Clinical trial NCT03102736
Conditions: Depression
Keywords: depression ketamine nitroprusside
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2017-02-14; Completion date: 2019-06-12
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the effects of the medication ketamine and the medication called nitroprusside in patients with major depression. Ketamine has both good and bad effects. Some studies have shown that ketamine improves depression. However, studies have also shown that it causes strange and sometimes unpleasant sensations referred to "psychotic" or "dissociative" symptoms. An example of a psychotic symptom would be hearing or seeing something that in reality is not there. The study team would like to see if nitroprusside can prevent the reported bad effects of ketamine without blocking the reported good effects. This might make ketamine a better treatment for depression.

Detailed description:
Ketamine is an effective fast-acting therapeutic intervention for patients with treatment refractory depression that is known to have the unwanted effect of inducing temporary psychotomimetic symptoms (i.e., delusions, hallucinations and thought disorganization) in some patients. The precise mechanisms of these psychotropic effects remain to be elucidated, but for several decades the NMDA-type glutamate receptor has been hypothesized to be of central importance. In this vain, recent studies of the antihypertensive agent nitroprusside - which increases the availability of the molecular nitric oxide, a known by-product of NMDA activity - have found evidence for antipsychotic properties both in humans with psychotic illness and healthy subjects given ketamine. Here, the clinical team proposes a study that will build on this work by evaluate the effects of nitroprusside on both the antidepressant and psychotomimetic effects of ketamine given to patients to treat refractory depression. In addition, as an exploratory aim, by collecting serial blood samples from the subjects, as the subjects are administered ketamine and nitroprusside, the clinical team will seek to determine functional markers of therapeutic effect and the mechanisms by which ketamine modulates both mood and psychotic states Research Question: The clinical team will test whether the effects of ketamine (KET) on mood and psychotic states is modified by co-administration with sodium nitroprusside (NP) in patients with depression. Furthermore, the clinical team will evaluate the extent to which the underlying biology of disease states and drug mechanisms can be inferred through analysis of brain-derived molecular material isolated from the peripheral circulation.

Specific Aims:

Aim I. To test whether co-administration with NP has any impact on the efficacy of KET as an antidepressant.

Aim II: To test the ability of NP to prevent the psychotomimetic effects of KET in patients with depression.

Research Hypotheses:

Research Hypothesis I. Patients pre-treated with NP will experience attenuated antidepressant effects (measured by MADRS score) following KET compared to pre-treatment with placebo.

Research Hypothesis II: Patients pre-treated with NP will experience attenuated psychotomimetic effects (e.g., CADSS score) immediately following KET compared to pre-treatment with placebo.

Arms: arm 1: Placebo saline given over 240 minutes + 0.5 mg/kg ketamine given over 40 minutes arm 2: 0.5 mcg/kg/min nitroprusside given over 240 min (4 hours) - 0.5 mg/kg ketamine given over the last 40 min of the nitroprusside infusion (starting at minute 200 the two drugs are given together)
Interventions: intervention 1: Placebos intervention 2: Ketamine intervention 3: Nitroprusside
Intervention descriptions: intervention 1: Placebo saline intervention 2: 0.5 mg/kg ketamine intervention 3: 0.5 mcg/kg nitroprusside

Protocol documents:
Prot_SAP_000.pdf: 
Pharmacologic Attenuation of Ketamine Using Nitroprusside 
PI: James Murrough 
NCT03102736 
Document Date: April 15, 2019


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
1 
Revised 7/09/18 
MSSM Protocol Template HRP-503a 
 
Brief Summary of Research (250-400 words): 
Ketamine is an effective fast-acting therapeutic intervention for patients with 
treatment refractory depression that is known to have the unwanted effect of 
inducing temporary psychotomimetic symptoms (i.e., delusions, hallucinations 
and thought disorganization) in some patients. The precise mechanisms of these 
psychotropic effects remain to be elucidated, but for several decades the NMDA-
type glutamate receptor has been hypothesized to be of central importance. In this 
vain, recent studies of the antihypertensive agent nitroprusside – which increases 
the availability of the molecular nitric oxide, a known by-product of NMDA 
activity –  have found evidence for antipsychotic properties both in humans with 
psychotic illness and healthy subjects given ketamine. Here, we propose a study 
that will build on this work by evaluate the effects of nitroprusside on both the 
antidepressant and psychotomimetic effects of ketamine given to patients to treat 
refractory depression. In addition, as an exploratory aim, by collecting serial 
blood samples from participants as they are administered ketamine and 
nitroprusside, we will seek to determine functional markers of therapeutic effect 
and the mechanisms by which ketamine modulates both mood and psychotic 
states. 
 
1) Objectives: 
Research Question 
 
We will test whether the effects of ketamine (KET) on mood and psychotic states is 
modified by co-administration with sodium nitroprusside (NP) in patients with 
depression. Furthermore, we will evaluate the extent to which the underlying biology 
of disease states and drug mechanisms can be inferred through analysis of  
peripheral blood biomarkers.  
 
Specific Aims 
 
Aim I. To test whether co-administration with NP has any impact on the efficacy of 
KET as an antidepressant.  
 
Aim II: To test the ability of NP to prevent the psychotomimetic effects of KET in 
patients with depression.  
 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
2 
Revised 7/09/18 
Aim III. Evaluate whether the neurobiological mechanisms governing changes in 
psychiatric states can be inferred through analysis of peripheral biomarkers isolated 
from blood. 
 
Research Hypotheses 
 
Research Hypothesis I. Patients pre-treated with NP will experience attenuated 
antidepressant effects (measured by MADRS score) following KET compared to pre-
treatment with placebo. 
 
Research Hypothesis II: Patients pre-treated with NP will experience attenuated 
psychotomimetic effects (e.g., CADSS score) immediately following KET compared 
to pre-treatment with placebo. 
 
Research Hypothesis III. Changes in peripheral biomarkers profiles will be correlated 
with changes in mental status (e.g., mood, perception) in depressed patients treated 
with KET with and without NP pre-treatment. 
 
2) Background 
KET has both rapid onset antidepressant (Berman et al. 2000) and psychotomimetic 
(Krystal et al. 1994) effects in humans. Among the many biochemical properties of 
this molecule is antagonism at the NMDA receptor (Anis et al. 1983), an ion channel 
that is highly permeable to calcium. There are a multitude of downstream processes 
affected by NMDA receptor modulation, one of which is nitric oxide (NO) synthesis 
(Bredt and Snyder 1989; Sattler et al. 1999). Taken together, these findings for 
several decades have formed the scientific basis for the hypothesis that the 
psychotropic properties of KET occur through modulation of NO homeostasis via 
NMDA activity.  
 
There is some direct evidence to support this notion with regard to psychosis. Studies 
of rodents co-administered the NO donor NP and either PCP or KET, for instance, 
support the idea that NMDA hypoactivity results in psychotic phenotypes through 
decreased NO synthesis (Bujas-Bobanovic et al. 2000; Kandratavicius et al. 2015). 
In humans, a molecular neuroimaging study of healthy subjects found KET-induced 
reduction of NMDA receptor availability was associated with increased psychotic 
phenomena (Stone et al. 2008). Similarly, a decrease in psychotic phenomena has 
been observed when the NP is administered to patients with primary psychotic illness 
(Hallak et al. 2013) as well as healthy human subjects given KET (personal 
communication with Dr. Jaime Hallak). NP administration may therefore block KET-
induced psychosis via enhancing NO availability (NP is a potent NO donor). 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
3 
Revised 7/09/18 
 
With regard to depression, there is less data. In a rodent model of depression, the 
antidepressant effects of KET were not reversed by NP (Vogt et al. 2015), suggesting 
regulation of psychotic and affective symptoms through different pathways. 
However, more recently a rodent model pointed to NO synthesis as being an 
indispensable component of the antidepressant mechanism of KET (Harraz et al. 
2016). Therefore, it is unclear if antidepressant effects of KET are related to NO 
availability. 
 
