies with the same protocol, there were no
serious side effects.
Sodium nitroprusside does have some potential for drug-drug interactions. The hypotensive effect
of sodium nitroprusside is augmented by that of most other hypotensive drugs, including ganglionic
blocking agents, negative inotropic agents, and inhaled anesthetics. Subjects taking any of these
drugs will be excluded from the study. Patients will also be advised not to take these medications
during the study1-4. 
Protections Against Risks
Protection against potential clinical risks: All research procedures and assessments will be
completed by trained and experienced personnel. We also strive to make the assessments as free
from burden as possible. Assessments will be scheduled at the convenience of subjects, and we
also arrange for transportation and parking. The research staff will be regularly in touch with the
participants during participation and will encourage them to contact a 24-7 number in the event of
an emergent need. If the participant develops worsening of symptoms, they will be referred for
treatment as appropriate.
Protection for risks associated with retinal imaging: Oversight of this study will come from local
IRBs. Subjects will be screened for exclusionary criteria, which include retinal diseases and past
adverse effects from ophthalmic medication used for pupil dilation. Participants will also be
provided with disposable sunglasses and asked to avoid driving and operating other potentially
dangerous equipment for 2 hours after pupil dilation. In the event of an adverse effect from the
medication for pupil dilation, there will be clinical staff (including my collaborators, Drs Miller)
available to the participant at the Retinal Imaging site (Mass Eye and Ear) to promptly assess and
treat the participant.
Protection against potential risks with SNP administration: All participants will undergo a physical
examination (PE), routine laboratory tests (CMP, CBC, CRP, TSH, Lipid panel), urine toxicology
tests and 12-lead-electrocardiogram to ensure medical stability. To monitor safety and tolerability,
participants will also be administered the Abnormal Involuntary Movement Scale, the Systematic
Assessment for Treatment Emergent Effects (SAFTEE), and the Columbia-Suicide Severity Rating
Scale prior to each infusion, after each infusion, and at follow-up. Hypotension is unavoidable with
this medication, but participants will be continuously monitored to avoid any potential complications
and there will be nursing available to help address any potential complications by stopping the
infusion and/or administrating fluids to help increase a patient’s blood pressure. Cyanide toxicity will
be avoided by providing low dosages of SNP to participants, which avoids this risk.
References:
1. Hallak, J. E. C. et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous
Sodium Nitroprusside: A Randomized, Double-blind, Placebo Controlled Trial. JAMA Psychiatry 70,
668 (2013).

(CCI) Committee on Clinical Investigations
Page 17 of 20
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B6.
RECRUITMENT AND CONSENT PROCEDURES
2. Stone, J. M. et al. The effect of sodium nitroprusside on psychotic symptoms and spatial working
memory in patients with schizophrenia: a randomized, double blind, placebo-controlled trial.
Psychol. Med. 46, 3443–3450 (2016).
3. Wang, X. et al. Sodium nitroprusside treatment for psychotic symptoms and cognitive deficits of
schizophrenia: A randomized, double-blind, placebo-controlled trial. Psychiatry Res. 269, 271–277
(2018).
4. Brown, H. E. et al. Efficacy and Tolerability of Adjunctive Intravenous Sodium Nitroprusside
Treatment for Outpatients With Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry 76,
691 (2019).
5. Holme MR, Sharman T. Sodium Nitroprusside. 2020 Oct 1. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32491419.
Recruitment
This randomized placebo control trial will include 32 early course schizophrenia subjects from a
diverse background. Department of mental health clients will not be recruited for the study and thus
IRB approval from Massachusetts Mental Health Center is not necessary. No healthy controls will be
included in the study.
Patients will be recruited through BIDMC and BILH clinics and if necessary, through affiliated MAPNET
clinics. Patients will be recruited via flyers/advertisements placed in clinic waiting rooms, public
information sessions at the clinic about the project, and asking clinicians to hand out study flyers to
subjects who they think may be interested. Patients will also be recruited by approaching the clinicians,
and if they agree, then approaching the subject for consent into the study. Interested patients will be
able to contact and call study staff for more information. ECS subjects will also be recruited from our
IRB approved retinal imaging study where patients have provided consent to be recontacted about
future studies via email (IRB 2019P000815). Subjects will be contacted by email only if they previously
consented to this. If interested, they will then receive a phone screening questionnaire. Upon first
contact, the study research assistant/coordinator will explain the study to patients. If they are interested
in continuing, a brief initial telephone screen will be administered, assessing inclusion criteria. Those
who agree to continue will be scheduled for an individual interview with the study research assistant at
BIDMC or through Microsoft Teams to assure privacy.
