Clinical trial NCT02487485
Conditions: Depression
Sponsor: Yale University
Start date: 2016-03-01; Completion date: 2020-01-01
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The aim of the study is to provide insight into the impact of the immunosuppressant drug sirolimus, on the antidepressant effects of the prototypal rapid-acting antidepressant medication, ketamine.

Detailed description:
This is a double blind, placebo-controlled, crossover, randomized controlled trial investigating the impact of sirolimus on ketamine's antidepressant effects in participants with antidepressant-resistant depressive symptoms.

Prior to this, there was a phase 1 which included monitoring 3 subjects over the course of 7 days after a single dose of sirolimus and ketamine in order to inquire about side effects or interaction effects.

Arms: arm 1: Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg orally. After two weeks, they will recieve another infusion of ketamine, and a single dose of placebo. arm 2: Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg placebo. After two weeks, they will recieve another infusion of ketamine, and a single dose of sirolimus 6 mg.
Interventions: intervention 1: Ketamine intervention 2: sirolimus intervention 3: Placebo
Intervention descriptions: intervention 1: . Subjects will receive an infusion of ketamine (0.5 mg/kg infusion over approximately 40 minutes). All subjects will receive two ketamine infusions-once with a placebo and once with a single dose of sirolimus (6 mg, oral administration). intervention 2: Subjects will receive a single 6 mg oral dose via oral solution of sirolimus or a dose of placebo approximately two hours prior to the infusions. As above, the order of placebo and sirolimus is randomized. The sirolimus dose as well as the placebo solution will be given in 6 ounces of orange juice. intervention 3: Placebo oral dose

Protocol documents:
Prot_SAP_000.pdf: 
 
                                     
Ver. 01/09/19 
 I. PRINCIPAL INVESTIGATOR:  
Chadi Abdallah, M.D.*† 
 
ADDITIONAL INVESTIGATORS & RESEARCH STAFF: 
Lynnette Averill, Ph.D.*, Willie Ford, Angelina Genovese, R.N., Brenda Martini, M.A.*, 
Elizabeth O’Donnell, R.N., James Yaffe, A.P.R.N.†, Gihyun Yoon, M.D.†, Prerana Purohit, 
M.A.*, Christopher Averill, B.S., Teddy Akiki, M.D.*, Jeremy Roscoe, B.A.*, Selin Goktas, 
M.A.*, Evelyn Alkin, M.A.*, Mohsin Raza*, Amanda Brennan, M.A.*, Samar Fouda, M.D.*, 
Mohammed Alarasi, MBBCH*, Ali Moravej, MPH*,  
 
* Individuals who will be obtaining consent  
† Individuals authorized to prescribe study medication  
 
II. TITLE:  
Examining the Impact of Sirolimus on Ketamine’s Antidepressant Effects  
 
III. PURPOSE:  
Ketamine is an anesthetic agent, recently found to exert a rapid and potent antidepressant effect in 
severely depressed patients. Controversy exists in the field regarding how ketamine works in the 
brain and thus what underlies its rapid and profound antidepressant effects. A better understanding 
of the mechanism of the neuropsychiatric effects of ketamine are critically important, as 
pharmacological modulation of these effects can assist in the development of novel medications 
for the treatment of multiple psychiatric disorders including depression and schizophrenia.    
 
The aim of the study is to provide insight into the impact of the immunosuppressant drug sirolimus 
(also known as rapamycin; known to have impact on depressive symptoms from molecular and 
preclinical studies), on the antidepressant effects of the prototypal rapid-acting antidepressant 
medication, ketamine. More specifically, the study will examine whether sirolimus shows 
significant interactive effects (i.e., synergy or antagonism) with ketamine in participants with 
treatment resistant depression as measured by the use of the clinician-administered Montgomery 
Asberg Depression Rating Scale (MADRS). We will also test the tolerability of the combined 
ketamine and sirolimus treatment. Secondary outcome measures are designed to measure the 
effects of sirolimus on the tolerability of ketamine.  
 