Building on this previous work, the proposed study seeks to characterize the effects of 
KET and NP on depressive and pro-psychotic states in patients with depression. This 
line of research has the potential to shed new light on the basic mechanisms of 
depression and psychosis, and to suggest a novel strategy to minimize unwanted side 
effects of KET for the treatment of depression. 
 
3) Setting of the Human Research 
The human research will be conducted at the Mood and Anxiety Disorders Program 
(MAP) outpatient clinic located in the Atran building , at the Adult 
Psychopharmacology Program suite of Mount Sinai School of Medicine, at the 
Clinical Research Center (CRC) and at the Psychiatry Infusion Suite located in the 
Icahn Building of Mount Sinai School of Medicine. 
 
4) Resources Available to Conduct the Human Research 
We will be recruiting from various sources in the community for this research study. 
They include online recruitment sources, community outreach and physician referrals. 
Dr. Murrough has years of experience conducting research studies and is well-suited 
to conduct human research. Our coordinators have experience conducting human 
research and are very well qualified. All staff members assisting with this trial are 
adequately informed about the protocol, the investigational products, and their trial-
related duties and functions. An anesthesiologist or other appropriately trained 
physician (e.g., Intensivist) will administer the study drugs to subjects.  
 
The following emergency equipment will be available in setting of study 
drug administration: 
• Defibrillator, suction device, two oxygen cylinders 
• Oxygen delivery devices (nasal cannulae) 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
4 
Revised 7/09/18 
• ECG monitor, pulse oximeter, and an expired carbon dioxide 
detection device (e.g., EasyCap, etc). 
• emergency benzodiazepine reversal, emergency opioid reversal, 
and   resuscitation drugs 
• manual resuscitation bag, tracheal intubation equipment 
• IV equipment: Angiocath, IV tubing, Saline Bag, IV starter kit 
• Saline flush, syringes, needles 
 
Code protocol: A study physician will be available throughout the infusion 
and during the subsequent monitoring period. In the event that additional 
medical back up is required, study personnel will call a “Team 7000” to 
activate the Hospital emergency response team, as well as call 911, which 
is the standard procedure for emergencies occurring in non-hospital space. 
 
5) Study Design 
a) Recruitment Methods 
The primary source of patients will be self-referrals generated from media 
advertisements.  In addition, we anticipate referrals from clinicians in the Mount 
Sinai Medical Center, New York City area hospitals affiliated with Mount Sinai, 
and community clinics, who are aware of our clinical and research program. If the 
participant is interested, he or she will contact the study team directly.  Subjects 
will be compensated for the time and inconvenience associated with participation 
in this protocol. Screening is done under GCO 06-0945: A Screening Protocol for 
Adult Patients with Mood and Anxiety Disorders. Advertisements include the link 
to an online pre-screening survey, which is IRB approved under GCO 06-0945. 
Any media advertisements will first be sent to the IRB for approval. 
 
b) Inclusion and Exclusion Criteria 
Inclusion Criteria: 
 
1) Male or female patients, 21-65 years of age; 
2) Female individuals who are not of childbearing potential (i.e., surgically 
sterile, postmenopausal for at least one year) or using a medically accepted 
reliable means of contraception. Women using oral contraceptive medication 
for birth control must also be using a barrier contraceptive. Women of 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
5 
Revised 7/09/18 
childbearing potential must also have a negative pregnancy test at screening 
and at pre-infusion;  
3) Participants must fulfill current DSM-5 criteria for Major Depression without 
psychotic features or Persistent Depressive Disorder with specifier of “with 
persistent major depressive episode”; 
4) Depression is at least moderate severity, defined as a CGI-S score of ≥ 4; 
5) Current major depressive episode is of at least 4 weeks duration; 
6) Each participant must have a level of understanding sufficient to agree to all 
tests and examinations required by the protocol and must sign an informed 
consent document; 
7) Each participant will agree to be compliant with study procedures required by 
the protocol; 
8) Each participant must be able to identify a family member, physician, or 
friend who will act as an emergency contact. 
 
 
Exclusion Criteria: 
 
1) Lifetime history of psychotic features, diagnosis of schizophrenia or any other 
psychotic disorder, or diagnosis of bipolar disorder; 
2) Lifetime histories of autism, mental retardation, pervasive developmental 
disorders, or Tourette’s syndrome; 
3) Current diagnosis of OCD or eating disorder (bulimia nervosa or anorexia 
nervosa); 
4) Subjects with DSM-V drug or alcohol abuse/dependence within the preceding 
2 years; 
5) Patients with schizotypal or antisocial personality disorder, or any clinically 
significant axis II disorder that would, in the investigator’s judgment, preclude 
safe study participation; 
6) Patients judged clinically to be at serious and imminent suicidal or homicidal 
risk, or suicide attempt within the past 1 year; 
7) Women who are either pregnant or nursing; 
8) Any serious, unstable medical illnesses including hepatic, renal impairment, 
gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, 
immunologic, or hematologic disease; 
9) History of congestive heart failure, established coronary artery disease, or 
valvular disease; 
10) History of cerebrovascular insufficiency; 
11) History of intrapulmonary arteriovenous shunts, co-arctation of the aorta or 
other conditions where cardiac outflow tract is obstructed; 
12) Vitamin B12 deficiency; 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
6 
Revised 7/09/18 
13) Clinically significant abnormal findings of laboratory parameters, physical 
examination, or ECG; 
14) Renal impairment, as reflected by a BUN > 20 mg/dL and/or creatinin 
clearance of  >1.3 mg/dL; 
15) Thyroid impairment, as reflected by a TSH > 4.2 mU/L; 
16) Hepatic injury, as reflected by AST or ALT greater than twice the upper limit 
of the reference range (AST: >80; ALT >110); 
17) Patients who have a positive urine toxicology for illicit substances at 
screening and within 24 hours of the infusion; 
18) Treatment with an irreversible MAOI within 2 weeks prior to randomization 
or fluoxetine within 4 weeks prior to randomization; 
19) Treatment with other antidepressants (classified as SSRIs, SNRIs, Atypical 
Antidepressants, MAOIs, TCAs) within one week of randomization; 
20) Previous recreational use of PCP or KET; 
21) Hypertension with systolic BP >160 mm Hg or diastolic BP >90 mm Hg at 
screening, systolic BP > 165 mm Hg or diastolic BP > 95 mm Hg immediately 
prior to treatment with study drug or hypotension with systolic BP < 90 or 
diastolic < 60 at screening or immediately prior to treatment with study drug; 
heart rate >110 or <60 at either of these time points; 
22) Treatment with sildenafil (Viagra), tadalafil (Cialis), Avanafil (Stendra), 
Vardenafil (Levitra) or other drugs in the same category of phosphodiesterase-
5 enzyme inhibitors within 2 weeks of infusion. 
 
In no case will it be recommended to a participant to discontinue a particular 
treatment if there is any evidence that the treatment is providing clinical benefit. 
Additionally, only the patient’s prescribing physician, and never the study 
physician, will take a patient off a medication. 
 
If urine toxicology is positive and not explained by a prescribed medication at any 
point during the study, the participant will be disqualified from the study. If this 
occurs, the patient will be provided with a referral for drug counseling and 
treatment if the patient wishes to seek treatment. 
 