In some cases, the consent procedure will occur remotely to allow only the screening and baseline
portions of the study to occur via video conferencing. A written informed consent form that outlines
what study procedures will occur remotely has been uploaded to RedCap. This consent form will
be emailed to the participant ahead of a scheduled phone or Microsoft Teams video-conferencing
call. During the phone/video call, a trained clinician or study research assistant will review the form
with the participant (and, when applicable, with their legal guardian) in a private room in order to
ensure HIPAA compliance. The research clinician or assistant will follow the same procedure as the
in-person consent. All subjects must understand the requirements, risks, and benefits of the
research protocol, which is approved by the Institutional Review Board BIDMC, before they are
allowed to sign. Subjects must understand that they have the right to refuse participation at any
time during the study. To more formally assess and document each subject’s ability to give informed
consent, the person obtaining consent will follow up the study description with an interactive
questionnaire addressing the main points of the informed consent procedure via RedCap. Then, the
participant may e-sign and date the RedCap consent form, after which the research clinician or
assistant will do the same. A copy of the signed consent form will be emailed to the participant.
When the participant is able to come into the laboratory for their first in-person visit, the PI, co-
investigator, or their representative will review the full (non-verbal) consent form with the participant
and obtain a physical signature on the consent form.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B7.
STUDY LOCATION
All subjects must understand the requirements, risks, and benefits of our research protocol before they
are allowed to sign. Subjects must understand what to do should they experience any discomfort
during the course of the study. Subjects must understand that they have the right to refuse
participation at any time during the study. To more formally assess and document each subject’s ability
to give informed consent, the person obtaining consent will follow up the description of the study with
an interactive PowerPoint presentation addressing the main points of the informed consent procedure.
The study investigator will ask the subject each question and document their response. Subjects who
are unable to answer the questions, even after additional information is provided, will be excluded from
the study. This process is designed to enroll only subjects who have the capacity to make the decision
to participate and to prevent undue influence on the subject to enroll in the study by their physician.
The PI, co-investigators, or their representative will obtain written consent after explaining the
procedures. These individuals are certified by the PI that they have in depth understanding of the study
and procedures. Only when the subject declares that they are comfortable with all aspects will the
subject be allowed to offer consent. The informed consent form will be signed by the subject and a
member of the study staff. All key personnel will have passed the web-based training course on the
responsible conduct of research.
Because people who are recruited for this investigation display symptoms of psychosis, we will use the
attached Assessment of Capacity form to assess ability to consent to participation. This form has been
used in previous studies with schizophrenia at our center. The form prompts the investigator to assure
that the subject is voluntarily choosing to participate in the study, has a factual understanding of the
study, has an appreciation of the significance of the facts about research participation and is able to
reason about his or her participation.
Subject Protection
Patients with schizophrenia, schizoaffective disorder may be considered a vulnerable population.
The multi-step consent process involving both a phone screening and in-person visit, or secure
remote process provide safeguards and opportunities for subjects to understand the study and
choose whether or not to partake. Subjects will be questioned to confirm their understanding of the
protocol and possible risks or adverse side effects of Sodium Nitroprusside, thus helping ensure
that subjects with incomplete understanding do not unwittingly consent to the study. Finally, we will
also complete a one-page Assessment of Capacity form to provide informed consent.
We will assure subjects both on the informed consent form and in person that refusal to partake in
the study or drop-out from the study at any point has no impact on continued services from their
current clinic or at BIDMC. Clinical interviews will be performed by a trained clinical staff who will be
able to reassure subjects or if necessary, provide counseling if they are distressed. Subjects will be
forewarned throughout the pre-screening and screening process that the protocol involves sitting in
a chair for up to 5 hours, and that they may take breaks at any time. Breaks will be offered to
subjects regularly, though they may decline to take them.