§ Aim 1: To characterize the effects of a single dose of sirolimus prior to a low dose of 
ketamine in subjects with antidepressant-resistant depressive symptoms.   
Design: 30 participants will be randomized into one of two groups at Time/Infusion 1 — 
ketamine+sirolimus (with placebo at Time 2) or ketamine+placebo (with sirolimus dose at 
Time 2).   
Hypothesis: Sirolimus will interact with ketamine by attenuating or potentiating the 
antidepressant effects.   
 
§ Aim 2: To examine the safety and tolerability of combined ketamine-sirolimus treatment.        
Design: The Systematic Assessment for Treatment Emergent Effects (SAFTEE) scale will 
be completed during each visit to compare the adverse events profile in the sirolimus and 
the placebo groups. 


 
 
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Hypothesis: Participants will tolerate the combined treatment with no residual adverse 
effects. 
§ Aim 3: To identify biological markers of the combined ketamine-sirolimus treatment.        
Design: Inflammatory biomarkers will be measured in 18 depressed participants who will 
receive open-label sirolimus+ketamine. 
Hypothesis: Twenty-four hours post-treatment, sirolimus+ketamine will significantly 
reduce the inflammatory biomarkers. 
 
 
IV. BACKGROUND   
Despite 50 years of scientific progress, major depression remains among the leading causes of 
distress and disability in the world1, 2 with a 21-fold increase in suicide attempts during major 
depressive episodes.3 In the United States, the estimated lifetime prevalence is approximately 
seventeen percent.4 One potential reason for this sad state of affairs is that depression is treated 
today in basically the same way as it was in the early 1960’s, when the prescription of tricyclic 
antidepressants became widespread.  Depression is treated predominately by medications that 
enhance the impact of two brain chemical messengers (serotonin, norepinephrine).  While more 
than 20 antidepressant medications are currently available, the efficacy of these medications is 
limited.5-8 These antidepressants only produce clinical remission in approximately 30% of patients 
in their initial clinical trial, after two drugs are tried, each new attempt at treatment only 10%-15% 
of patients would remit, and after multiple trials over a year only 60%-70% of patients would have 
a satisfactory response to treatment.  Further, among those patients who do respond, clinical 
response only emerges, on average, after 7 weeks of treatment.9 From these data, it is evident that 
there is tremendous societal need for a novel class of antidepressants that can offer (1) rapid acting 
effects and (2) efficacy in patients not achieving adequate benefit from existing medications. Over 
the last decade, accumulating evidence has shown that low dose of ketamine, a N-methyl-D-
aspartate (NMDA) receptor antagonist, may possess both of these properties.10  
Members of our research group produced the first hint of a new approach that might address some 
of the limitations of existing antidepressant treatments.  We have studied ketamine, a drug that acts 
on brain systems that use glutamate as a chemical messenger11 and noted a very interesting clinical 
report from the late 1950s12 and later basic animal research studies13 that suggested that drugs that 
blocked elements of glutamate signaling in the brain might have antidepressant effects.  In 2000, 
we published a report suggesting that ketamine might have remarkable antidepressant effects.14 
First, rather than taking 7 weeks to respond, patients began to respond to treatment as early as 
within several hours of the first dose of ketamine.  Second, rather than producing response in 10%-
15% of patients “treatment-resistant” depression symptoms, 50% of patients met response criteria 
within 24 hours of their first ketamine.  Subsequent studies by other groups using ketamine and 
other ketamine-like drugs essentially replicated these observations in patients with unipolar and 
bipolar (manic-depressive) depression.15-19 Other groups, for example, showed that suicidal 
thoughts or feelings that had failed to respond to other medication and psychotherapy treatments 
responded rapidly to ketamine.20 In addition, ketamine worked even in patients who failed to 
respond to electroconvulsive therapy.21 Most importantly, the antidepressant effects of ketamine 
appear to be sustained by repeated ketamine administration.22, 23 To date, more than 15 studies 
have investigated the efficacy of 0.5 mg/kg ketamine infusion in more than 300 depressed 