As part of the initial screening, subjects will be asked to provide emergency 
contact information, and their consent obtained to call the emergency contact to 
confirm that they are willing and able to serve as such.  
 
Finally, a capacity evaluation will be conducted by an independent psychiatrist  in 
order to ensure sufficient subject understanding of the potential risks and benefits 
or participating in the study. 
 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
7 
Revised 7/09/18 
c) Number of Subjects 
Our goal is for 40 individuals to be randomized in this study. Based on our 
expected screen fail rate, we expect to enroll approximately 100 patients who will 
sign the consent for and be screened for study eligibility.  
 
d) Study Timelines 
Subjects undergo a screening period that may last up to four weeks (Visit 0). 
Eligible subjects then undergo the PLC/KET Test Infusion (Visit 1) and undergo 
evaluation of treatment response 24 hours following the infusion (Visit 2). For 
subjects who meet criteria to continue in the study, they are randomized to one of 
two treatment conditions (PLC/KET or NP/KET) to take place up to four weeks 
from the Test Infusion (Visit 3). Subjects will again return for evaluation 1 week 
(+/- 2 days) following Visit 1(Visit 2a). After the second infusion (Visit 3), 
subjects will return for evaluation at 24 hours (Visit 4) and 1 week (+/- 2 days) 
following Visit 3 (Visit 5). Subjects will return for a final exit visit (Visit 6) 14 
days (+/- 2 days) following the second infusion (Visit 3). Therefore, the total 
study participation time will be up to 10 weeks. 
 
We anticipate a 2-year project period, during which time approximately 100 
patients will be screened, with 40 patients randomized. However, after 8 patients 
have completed the study, the results will be unblinded to an independent 
statistician and an interim analysis conducted. On this basis, the study may be 
terminated, or it may be continued towards the goal of randomizing 40 total 
patients. A second interim analysis will be conducted once the sample size has 
doubled, and 16 patients have completed the study. The statistician will receive 
de-identified coded data only.   
 
e) Study Endpoints 
Primary Outcomes 
(a) Change in Montgomery–Asberg Depression Rating Scale 
(MADRS) compared across PLC/KET and NP/KET 
administrations. 
(b) Change in four-item positive symptom subscale of the Brief 
Psychiatric Rating Scale (BPRS), Clinician-Administered 
Dissociative States Scale (CADSS) and Visual Analog Scale 
(VAS) scores from Time 0 to Time 40 minutes compared 
across PLC/KET and NP/KET administrations. 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
8 
Revised 7/09/18 
 
Secondary Outcome 
Change in molecular profiles obtained from blood draws of 
subjects at set time points that parallel clinical ratings during 
infusions of the agents under investigation and post-infusion 
follow up.  
 
Statistical Analysis 
The null hypotheses of this study are that (a) pre-treatment with NP does 
not attenuate the antidepressant effects of KET (b) pre-treatment with NP 
does not reduce psychotic rating scores induced by KET, and (c) there are 
no changes in molecular measurements over the course of KET and/or NP 
infusions that correlate with clinical ratings. These hypotheses will be 
tested against their corresponding alternatives, namely that pre-treatment 
with NP effectively attenuates both the antidepressant and pro-psychotic 
effects of KET and that molecular changes in reflecting real-time changes 
in mental status can be tracked using serial blood draws.  
Data will be analyzed using repeated measures General Linear Models 
with Time and Treatment Condition as within-subject variables. Overall F 
tests for significance will be followed up by post-hoc t-tests comparing 
rating scores between the treatment conditions.  
The statistician will receive de-identified coded data only.  
 
f) Procedures Involved in the Human Research 
The current protocol consists of 8 study visits, as well as a phone call check-in 
(Study Visit 0: Screening; Study Visit 1: PLC/KET infusion; Study Visit 2: 24-
hour follow-up of Study Visit 1; Study Visit 2a: 7-day follow-up of Study Visit 1; 
Phone-call follow-up of Study Visit 1; Study Visit 3: PLC/KET or NP/KET 
infusion; Study Visit 4: 24-hour follow-up of Study Visit 3; Study Visit 5: 7-day 
follow-up of Study Visit 3; Study Visit 6: study exit evaluation). Below, we first 
outline procedures for study drug administration that apply to both Study Visits 1 
and 3. Then, we describe in more detail the procedures that will occur on each of 
the Study Visits. See Table 1 for an outline of the events occurring at all visits. 
 
Description of Study Drug Procedures  
 
 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
9 
Revised 7/09/18 
Study drugs are administered on Study Visits 1 (single-blind) and 3 (double-
blind). Visits 1 and 3 will occur up to four weeks apart to allow subject depression 
levels to return to baseline, a necessary component of the study design in order to 
test whether NP has any effect on the antidepressant action of KET. At Visit 1, 
participants will receive single-blind placebo (PLC) followed by KET (0.5 
mg/kg/hour for 40 minutes), in which they are blind to the PLC/NP condition but 
are aware they are receiving KET. Subjects return to the clinic 24 hours following 
Visit 1, at which time their eligibility to continue and be randomized in the study 
is determined. The criteria for continuing is a significant antidepressant response 
to KET as demonstrated by MADRS score of >= 50% improvement from 
baseline. Eligible subjects are randomized to one of two treatment conditions for 
Visit 3 (double-blind):  PLC/KET or NP/KET (NP dose: 0.5 
micrograms/kg/minute for 240 minutes), where again, the blinded condition is 
PLC/NP, but the subjects are aware they are receiving KET.  Ineligible subjects 
(i.e., ketamine non-responders) will be scheduled to return to the clinic for an exit 
visit 1 week (7 +/- 2 days) following the first infusion. The appearance of the 
nitroprusside will be protected to allow this drug to be blinded. Given the 
potential lengthy duration between visits (between 2 and 4 weeks), subjects will 
return to the clinic approximately 1 week (7 +/- 2 days) following V1 (PLC/KET) 
for a check-in (Visit 2a) with the study doctor in order to ensure subject safety, as 
well as to be evaluated for remission of depressive symptoms. Additionally, a 
phone call MADRS will be administered 3 to 4 days following the in-person 
check-in, which will serve as the final determinant of the subject’s return to 
baseline (defined as receiving a score within 20% of the baseline MADRS). If the 
subject has not returned to baseline, the V3 will be rescheduled for a date 
approximately two weeks following its initial appointment in order to allow 
maximum time (4 weeks) for a return to baseline, and the two check-ins (Visit 2a 
and by-phone check-in) will be repeated for the next two weeks, for a total of 4 
additional check-ins. Following the V3 infusion visit, subjects again return to the 
clinic at 24 hours (Visit 4) and at 7 +/- 2 days (Visit 5) following the second 
infusion day, and once more 14 +/- 2 days after the infusion for the Exit Visit 
(Visit 6).  
 