Again, if during the consent process or any study visit, study staff notice the subject expressing
suicidality, homicidality appearing agitated or distressed, or if they score 4 or higher on the PANSS
question G6 “Depression”, they will be instructed to pause the protocol and immediately contact the
investigator (Drs. Lizano or Brady, all trained psychiatrists), who will perform a safety assessment,
contacting outpatient providers or emergency services as deemed necessary.
Privacy
Screening will be performed by phone or via Microsoft Teams and we will assure that the participant
is located in a place where they can securely answer any sensitive questions. Initial screening for
the study will take place over the phone/Microsoft Teams via a screening questionnaire. At the start

(CCI) Committee on Clinical Investigations
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B8.
DATA SECURITY
of the phone call, the potential subject will be forewarned of the possibility of sensitive questions in
the screening questionnaire. They will be offered the choice to defer the phone screening
questionnaire to a different time if they are uncomfortable answering questions over the phone at
that time. Assessments and procedures for the study will take place in private suites and rooms at
BIDMC, and OCTA assessments will take place at Massachusetts Eye and Ear's, which will afford
protection against a participant’s violation of privacy. Some of these assessments can be performed
virtually. We will also limit the information that is being collected to only the minimum amount of
data necessary to accomplish the research purposes.
Physical Setting
Urine toxicology screen, urine pregnancy test, consenting, screening and baseline assessments will
take place in Dr. Lizano’s lab space at BIDMC. Subsequent medical screening (blood tests, vital
signs, EKG) and SNP infusion visits will occur in the BIDMC Clinical Research Center. The visits
will be completed with a single subject at a time, ensuring privacy. Data will also be stored at
BIDMC.
To ensure confidentiality, the entry of self-reported data into electronic format will be identified only by
subject number, visit number and date of visit. By recording the study data in this manner, the
information can be considered de-identified and therefore compliant with the Standards for Privacy of
Individually Identifiable Health Information (“Privacy Rule”) of the Health Insurance Portability Act of
1996 (HIPAA). Any data that is transmitted electronically will be fully encrypted and password
protected. Subjects’ names will never be entered into a database; each will uniquely be identified by
an ID number. Consent forms and any study measures that are completed on paper will be kept and
filed in separate locked office cabinets accessible only to lab personnel (75 Fenwood Road 5th floor
office, Boston MA 02215). Computer data files are labeled using arbitrary identification codes to
preserve confidentiality as well.
A master data file containing the associations between each participant’s demographic information
(e.g., age and gender) and their unique identification code will be kept on a password protected
computer. This information is used to report the gender and age of the subject sample in publications,
required by many journals. Only lab research will have access to this computer and this file.
Data collected by a computer will be stored on computers within the laboratory and also stored in a
backup format on the lab’s RAID array and/or on external media such as recordable DVDs or
encrypted external hard drive. No identifying information will be kept in relation to these data. Data
collected by questionnaire or written record by the experimenter will be kept in a locked office in the
laboratory along with the Informed Consent Forms. Only lab research personnel will have access to
informed consent forms or other such personal information about the subject.
The data collected from these studies will be conducted in private locations where subjects can be
assured their information is collected privately and in a strictly confidential manner. All consent forms,
questionnaires and related hard copy forms with personal identifiers will be securely stored in a file in
a locked office. The files in this office are accessible only to lab research personnel. Each
participant’s computerized data will be labeled with a unique identification code that bears no
resemblance to the participant’s name. All behavioral, SS-OCTA and routine laboratory test data will
be stored on computer hard drives in the laboratory. Back-ups of all data files will be stored on
encrypted external storage devices within the laboratory (e.g., external hard drives, CD-R).
Individually identifiable data will not be released to anyone outside of the lab unless required by law
and/or necessary for oversight purposes.

(CCI) Committee on Clinical Investigations
Page 20 of 20
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:7/17/23
B9
Multi-Site Studies
B10
Dissemination of Research Results
Is the BIDMC the coordinating site?
Yes
No
Is the BIDMC PI the lead investigator of the multi-site study?
Yes
No
We appreciate the time and effort that our research subjects provide for the advancement of
medicine. We will acknowledge our subjects in manuscripts that arise from this work. We will provide
our participants with our contact information if they are requesting study progress. At the completion
of the study, we will send each participant a letter thanking them and giving them an update regarding
our findings.