 
 
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patients.14, 15, 20, 24-36 These studies consistently showed a rapid antidepressant action within 4-hours 
of ketamine’s administration, with a short-term response rate ranging from 43% to 90%.31, 37 
 
The mechanisms of action and underlying neurobiology of ketamine’s antidepressant effects are 
not yet fully known or understood. We believe that advancing our understanding of how ketamine 
acts on the brain to produce its antidepressant effects is critical for improving the effectiveness and 
safety of ketamine and/or novel drugs development from the ketamine model. The safety concerns 
related to ketamine emerge from its abuse liability and its propensity to produce transient changes 
in cardiorespiratory function as well as perception and mentation in humans.  In order to limit the 
risks of ketamine or to engineer a better ketamine, we need to better understand how it works. 
 
There is controversy in the field regarding how ketamine produces its antidepressant effects. 
Specifically, investigators argue whether the rapid-antidepressant effects of the drug are secondary 
to direct action or indirect consequence of ketamine’s effects on brain networks.  Stress and 
depression appear to strip the brain of fine connections between nerve cells (dendritic spines) 
within brain circuits that regulate mood.  Ketamine appears to cause these fine connections to 
regrow rapidly in animals for a period that lasts as long as the antidepressant effects of a single 
ketamine injection last in humans, i.e., up to 
a few weeks.38   
 
The indirect network effects of ketamine, 
sometimes described as “stimulating the go 
pathway” described in figure 1,39 is central to 
our proposal. One line of research suggests 
that the ability of ketamine to stimulate 
glutamate release and to thereby activate a 
signaling pathway in nerve cells involving a 
protein called “the mammalian target of 
rapamycin” (mTOR).  According to this 
theory, the co-administration of sirolimus, an 
immunosuppressant 
drug 
commonly 
prescribed for prophylaxis of renal transplant 
rejection, should reduce the antidepressant 
effectiveness of ketamine.  
 
However, the other major hypothesis is 
related to the ability of ketamine to directly 
block signaling via the “stop pathway”, i.e., 
to remove an inhibition on dendritic spine 
growth.40 By blocking a very specific sub-
type of receptor target for glutamate in the 
brain (NR2B subunit-containing NMDA 
glutamate receptor), ketamine may directly 
help dendritic spines to regrow in a manner 
that is independent of mTOR.  Sirolimus has 
been repeatedly shown to have the potential 
 
Figure 1. The top figure illustrates the presence of 
synaptic (receives directly released glutamate) and 
extrasynaptic (receives glutamate “spillover” from 
the synapse) glutamate receptors.  Ketamine may 
exert its treatment effects either indirectly by 
increasing glutamate release and stimulating the 
“go pathway” (synaptic AMPA glutamate receptors) 
or by blocking the “stop pathway” (extrasynaptic 
NR2B-containing NMDA glutamate receptors). 


 
 
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to produce anti-depressant effects in animals41, 42 and to have beneficial effects in animal models 
of other neuropsychiatric disorders,43 perhaps by having anti-inflammatory effects in the brain.  A 
study suggests that standard antidepressant administration reduces mTOR levels, an effect that 
would mimic the acute effects of sirolimus.44 Thus, if the direct effects of ketamine on the “stop 
pathway” pertain, then the antidepressant effects of sirolimus might increase the efficacy of 
ketamine. 
 