Each treatment day (Visit 1 and 3) involves Infusion 1 (PLC or NP) and Infusion 
2 (KET). Prior to Infusion 1 (PLC on Study Visit 1; PLC or NP on Study Visit 3) 
an indwelling catheter will be placed in the antecubital veins of each arm, and 
pulse, blood pressure, pulse-oximetry, and an EKG strip will be placed for 
continuous vital monitoring, which will be performed throughout the infusions. 
One of these catheters will be used for the administration of NP/PLC, and one 
will be used for the administration of KET; this is to ensure no interaction effects 
between the drugs given in the same line. At Time 0, Infusion 1 will begin 
through an infusion pump and will continue until Time 240 minutes. At Time 200 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
10 
Revised 7/09/18 
minutes, Infusion 2 (KET on both Study Visits 1 and 3) will begin and will 
continue until Time 240 minutes, at which point all medication administration 
will be complete for the Study Visit. Clinical ratings (BPRS, CADSS, VAS; see 
below) will be collected at regular intervals before, during and after the infusion 
period by clinical raters.  Blood draws may be conducted at baseline and Time 
+240 min on V1 and V3 infusion days, as well as at the 24-hour V2 and V4 visits, 
for a total of six blood draws; however, this is an optional procedure that will 
occur under a different protocol (GCO 11-1617). On the two infusion days, the 
blood will be drawn through one of the indwelling catheters that are used for 
study drug administration. 
 
A urine toxicology screen will be performed before the first infusion and must be 
negative for illicit substances in order to proceed with the infusion. For females, a 
urine pregnancy test will confirm non-pregnancy prior to the infusions.  
Prior to the infusion VS will be assessed by nursing staff and confirmed by an 
MD and will need to be stable as per inclusion/exclusion criteria. Patients will be 
monitored by study nursing staff and by an MD throughout the infusions and for 1 
hour of observation after the infusions end. Furthermore, a study anesthesiologist 
will oversee the study drug infusions. At the end of the observation period a study 
doctor will evaluate the patient, then the patient will be discharged home 
accompanied by a responsible adult. Patients will be instructed not to drive for 24 
hours following the infusions.  
 
Description of Study Visit Procedures: 
 
Study Visit 0: Screening 
Summary of study procedures during this phase: 
• Informed Consent 
• Structured Psychiatric Interview (SCID) 
• Physician Evaluation 
• Medical History 
• Adverse Events Documentation 
• Concomitant Medication Documentation 
• Physical Exam 
• Vital Signs 
• Routine Laboratory Tests 
• Urine Toxicology 
• Urine Pregnancy Test (if applicable) 
• EKG 
 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
11 
Revised 7/09/18 
After receiving complete disclosure about the research and opportunity to 
fully review the consent form, potential participants will be given the 
opportunity to ask questions. If they choose to take part in the study, then they 
will be asked to sign the written informed consent form. Psychiatric history 
will be obtained by a member of the research team using the SCID and the 
DSM-5 Diagnostic Criteria. A medical history and physical examination will 
be performed for each patient and basic laboratory tests ordered. This will 
include: ECG, vital signs (including orthostatic blood pressure 
measurements), complete blood cell counts, electrolytes, thyroid functioning 
test, liver function tests, urinalysis, and toxicology screening.  A urine 
pregnancy test will be performed in premenopausal women. Results of these 
tests will identify patients who should be included or excluded based on 
criteria stated earlier in this protocol.  
 
Study Visits 1 and 3: Test days 
 
Summary of study procedures during this phase: 
• Vital Signs 
• Urine Toxicology 
• Urine Pregnancy Test (if applicable) 
• Study Drug Infusion 1 and Infusion 2 
• Blood draws before/after infusion (if applicable) 
• Clinical ratings before/during/following infusion 
 
Study Visit 1 will occur up to 4 weeks after Study Visit 0. At this Visit, all 
participants will first receive PLC for Infusion 1 and KET for Infusion 2. 
Details of the dosing and timing for these infusion sequences, as well as the 
associated clinical ratings and blood draws, is explained in the “Description of 
Study Drug Procedures” section above. 
 
Study Visits 2 and 4 (24-h follow ups) 
 
Participants will return to the study site 24 hours after Study Visit 1 for Study Visit 2. At 
this visit, safety and efficacy assessments will be performed (no drugs will be 
administered). The research team will analyze the outcomes of the MADRS and 
CADDS for each participant obtained on this day. In order to best assess the 
capacity of NP to attenuate the pro-psychotic and antidepressant effects of KET, 
only those participants who show improvement in MADRS ≥ 50% compared to 
baseline will be eligible to return for Study Visit 3. 
 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
12 
Revised 7/09/18 
Participants who meet these criteria will return for Study Visit 3 up to 4 weeks 
later (depending on the amount of time required for the patient’s MADRS score to 
return to baseline). These participants will be randomized to receive a drug 
administration sequence of either PLC/KET or NP/KET at Study Visit 3. 
All patients who return for Study Visit 3 will return to the study site within 24 
hours for Study Visit 4. At this visit, safety and efficacy assessments will be 
performed (no drugs will be administered).  
 
Study Visits 2a and 5 (7-day follow-ups) and Phone Call Check-In 
Approximately 1 week (7 +/- 2 days) after Visit 1, participants will return to the 
study site for an in-person visit (Visit 2a), which will consist of meeting with the 
study doctor and completing a MADRS with the clinical rater. Provided that there 
are no clinical concerns, a phone call MADRS will be scheduled 3-4 days 
following the in-person check-in in order to determine whether the patient has 
returned to baseline (within 20% of baseline MADRS). As stated above, if the 
participant has not returned to baseline before the second infusion, the infusion 
will be rescheduled to a date approximately 2 weeks ahead of the original 
appointment, and these two check-ins will be repeated twice more over the course 
of the next 2 weeks (visit 2b, 2c and two phone calls), for a total of four additional 
check-ins. 
Approximately 1 week (7+/- 2 days) after Visit 3, participants will return to the 
study site for an in-person visit (Visit 5), which will consist of meeting with the 
study doctor and completing a MADRS with the clinical rater. 
 
Visit 6 (Exit Visit) 
14 days +/- 2 days after Visit 3, and 7 days after Visit 5, all participants will 
return for Study Visit 6 (Exit Visit). Safety and efficacy assessments will be 
performed, and the patient will have completed the study.  
 
Description of Study Instruments 
 
The Structured Clinical Interview for DSM-5 Axis I Disorders (SCID) (First 
et al. 2012) is a semi-structured interview that provides probe questions as well as 
follow-up questions to be asked by the clinician to assist in diagnosis. It includes 
an overview to obtain information about demographics, work, chief complaint, 
history of present illness, past history, treatment history, and current functioning. 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
13 
Revised 7/09/18 
The main body of SCID (patient edition) includes 9 modules that are designed to 
diagnose 51 mental illnesses in all.  
 
The Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) is used 
to assess acute behavioral changes during the infusions. Four key BPRS items for 
the positive (+) symptoms of psychosis will be used: conceptual disorganization, 
hallucinatory behavior, suspiciousness, and unusual thought content. Three items 
representing the negative (-) symptoms of psychosis will also be used: blunted 
affect, emotional withdrawal, and motor retardation. 
 
The Clinician-Administered Dissociative States Scale (CADSS) (Bremner et al. 
1998) is used to measure dissociative effects during the infusions. The scale 
includes 19 questions and 8 observer ratings scored from 0 (not at all) to 4 
(extremely). The CADSS measures impairment in body perception, 
environmental perception, time perception, memory impairment, and feelings of 
unreality. 
Visual Analog Scales. These scales are scored in millimeters from the 
left-hand side of a 100-mm line to a perpendicular mark made by the 
patient at a point corresponding to the apparent magnitude of the feeling 
state. Range: 0 ("not at all") to 100 ("most ever"). 
Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery 
and Asberg 1979). This is a 10-item instrument used for the evaluation of 
depressive symptoms in adults and for the assessment of any changes to 
those symptoms.  Each of the 10 items is rated on a scale of 0 to 6, with 
differing descriptors for each item. These individual item scores are added 
together to form a total score, which can range between 0 and 60 points. 
The estimated time to administer this scale is 20 minutes. Inter-rater 
reliability of the scale is high and scores correlate significantly with those 
of the HAM-D. On the infusion days a modified MADRS will be used that 
will exclude the sleep and appetite items. 
Quick Inventory of Depressive Symptomatology, Self Report (QIDS-
SR): The Quick Inventory of Depressive Symptomatology, Self Report 
(QIDS-SR) is a 16-item self rated instrument designed to assess the 
severity of depressive symptoms. The 16 items cover the nine symptom 
domains of major depression as indicated by the DSM, and are rated on a 
scale of 0-3. Total scores range from 0 to 27, with ranges of 0-5 (normal), 
6-10 (mild), 11-15 (moderate), 16-20 (moderate to severe), and 21+ 
(severe). 
Columbia-Suicide Severity Rating Scale (C-SSRS): The Columbia-
Suicide Severity Rating Scale (C-SSRS) is a comprehensive, semi-


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
14 
Revised 7/09/18 
structured interview that uniquely measures the full spectrum of 
suicidality including passive and active suicidal ideation, suicidal intent as 
well as suicidal behaviors. Subjects will be assessed at every visit with the 
CSSRS by a study clinician. Any subject with an increase in suicidality 
and all those subjects found to have a plan or intent will undergo thorough 
assessment by the study psychiatrist who will determine the appropriate 
course of action, including whether acute intervention is needed and 
whether it is in the best interest of the subject to continue in the study. If 
necessary, the study psychiatrist will seek consultation from the study PI 
or medical monitor. If continued participation is deemed not to be in the 
best interest of study subject, s/he will be discontinued from the study. 
 
g) Data Management and Confidentiality 
Case report forms and source documents are completed electronically using 
the institution’s REDCap data capture system, a secure web-based application 
protected by Mount Sinai’s server and managed by IT, which will obviate the 
need for data entry and data cleaning at time points separate from data 
capture, reducing the risk of error. The case report forms and source 
documents are based on established instruments or are developed from 
adaptations of NIH and industry-sponsored clinical trial protocols. Study data 
are recorded without specific patient identifying information. Patient 
identifiers are sequestered in a separate REDCap database. Access to both 
study databases is password protected and only IRB approved study members 
have access.  
 
All data will be obtained for research purposes only. We will collect 
information about participants’ psychiatric history, including previous 
treatments, medical history, and family history. As part of the medical 
evaluation, we will collect blood and urine specimens for analysis, and 
perform an ECG. The outcome of these tests will be shared with the 
participant. In the event that we detect a medical condition that requires 
treatment, we will provide the participant with an appropriate referral.  
In addition, data will include clinical ratings and patient self-ratings. These 
data will not be shared with the participants.  
 
h) Provisions to Monitor the Data to Ensure the Safety of subjects 
This information is only required when Human Research involves more 
than minimal risk to subjects. 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
15 
Revised 7/09/18 
Part I describes the safety monitoring activities that will be undertaken in 
during the study.  This should be completed for all studies that require 
more than the basic minimum Data and Safety Monitoring Plan (DSMP).   
Part II describes Data and Safety Monitoring Committees or Boards and 
should be completed when one is needed for the DSMP. 
 
Part I: Elements of a Data and Safety Monitoring Plan (DSMP) 
1. List the name(s) of the individual(s) at MSSM who will be responsible 
for data and safety monitoring of this study. For each individual, indicate 
their role, name, title, and department information. The Principal 
Investigator may be the only monitor of a study.  
If the qualifications of an individual to serve as a monitor are not 
contained in the PPHS application, they must be added to the DSMP either 
as a narrative description or as a CV. 
 
MSSM Principal Monitor: James Murrough, MD PI 
Indicate whether this person is the PI, a Team Member, or is Independent: 
Last Name: James 
First Name: Murrough 
Academic Title: Assistant Professor 
Department: Psychiatry 
Mailing Address: 1 Gustave L. Levy Place, Box 1230 
Phone: 212-241-7574 
Fax: 212-241-3354 
E-mail: james.murrough@mssm.edu 
 
2. Justify your choice of principal monitor in terms of the assessed risk to 
the research subject‘s health and wellbeing. In high risk studies when the 
principal monitor is independent of the study staff, indicate the 
individual’s credentials, relationship to the PI, and the rationale for 
selection.  
Dr. Murrough is intimately knowledgeable of this study and also be 
involved in the clinical care of the subjects and will provide oversight of 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
16 
Revised 7/09/18 
the entire study. He has been involved in many KET studies in Mood and 
Anxiety Program (MAP). 
 
3. List the specific items that will be monitored for safety (e.g., adverse 
events, subject compliance with the protocol, drop outs, etc.).  
Adverse events, subject compliance with the protocol, side effects and 
dropouts will be closely monitored. 
 
4. Indicate the frequency at which ACCUMULATED safety and data 
information (items listed in number 3 above and interim analysis of 
efficacy outcomes) will be reviewed by the monitor(s) or the Data 
Monitoring Committee (DMC). Although this information must be 
reviewed at least annually, the higher the study risks, the more frequently 
reviews must be scheduled.  
 
All accumulated data will be reviewed annually by the PI and the IRB. In 
addition, data and safety will be monitored in an ongoing fashion by the 
PI. 
5. Where applicable, describe rules which will guide interruption or 
alteration of the study design.  
N/A 
6. Where applicable, indicate dose selection procedures that will be used 
to minimize toxicity.  
The dose of KET is fixed with 0.5 milligrams/kg/hour infusion over 40 
min. NP is administered at the lowest therapeutic dose used for treatment 
of hypertension, 0.5micrograms/kg/min. The time of 240 minutes for the 
infusion was determined through the only published study of the use of NP 
as a psychotropic medication in humans (Hallak, 2013).  
7. List any specialized grading system that will be used to evaluate 
adverse events (e.g., National Cancer Institute Common Toxicity Criteria).  
Grading of severity and attribution to research will be conducted at each 
visit and noted on the treating cover sheet. 
(1) Attribution of adverse events: 
Unrelated: Adverse event(s) will clearly not related to the investigational agent(s) 
Unlikely: Adverse event(s) will doubtfully be related to investigational agent(s) 
Possible: The adverse(s) events may be related to the intervention(s) 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
17 
Revised 7/09/18 
Probably: The adverse(s) event is likely related to the intervention(s) 
Definite: The adverse(s) event is clearly related to the intervention(s) 
 
(2) Plan for Grading Adverse Events: 
The FDA’s definition of serious adverse events (21CRF 312) (AE) include any 
untoward medical occurrence that at any age results in death or the immediate risk 
of death, hospitalization or the prolongation of an existing hospitalization, 
persistence or significant disability/incapacity or congenital anomaly/birth defect 
(NH Guide, 6/11/99). 
 
Grade of Risk: 
1= Non Serious Adverse Event 
2=Serious Adverse Event 
 
8. Describe procedures that will be used to assure data accuracy and 
completeness. 
The PI will monitor the accuracy and completeness of the data. The following 
elements will be monitored: recruitment procedures and pace; adherence to the 
exclusion/inclusion criteria; deviation from protocol; the timeliness of 
documentation and data entry; and the accuracy and confidentiality of all 
information both in study documents and study database. 
9. Should a temporary or permanent suspension of your study occur, in 
addition to the PPHS, indicate to whom (NIH, FDA, sponsor, IRB) will 
you report the occurrence. 
N/A 
 
Part II. Data Monitoring Committee/Data Safety Monitoring Board (DMC/DSMB) 
 
A local Data Safety and Monitoring Board (DSMB) for ketamine depression protocols is 
currently in place at Mount Sinai and will provide oversight for the current trial. 
 