Molecular studies in animals have found that synaptic deficits are precipitated by reduction in 
neurotrophins such as BDNF,45 and by inhibition of mTOR signaling pathway.46 Inhibition of 
mTOR signaling or reduction of BDNF leads to depressive-like behavior and blocks the effect of 
antidepressants in animal models of depression.45, 46 Enhancing mTOR signaling or increasing 
BDNF produces antidepressant effects in preclinical studies.45, 46 In humans, reduced central and 
peripheral BDNF levels were found in depressed patients45, 47 and a functional variant of BDNF 
polymorphism (Val66Met) has been related to depression, especially in males.48 Together these 
data posit that enhancing DBNF and mTOR signaling leading to prefrontal synaptic formation 
(synaptogenesis), and reversal of stress/depression-induced neuronal atrophy and synaptic 
dysconnectivity is a required step for efficacious antidepressant treatment. Traditional 
antidepressants, targeting the monoaminergic system, were found to increase BDNF and 
synaptogenesis.45, 49 However, these effects were only evident following chronic treatment, which 
is in line with the delayed antidepressant response to these drugs in humans. Therefore, it is 
proposed that rapid acting antidepressants would need to directly target the induction of mTOR 
signaling, the increase of BDNF levels, and the ultimate enhancement of prefrontal 
synaptogenesis.  
 
Thus, we have the basis for proposing to test the interactive effects of ketamine and sirolimus, a 
simple clinical trial that has: 1) the potential to shed fundamental light on how ketamine produces 
rapid clinical improvement and 2) to suggest a strategy for increasing the effectiveness of 
ketamine.  If sirolimus reduces the antidepressant effects of ketamine, then we will know that 
stimulation of mTOR is critical to the antidepressant effects of ketamine, leading us to test other 
drugs that directly stimulate this signaling pathway. 
 
The results of Phase 1 & 2 of this study have shown sirolimus pretreatment significantly prolong 
the antidepressant effects of ketamine and triples the antidepressant response rate at 2 weeks 
following treatment (see Fig. 2) 50. Given the role of the immune system in the pathology and 
treatment of depression, it was proposed that the anti-inflammatory effects of the combined 
treatment of sirolimus+ketamine underlie the robust enhancement in treatment response rate. 
Therefore, we will conduct a pilot study to determine the effects of sirolimus+ketamine on a range 
of inflammatory biomarkers implicated in the pathology of depression. The aim of this Phase 3 of 
the study is to provide preliminary data about target engagement of the sirolimus+ketamine 
treatment. The treatment and follow-ups will be comparable to the Phase 2 study, but only open-
label sirolimus+ketamine will be administered and the weekly follow-ups will be extended to 4 
weeks post-treatment. 
 
V. SIGNIFICANCE: 
The proposed project has potential to yield results critical to developing rapid-acting 
antidepressant medications based on the ketamine model. Specifically, if our results indicate 


 
 
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synergistic antidepressant effects, then we can pursue the combination of immunosuppressant and 
antidepressant therapy as a new approach to the treatment of depression.  If we see antagonist 
effects of sirolimus on ketamine, then we will have learned that stimulating the mTOR signaling 
pathway is critical to the antidepressant effects of ketamine, resolving a major controversy in the 
field and implicating drugs facilitating mTOR signaling in the treatment of depression.  
 
This proposal has potential to provide critical insights into the mechanisms of ketamine’s 
antidepressant effects thus advancing our understanding of the neurobiology of depression and 
informing novel drug development for a new generation of rapid-acting antidepressants.  
 
VI. RESEARCH PLAN: 
 
This project will be divided into three phases as described below:  
 
Phase One: Open Label 
We anticipate recruiting 3 male or female Veterans or civilians, between the ages of 21-65 years, 
for an open-label, extended-observation trial in order to first evaluate the safety of combining 
Ketamine with Sirolimus (same inclusion/exclusion criteria, recruitment procedures, and 
assessments as detailed below under Phase two of the study). Specifically, we will implement a 
10- hour post-Sirolimus observation period that will take place in the Biostudies Unit (9th floor, 
building 1). Participants will then be asked to return to Biostudies on the morning following the 
administration of Rapamycin and Ketamine for additional assessment. Transportation will be 
arranged from Biostudies to the participants’ homes and back to Biostudies the following day. In 
addition, the participants will be provided with a direct telephone number that they can use at any 
time between the end of the 10-hour observation phase and their appointment on the following day 
so they can contact a study psychiatrist in case of emergency or adverse effects. For 7 days after 
the treatment, a study clinician will contact subjects daily to inquire about side effects or interaction 
 