The DSMB will ensure the safety of study participants and the integrity of the data 
collection in the projects. To achieve this goal, the DSMB will perform an ongoing 
evaluation of the safety of patients participating in the clinical outcomes in the clinical 
trial. This includes monitoring adverse events and overall clinical outcomes in the 
studies. Through this process the board will evaluate the need for study termination 
and/or modification of study criteria for inclusion, exclusion, or discontinuation.  In 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
18 
Revised 7/09/18 
addition, the DSMB will be responsible for the evaluation of the adherence to written 
protocols regarding the protection of human subjects and the assurance of identity 
protection as specified in the Data Sharing Section. The DSMB will expeditiously review 
all serious adverse events and perform ongoing scheduled reviews of non-serious adverse 
events and study dropouts. The DSMB includes the following members: The Oversight 
Committee members are to include:  Lawrence Price, MD, Professor of Psychiatry, 
Brown University; Menachem Weiner, MD, Icahn School of Medicine Professor of 
Anesthesiology; Charles Kellner, MD, Professor of Psychiatry, Icahn School of Medicine 
at Mount Sinai; and Dr. Mark Green, Professor of Neurology and Professor of 
Anesthesiology, Icahn School of Medicine at Mount Sinai.  The board will review the 
project’s data and safety on bi-annual basis and report their findings to the PI. 
 
i) Withdrawal of Subjects 
Investigators may elect to withdraw the patient due to safety concern or 
non-adherence to the study protocol. Subjects may withdraw at any point 
in the study.  
 
6) Risks to Subjects 
Risks associated with NP [The following information was derived from the FDA 
package insert for NP (Nitropress [package insert]. Lake Forest, IL: Hospira 
Inc; 2014).]  
The principal hazards of NP excessive hypotension and excessive accumulation of 
cyanide. Transient excesses in the infusion rate of NP can result in excessive 
hypotension, sometimes to levels so low as to compromise the  
perfusion of vital organs. These hemodynamic changes may lead to a variety of 
associated symptoms. Hypertensive patients, and patients concomitantly receiving 
other antihypertensive medications, may be more sensitive to the effects of NP than 
normal subjects. NP infusions at rates above 2 μg/kg/min generate cyanide ion (CN−) 
faster than the body can normally dispose of it. The true rates of clinically important 
cyanide toxicity cannot be assessed from spontaneous reports or published data. Most 
patients reported to have experienced such toxicity have received relatively prolonged 
infusions, and the only patients whose deaths have been unequivocally attributed to 
NP-induced cyanide toxicity have been patients who had received NP infusions at 
rates (30-120 μg/kg/min) much greater than those now recommended. Elevated 
cyanide levels, metabolic acidosis, and marked clinical deterioration, however, have 
occasionally been reported in patients who received infusions at recommended rates 
for only a few hours and even, in one case, for only 35 minutes. Cyanide toxicity may 
manifest itself as venous hyperoxemia with bright red venous blood, as cells become 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
19 
Revised 7/09/18 
unable to extract the oxygen delivered to them; metabolic (lactic) acidosis; air hunger; 
confusion; and death. Cyanide toxicity due to causes other than NP has been 
associated with angina pectoris and myocardial infarction; ataxia, seizures, and 
stroke; and other diffuse ischemic damage. 
The adverse reactions described in this section develop less rapidly and less 
commonly than the hypotension and cyanide toxicity highlighted above. NP can 
cause sequestration of hemoglobin as methemoglobin. The back-conversion process 
is normally rapid, and clinically significant methemoglobinemia (>10%) is seen only 
rarely in patients receiving NP; even patients congenitally incapable of back-
converting methemoglobin should demonstrate 10% methemoglobinemia only after 
they have received about 10 mg/kg of NP (a patient receiving NP at the maximum 
recommended rate (10 μg/kg/min) would take over 16 hours to reach this total 
accumulated dose). Thiocyanate build-up may occur in NP infusions at high doses 
and rates. It is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 
mmol/L (60 mg/L) and life-threatening when levels are 3 or 4 times higher (200 
mg/L). To keep the steady-state thiocyanate level below 1 mmol/L, a prolonged 
infusion of NP should not be more rapid than 3μg/kg/min. Other, nonspecific adverse 
reactions that have been reported with NP include abdominal pain, apprehension, 
diaphoresis, “dizziness,” headache, muscle twitching, nausea, palpitations, 
restlessness, retching, retrosternal discomfort, bradycardia, electrocardiographic 
changes, tachycardia, rash, hypothyroidism, ileus, decreased platelet aggregation, 
flushing, venous streaking, and irritation at the infusion site. 
NP should not be used in the setting of compensatory hypertension, where the 
primary hemodynamic lesion is aortic coarctation or arteriovenous shunting. NP 
should not be used to produce hypotension during surgery in patients with known 
inadequate cerebral circulation, or in moribund patients (A.S.A. Class 5E) coming to 
emergency surgery. Patients with congenital (Leber’s) optic atrophy or with tobacco 
amblyopia have unusually high cyanide/thiocyanate ratios, and NP should be avoided 
in these patients. NP should not be used for the treatment of acute congestive heart 
failure associated with reduced peripheral vascular resistance such as high-output 
heart failure that may be seen in endotoxic sepsis. Like other vasodilators, NP can 
cause increases in intracranial pressure. In patients whose intracranial pressure is 
already elevated, NP should be used only with extreme caution. The hypotensive 
effect of NP is augmented by that of most other hypotensive drugs, including 
ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics. 
Caution should also be exercised in patients with hepatic insufficiency, anemia, 
hypovolemia, abnormalities of the pulmonary ventilation/perfusion ratio, and high 
surgical risks. NP has not been tested for effects on fertility. 
 
 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
20 
Revised 7/09/18 
Risks associated with KET 
KET is a sedative/analgesic and general anesthetic for human and veterinary use. It 
may produce mild to moderate increases in blood pressure, heart rate, and cardiac 
output due to its sympathomimetic effects and can provoke ischemia in patients with 
underlying coronary artery disease. Overall, however, KET has a favorable acute safety 
profile. Over the past several decades, KET has been administered as an anesthetic to 
several million adults and children. 
 
The reported incidence of KET-induced perceptual disturbances varies from less than 
5% to greater than 30% (Knox et al. 1970; White et al. 1980) and may manifest as vivid 
dreaming, visualization of psychedelic color, suspension in space, kaleidoscopic 
floating, and out-of-body experiences. Some patients describe these psychic 
experiences as bizarre or frightening, while others find them pleasurable, joyful, and 
fascinating. Indeed, KET is also known as “Special K” as a drug of abuse related to 
PCP. For that reason KET was placed in Schedule III of the Controlled Substance Act 
in 1999. Nonetheless, when perceptual disturbances occur, they are usually mild and 
of short duration (Green and Johnson 1990). KET administration has transient effects 
on symptoms, usually lasting less than 60 minutes and rarely lasting longer than 2 hours 
(Carpenter 1999). The perceptual disturbances may be more common in those with 
preexisting psychosis (Lahti et al. 1995). 
 
Several studies have addressed the question of prolonged psychological effects in the 
general population secondary to its anesthetic use and concluded that KET does not 
place patients at a greater risk than other anesthetics (Hersack 1994; Reich and Silvay 
1989; Schorn and Witwam 1980). There is no evidence in these long-term studies that 
individuals exposed to KET are at risk of abusing it on follow-up.  
 
Both ourselves and others have safely used KET in a large number of 
psychophysiological studies in patients with psychiatric disorders as well as in healthy 
with doses similar to that of the present study. A meta-analysis of a number of these 
studies found no evidence of behavioral sensitization following repeated KET exposure 
(Cho et al. 2005). 
 
7) Provisions for Research Related Injury 
We have described above the potential risks of the research procedures and the 
safeguards that will be used to minimize risks. These include termination of research 
participation if it is believed that such participation endangers a patient’s welfare. 
Monitoring procedures are used to evaluate potential side effects of treatment or of 
research procedures. The protocol stipulates an extensive medical and psychiatric 
evaluation of all patients as a condition for research participation.  


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
21 
Revised 7/09/18 
Patients are monitored for potential reactions during the clinical trial. A 
physician is on-call at all times between clinic visits so that adverse reactions 
can be evaluated and treated promptly. 
In general, if subjects are injured or made sick from taking part in this research 
study, medical care will be provided. Generally this medical care will be billed to 
the health care insurance. However, ISMMS may be responsible for the costs of 
any direct research-related injury. 
 
8) Potential Benefits to Subjects 
The possible benefits to the patient (remission or improvement of MDD 
symptoms) and to others (development of a new drug with rapid 
antidepressant effects based on the elucidation of a new molecular pathway 
and/or development of a new drug that minimizes  the pro-psychotic side 
effects of KET) are reasonable in relation to the risks of this study. All study 
participants will receive without cost an extensive psychiatric and medical 
evaluation. All participants will receive reimbursement of travel expenses. No 
other direct benefits result from study participation.  
 
9) Provisions to Protect the Privacy Interests of Subjects 
Adequacy of Protection Against Risks Recruitment and Informed Consent   
Interested individuals contacting the clinic by phone will be informed that the 
information they give over the phone is written down and discussed by the 
research team. They will be advised that if they do not enroll in research with 
the clinic, the information will be destroyed, and that if they do enroll, the 
information becomes part of their research chart, which is destroyed after 
seven years. An initial phone screening is completed after they give verbal 
authorization.  
If an individual appears to meet enrollment criteria and is interested in 
participating, a face-to-face interview will be conducted by one of the project 
investigators. Referring clinicians will be asked to inform potential 
participants of the possible alternatives to participating in the study. A release 
of information will be obtained for review of any available historical and 
clinical data. A written authorization form is also obtained from each patient, 
permitting the research team to use, create, or disclose his or her PHI for 
research purposes. The nature of the project, procedures, relative risks and 
benefits, and alternatives to participation in the project will be discussed with 
each patient. Following this discussion, he or she will be given a copy of the 
consent form to review at their leisure, and any questions are answered. Study 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
22 
Revised 7/09/18 
visits and procedures will take place at the MAP clinic in the Atran Building.  
The PI or one of the co-Is of the protocol will seek written voluntary informed 
consent from all participants prior to study entry. The initial consent form 
describes the nature of the procedures and time requirements, potential risks, 
the confidentiality of information, and the rights of research participants. If 
the individual remains interested in the project, written informed consent is 
obtained, and medical and psychiatric screening procedures are undertaken to 
confirm eligibility. A copy of the consent form is provided to all participants. 
If the individual decides not to participate in this study, a staff member 
provides reasonable and timely assistance in obtaining an alternative referral, 
if so desired. The decision not to participate does not affect eligibility to 
participate in future studies, to receive treatment at Mount Sinai, or to receive 
treatment on a private basis from a referring clinician.  
The consent process also includes documentation of permission to obtain 
previous medical records, including contact with previous physicians, 
pharmacies, and family members. The IRB-approved forms for informed 
consent are made part of the patient’s permanent medical record, with a copy 
filed in the research chart.  
End of Study 
There are three areas in which safeguards to protect research participants from 
undue risk require discussion. These include the procedures used to obtain 
informed consent, the procedures used to insure confidentiality of the 
participants’ data, and the procedures used to minimize possible risks 
associated with the study procedures. In the consent form and discussion with 
an investigator, patients are advised fully of the procedures to be used, the 
amount of time required of them, the possible risks and benefits of the 
procedures, their right to refuse participation in the study without prejudice, 
their right to terminate participation at any moment without prejudice, and the 
name and telephone number of the PI.  
In the informed consent form, patients are told that the information they 
provide and all findings will be kept strictly confidential, with access limited 
to the research staff at the research sites and the possible exception of state or 
federal regulatory personnel. No one but the Project Manager has access to the 
master list linking patients’ names to code numbers. All information obtained 
is coded. The respective master lists are kept under strict lock and key. 
Identifiable information is kept in locked file drawers and password protected 
computer files. Results are published as group data without the use of 
characteristics that would identify individual subjects. We quote information 
only by number in conference discussions, scientific reports, or publications, 
in order to maintain anonymity. 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
23 
Revised 7/09/18 
 
 
10) 
Economic Impact on Subjects 
The study drug will be provided at no cost to the subjects.  
 
11) 
Payment to Subjects 
Participants will be paid according to the following schedule: 
Visit 
Compensation 
Screening Visit 
$50 
Treatment Day 1  
$100 
Post-Treatment Assessment Visit (24-hour) 
$25 
Post-Treatment Assessment Visit (7-day) * 
$25 
Treatment Day 2  
$100 
Post-Treatment Assessment Visit (24-hour) 
$25 
Post-Treatment Assessment Visit (7-day) 
$25 
Study Exit Visit 
$25 
Total for participation in all parts of the study: $375 
* this visit may be repeated up to 2 times, for a total additional payment of 
$50.  
12) 
Consent Process 
If an individual appears to meet enrollment criteria and is interested in participating, a 
face-to-face interview will be conducted by one of the project investigators. Referring 
clinicians will be asked to inform potential participants of the possible alternatives to 
participating in the study. A release of information will be obtained for review of any 
available historical and clinical data. A written authorization form is also obtained 
from each patient, permitting the research team to use, create, or disclose his or her 
PHI for research purposes. The nature of the project, procedures, relative risks and 
benefits, and alternatives to participation in the project will be discussed with each 
patient. Following this discussion, he or she will be given a copy of the consent form 
to review at their leisure, and any questions are answered. Study visits and procedures 
will take place at the Mood and Anxiety Disorders Program (MAP) outpatient clinic , 
the Clinical Research Center (CRC), the Adult Psychopharmacology Program suite, 
and the Psychiatry Infusion Suite. 
 
The PI of the protocol will seek written voluntary informed consent from all 
participants prior to study entry. The initial consent form describes the nature of the 
procedures and time requirements, potential risks, the confidentiality of information, 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
24 
Revised 7/09/18 
and the rights of research participants. If the individual remains interested in the 
project, written informed consent is obtained, and medical and psychiatric screening 
procedures are undertaken to confirm eligibility. A copy of the consent form is 
provided to all participants. 
 
 
If the individual decides not to participate in this study, a staff member provides 
reasonable and timely assistance in obtaining an alternative referral, if so desired. The 
decision not to participate does not affect eligibility to participate in future studies, to 
receive treatment at Mount Sinai, or to receive treatment on a private basis from a 
referring clinician. Patients will be also given the opportunity to withdraw from the 
study prior to analysis of their data. 
 
The consent process also includes documentation of permission to obtain 
previous medical records, including contact with previous physicians, 
pharmacies, and family members. The IRB-approved forms for informed 
consent are made part of the patient’s permanent medical record, with a copy 
filed in the research chart. 
 