Figure 1. The Study Drug Effect on Montgomery Åsberg Depression Rating Scale (MADRS). (A) There is a 
significant main effect of time (F(8,245) = 43.5, p < 0.0001), demonstrating significant decrease in MADRS scores from 
baseline. There is also significant interaction between treatment and time (F(8,245) = 2.0, p = 0.04), with overall 
reduction in depression scores following treatment with rapamycin+ketamine (Rapamycin; blue line), compared to 
post placebo+ketamine (Placebo; red line). (B) Response rate was significantly higher following treatment with 
rapamycin+ketamine (Rapamycin; blue), compared to post placebo+ketamine (Placebo; red). NOTES: Response was 
defined as 50% improvement in MADRS from baseline; Error bars are standard errors of mean (SEM); d` = Cohen’s 
d` effect size compared to pretreatment MADRS scores; Comparison at each time point is marked with * for p ≤ 0.05 
and t for p = 0.12; 


 
 
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Page 6 
 
effects that participants may be experiencing as a result of the study medications. The Phase One 
procedures are further detailed below:  
 
Phase One Research Procedures 
 
Day 1: 
T-130 min: Subjects will present to the VACHS to complete vitals and provide a urine sample for 
drug and pregnancy testing.  
T-120 min: Subjects will receive a single 6 mg oral dose of sirolimus. They will be monitored for 
any acute allergic reaction or other adverse event. Clinical assessments administered including 
PSWQ, PSQI, MADRS, QIDS-SR, CGI, HAM-A, CADSS, PANSS (assessment measures are 
described below). 
T-60: Intravenous lines started.  
T 0*: Blood draw for sirolimus level. Ketamine infusion begins (0.5 mg/kg infused over 
approximately 40 minutes). Subjects will be monitored closely by study physician and nurse.  
T+15: Blood draw for sirolimus and ketamine levels. 
T+30: CADSS, PANSS.  
T+40: Blood draw for sirolimus and ketamine levels. 
T+60**: MADRS, QIDS-SR, CGI.  
T+120: CADSS, PANSS, MADRS, QIDS-SR, CGI. 
T+230: MADRS, QIDS-SR, CGI, HAM-A. 
 
Ten hours post sirolimus administration, subjects will be evaluated by a study physician or APRN 
and will be medically cleared for discharge. Subjects will be provided with a study physician’s 
direct telephone number that they can use at any time in case of emergency or adverse effects.  
 
*Blood pressure, heart rate, and oxygen saturation will be recorded every 10 minutes during 
infusion (T0-40 minutes).  
Ketamine Administration Notes:  
Subjects in Phase One will receive one infusion of ketamine (0.5 mg/kg infusion over 
approximately 40 minutes). The ketamine dose and route of administration are similar to that seen 
in previous investigations and has demonstrated high safety and tolerability.  
 
A physician who is trained and has significant experience with both ketamine and infusion studies 
will oversee and administer the ketamine infusions. A nurse will also be present with the subject 
from the insertion of bilateral cannula for drug infusion and blood sampling, through to recovery 
following ketamine infusion. 
Sirolimus Administration Notes:  
Subjects will receive a single 6 mg oral dose via oral solution of sirolimus approximately two 
hours prior to the Ketamine infusion. The sirolimus dose will be given in 2 ounces of orange juice 
with 4oz of water. As for the tolerability of single dose of sirolimus, based on data in healthy 
subjects51 and consultation with Dr. Richard Formica, Director of Transplant Medicine, Yale 
University, an expert with sirolimus treatment, it is expected that a single 6 mg oral dose will 
produce minimal adverse effects. 
 