13) 
Process to Document Consent in Writing 
We will be using the standard PPHS consent template 
 
14) 
Vulnerable Populations 
Indicate specifically whether you will include or exclude each of the following 
populations: 
Include 
Exclude 
Vulnerable Population Type 
 
X 
Adults unable to consent 
 
X 
Individuals who are not yet adults (e.g. infants, children, teenagers) 
 
X 
Wards of the State (e.g. foster children) 
 
X 
Pregnant women 
 
X 
Prisoners 
 
The proportion of ethnic minorities (vs. Caucasian) in the total sample will be consistent 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
25 
Revised 7/09/18 
with the population proportions in the NYC metropolitan areas. We appreciate that 
minority groups tend to be underrepresented in research samples of major depressive 
disorder. Therefore, we will specifically aim to recruit minority patients to assure that the 
sample represents the community. However, the size of the racial sub-samples may be 
too small to identify statistically meaningful differences. 
 
 
Anticipated ethnic/racial distribution: Patients will be recruited from the catchment area 
of the Mount Sinai Medical Center, which is characterized by a diverse ethnic 
distribution consisting of 49 percent Hispanics, 38 percent Blacks and 7 percent Whites, 
and from the catchment area of our affiliated hospitals which are comprised of 22 percent 
Hispanics, 23 percent White non-Hispanics, 26 percent Asians and 24 percent Blacks.  
The diversity of the population in our catchment areas permits the recruitment of patients 
from most of the major ethnic groups including Asians and Pacific Islanders, Blacks, 
Hispanics from Mexico, Puerto Rico, Cuba, Central and South America, and Caucasians. 
 
There is general agreement in the literature that the prevalence of MDD is greater in 
women than in men. Therefore, we expect to recruit about 2/3 women and 1/3 men.  
 
Inclusion of Children 
This study will not include individuals under the age of 21. The rationale for this 
exclusion is that insufficient data are available in adults to judge the potential risk 
in children. 
 
15) 
Multi-Site Human Research (Coordinating Center) 
N/A 
16) 
Community-Based Participatory Research 
N/A 
17) 
Sharing of Results with Subjects 
N/A 
18) 
IRB Review History 
N/A 
 
19) 
Control of Drugs, Biologics, or Devices 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
26 
Revised 7/09/18 
Note: The IDS has its own forms that must be completed and a review process 
that must be followed before the IDS representative will sign off on Appendix B 
for submission to the PPHS. 
 
The pharmacist prepares the IV medication (KET and NP) in a 100 ml NS bag, 
and a nurse from the GCRC comes to retrieve it the morning of infusion, such that 
a fixed dose of ml per kg is administered.  
 
At approximately 9 am each patient will begin Infusion 1 (NP or PLC), then 200 
minutes later Infusion 2 (KET) will commence. The KET and NP will be stored 
and dispensed by the research pharmacy. 
 
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Ketamine and Phencyclidine, Selectively Reduce Excitation of Central Mammalian 
Neurones by N-Methyl-Aspartate.” British Journal of Pharmacology 79 (2): 565–
75. 
Berman, R M, A Cappiello, A Anand, D A Oren, G R Heninger, D S Charney, and J H 
Krystal. 2000. “Antidepressant Effects of Ketamine in Depressed Patients.” 
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Carpenter, W T. 1999. “The Schizophrenia Ketamine Challenge Study Debate.” 
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Cho, Hyun-Sang, Deepak C D’Souza, Ralitza Gueorguieva, Edward B Perry, Steven 
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2, Review and Implications.” Annals of Emergency Medicine 19 (9): 1033–46. 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
27 
Revised 7/09/18 
Hallak, Jaime E C, Joao Paulo Maia-de-Oliveira, Joao Abrao, Paulo R Evora, Antonio W 
Zuardi, Jose A S Crippa, Paulo Belmonte-de-Abreu, Glen B Baker, and Serdar M 
Dursun. 2013. “Rapid Improvement of Acute Schizophrenia Symptoms after 
Intravenous Sodium Nitroprusside: A Randomized, Double-Blind, Placebo-
Controlled Trial.” JAMA Psychiatry 70 (7). American Medical Association: 668–76. 
doi:10.1001/jamapsychiatry.2013.1292. 
Harraz, M M, R Tyagi, P Cortés, and S H Snyder. 2016. “Antidepressant Action of 
Ketamine via mTOR Is Mediated by Inhibition of Nitrergic Rheb Degradation.” 
Molecular Psychiatry 21 (3): 313–19. doi:10.1038/mp.2015.211. 
Hersack, R A. 1994. “Ketamine’s Psychological Effects Do Not Contraindicate Its Use 
Based on a Patient's Occupation.” Aviation, Space, and Environmental Medicine 65 
(11): 1041–46. 
Kandratavicius, Ludmyla, Priscila Alves Balista, Daniele Cristina Wolf, Joao Abrao, 
Paulo Roberto Evora, Alfredo Jose Rodrigues, Cristiano Chaves, et al. 2015. 
“Effects of Nitric Oxide-Related Compounds in the Acute Ketamine Animal Model 
of Schizophrenia.” BMC Neuroscience 16 (January): 9. doi:10.1186/s12868-015-
0149-3. 
Knox, J W, J G Bovill, R S Clarke, and J W Dundee. 1970. “Clinical Studies of Induction 
Agents. XXXVI: Ketamine.” British Journal of Anaesthesia 42 (10): 875–85. 
Krystal, J H, L P Karper, J P Seibyl, G K Freeman, R Delaney, J D Bremner, G R 
Heninger, M B Bowers, and D S Charney. 1994. “Subanesthetic Effects of the 
Noncompetitive NMDA Antagonist, Ketamine, in Humans. Psychotomimetic, 
Perceptual, Cognitive, and Neuroendocrine Responses.” Archives of General 
Psychiatry 51 (3): 199–214. 
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Ketamine Stimulate Psychosis in Schizophrenia.” Neuropsychopharmacology : 
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9–19. doi:10.1016/0893-133X(94)00131-I. 
Montgomery, S A, and M Asberg. 1979. “A New Depression Scale Designed to Be 
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Overall, John E, and Donald R Gorham. 1962. “The Brief Psychiatric Rating Scale.” 
Psychological Reports 10 (3). Ammons Scientific: 799–812. 
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Reich, D L, and G Silvay. 1989. “Ketamine: An Update on the First Twenty-Five Years 
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D’anesthésie 36 (2): 186–97. doi:10.1007/BF03011442. 
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“Specific Coupling of NMDA Receptor Activation to Nitric Oxide Neurotoxicity by 
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Schorn, T O, and J G Witwam. 1980. “Are There Long-Term Effects of Ketamine on the 
Central Nervous System?” British Journal of Anaesthesia 52 (10): 967–68. 


 
Protocol Title: 
Pharmacologic attenuation of ketamine using nitroprusside 
Principal Investigator 
Name/Contact Info:  
James Murrough/ james.murrough@mssm.edu 
Primary Contact 
Name/Contact Info 
Charlotte Pierce / charlotte.pierce@mssm.edu  
Date Revised: 
4/15/2019 
Study Number: 
HSM#16-00928/GCO#16-1580 
 
28 
Revised 7/09/18 
Stone, James M, Kjell Erlandsson, Erik Arstad, Lisa Squassante, Vincenzo Teneggi, 
Rodrigo A Bressan, John H Krystal, Peter J Ell, and Lyn S Pilowsky. 2008. 
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Receptor Occupancy: A [(123)I]CNS-1261 SPET Study.” Psychopharmacology 197 
(3): 401–8. doi:10.1007/s00213-007-1047-x. 
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of Ketamine in Mice.” European Neuropsychopharmacology : The Journal of the 
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