 
 
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Page 7 
 
Day 2 /Follow-Up: 
Subjects will present to the VACHS to complete clinical assessments and a brief cognitive 
assessment. Procedures for this 24-hour follow-up will be identical to Phase Two follow-up 
procedures described below; however, subjects who participate in this 24-hour follow-up for 
Phase One will not receive any medications or infusions at follow-up. They will be asked about 
any residual side effects of other adverse events (AEs) and any appropriate referral for treatment 
will be made as necessary. Transportation to and from Biostudies will be arranged.   
 
Days 3-7/ Phone Follow-Up: 
After the Day 2 in-person follow-up, to further assess the safety of combined ketamine and 
sirolimus, a study clinician will contact Phase One participants by telephone, daily until Day 7. 
During these daily telephone follow-ups, subjects will be asked about potential side effects or 
interaction effects they may be experiencing related to the study medications.  
 
 
After three participants undergo Phase One of this study, The PI will report findings and any issues 
to the Data and Safety Monitoring Committee (DSMC). The PI will not proceed to Phase Two of 
the study without a review and recommendation of continuation by the DSMC and subsequent full 
HSS review and approval of the DSMC’s report.  
 
Note: Participation in Phase One will not exclude subjects from participating in Phase Two if they 
so choose.  
 
A. Phase Two Research Procedures (following DSMC approval) Subjects:  
We anticipate recruiting and screening approximately 75 male and female Veterans and non-
Veterans/civilians, between the ages of 21-65 years, in order to meet our target enrollment goals. 
In order to account for subject dropouts and the potential need to discontinue subjects before study 
completion (see below for discontinuation criteria) and retain a sample of 30 subjects completing 
the double-blind treatment phase, 45 eligible subjects who meet criteria for Major Depressive 
Episode as determined by the Mini International Neuropsychiatric Interview (MINI) the study 
inclusion criteria outlines below, will be randomized into the study.  Note, this study will not 
include a healthy control group as we are interested specifically in the antidepressant effects of 
ketamine and sirolimus and therefore require subjects with current depression.  
 
B. Inclusion and Exclusion Criteria: 
 
Inclusion Criteria:  
1. Veterans and non-Veterans between the ages of 21-65.  
2. Diagnosis of Major Depressive Episode (unipolar or bipolar) as determined by the Mini 
International Neuropsychiatric Interview (MINI).  
3. Antidepressant-resistant depressive symptoms, defined by a history of failure of one or 
more adequate antidepressant trials.  
4. Stable doses of antidepressants (if prescribed) for a period of four weeks or longer at the 
time of randomization, except for MAOIs which are prohibited (see Table 1 for 
exclusionary medications). 


 
 
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Page 8 
 
5. Stable course of psychotherapy (if engaged in) for a period of four weeks or longer at the 
time of randomization.   
6. Females will be included if they are not pregnant or breastfeeding and agree to utilize a 
medically accepted birth control method (to include oral, injectable, or implant birth 
control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, 
abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or 
surgically sterile. For those women who are taking an oral contraceptive, we will also ask 
that they use (or ask their partners to use) a barrier method contraceptive.  
7. Able to provide written informed consent according to VA HSS guidelines.  
8. Ability to read and write in English.  
9. A score greater than or equal to 18 on the Montgomery Åsberg Depression Rating Scale 
(MADRS). 
 
Exclusion Criteria:  
1. Subjects with a diagnostic history of schizophrenia or schizoaffective disorder, or currently 
exhibiting manic or mixed episodes or psychotic features as confirmed by the Mini 
International Neuropsychiatric Inventory. 
2. Current, ongoing serious suicidal risk as assessed by evaluating investigator or by scoring 
5 or more on the item-10 of the MADRS. 
3. Patients with unstable or inadequately controlled medical conditions. 
4. Patient requiring prohibited medication (see Table 1).  
5. Patient with history of organ transplant.  
6. Meet criteria for a diagnosis of substance dependence (amphetamines, cocaine, 
hallucinogens, inhalants, opioids, sedatives/hypnotics/anxiolytics) within the three months 
prior to screening date.  
7. Positive urine drug screen for  cannabis, cocaine, PCP, or barbiturates. 
8. Positive pregnancy test at screening at any screen given during the study.  
9. Known sensitivity to sirolimus or ketamine. 
10. History of sensitivity to heparin or heparin-induced thrombocytopenia.  
11. Resting blood pressure lower than 85/55 or higher than 150/95, or resting heart rate lower 
than 45/min or higher than 100/min.  
 
Table 1. 
Concomitant Treatments that are prohibited 
Use category 
Type of medication 
Details 
Prohibited 
MAOIs 
Prohibited 4-week prior to 
randomization. 
 
VNS, ECT, deep brain stimulation 
VNS, ECT, or within 6 months at 
randomization is exclusionary. 
 
Memantine 
Prohibited 4-week prior to 
randomization. 
 
Barbiturates 
Prohibited 2-week prior to 
randomization. 
 
Cidofovir, Mifepristone, Posaconazole, 
Streptozocin, Ketoconazole, 
Voriconazole 
 
Prohibited 2-weeks prior to 
randomization and throughout the 
study.  


 
 
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Table 1. 
Concomitant Treatments that are prohibited 
Use category 
Type of medication 
Details 
 
Adenovirus vaccine, live; BCG live 
intravesical; Influenza nasal vaccine, 
live; Measles/Mumps/Rubella vaccine, 
live; Rotavirus vaccine, live; Smallpox 
vaccine (live vaccinia virus); Typhoid 
vaccine, live; Varicella vaccine, live; 
Yellow fever vaccine, live; Zoster 
vaccine, live 
 
Strong inducers (e.g., rifampin, 
rifabutin) and strong inhibitors (e.g., 
itraconazole, erythromycin, 
telithromycin, clarithromycin) of 
CYP3A4 and P-gp 
Prohibited 2-weeks prior to 
randomization and for 3 months 
after completing the study. 
 
 
 
 
 
 
Prohibited 2-weeks prior to 
randomization and throughout the 
study. 
Permitted 
with 
restrictions* 
 
Benzodiazepines (stable dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modulators of CYP3A4 and P-gp; drugs 
that could increase sirolimus blood 
concentrations (e.g., bromocriptine, 
cimetidine, cisapride, clotrizamole, 
danzol, diltiazem, fluconazole, protease 
inhibitors, metoclopramide, nicardipine, 
troleandomycin, verapamil); drugs and 
other agents that could decrease 
sirolimus levels (e.g., carbamazepine, 
phenobarbital, phenytoin, rifapentine, 
St. John’s Wort); drugs with 
concentrations that could increase when 
given sirolimus (e.g., verapamil).  
Benzodiazepines are permitted 
only if the patient has been taking a 
stable regimen and dose at least 4 
weeks prior to randomization.  The 
dosage prior to randomization 
should be no more than 
Clonazepam maximum dose 
3 mg/day or equivalent. 
For patients reporting significant 
treatment-emergent nervousness, 
restlessness, and/or akathisia, study 
clinicians are allowed to increase 
the dose of the concomitant 
benzodiazepine anxiolytic up to 
additional clonazepam 1 mg/day 
equivalents. 
 
Permitted only at the discretion of 
the prescriber after careful review 
of concomitant medications.  
 
 


 
 
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Notes: Sedatives, hypnotics, benzodiazepines, sedating antihistamines or other 
psychotropic medications are not permitted within 8 hours of treatment sessions; except – 
at the discretion of the investigator – for medications that will results in 
discontinuation/withdrawal symptoms or that may alter the risk benefit ratio.  
*All prescribers will be provided with the list of prohibited and restricted medications as 
detailed in the sirolimus manufacturer information and made aware that medications should 
be used with caution.  
 
Privacy:  
All reports generated from the data obtained through this study will protect the confidentiality of 
the subjects who participate in this study.  In case of a medical emergency, the medication group 
blinding can be broken by the principal investigator or a designated covering staff member, in 
order to supply information required for emergency medical care of research subjects. All subjects 
will be given a “wallet card” which identifies them as a study participant and lists the emergency 
contact numbers.  If a subject shows clinical deterioration (worsening of depressive symptoms that 
is higher than 25% of baseline MADRS scores), the participant will exit the study and a study 
psychiatrist (or APRN) will determine whether a higher level of care (e.g. referral to treating 
psychiatrist or referral to emergency or inpatient care) is needed. 
 
Selection:  
Subject eligibility will first be determined via telephone screening and if records are available, by 
a preliminary medical record review. A waiver of HIPAA authorization and written informed 
consent will be obtained for a brief initial phone pre-screen (see Appendix 1) and preliminary 
medical record review. The phone pre-screen and preliminary medical record review will be done 
to determine obvious exclusions from the study protocol and to prevent subjects from making 
unnecessary travel for screening. A separate Phone Pre-screen Identification Page (see Appendix 
2) will be completed during each telephone pre-screen so the research staff will have the necessary 
information to access potential participants’ medical records (with the proper verbal assent) and 
re-contact them for purposes of appointment scheduling.  This identification page will be stored in 
a separate location from the screening form that will only list the subject ID.  
 
Recruitment: 
Subjects will be recruited by flyers, public advertisements (e.g., print, newspaper, radio, bus, 
billboards, online postings (including Trialfacts/Rewards for Research online marketing and 
recruitment service and Craigslist.com), social media (e.g., Facebook, Twitter, Instagram), digital 
media (e.g., TV, online radio, podcasts),by word of mouth, clinician referral, contact with 
community service groups and clinics, and through IHR0010, Screening for Depressive, Anxiety, 
and Trauma and Stress-Related Disorders. We intend to register our study on clinicaltrials.gov. 
We may also utilize the National Center for PTSD newsletter to advertise the study. Subjects will 
be identified by their response to advertisements and/or internal recruiting. The subjects will be 
asked to call us if they are interested in participating in the research study. A waiver of HIPAA 
authorization and written informed consent will be requested for a phone screen and preliminary 
medical record review in advance of scheduling the in-office screening procedures. There will not 
be any web-based questionnaires utilized for pre-screening subjects in this study. All available 
research staff are responsible for recruiting potential subjects.  


 
 
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Page 11 
 
 
Research Plan and Study Procedures: 
This is a double blind, placebo-
controlled, 
crossover, 
randomized 
controlled trial investigating the impact 
of 
sirolimus 
on 
ketamine’s 
antidepressant effects in participants 
with 
antidepressant-resistant 
depressive symptoms. Participants will 
be treated twice with ketamine 0.5 
mg/kg infused over 40 minutes, 
combined with a single dose of 
sirolimus 6 mg orally or placebo. The 2 
infusions of ketamine are separated by 
at least 2 weeks interval because based 
on previous studies the majority of 
patients 
return 
to 
their 
baseline 
depression severity within this time 
period. A description of each study visit 
is provided here and summarized in 
Figure 3. See Table 1 for detail 
regarding the schedule of study events.  
 
 
Day 0-Baseline Screening: 
Individuals deemed eligible after the 
telephone pre-screening will undergo a 
full in-person screening appointment at 
the VA Connecticut Healthcare System 
(VACHS), 
West 
Haven 
campus.  
During the evaluation, the study 
procedures will be described and the 
subject’s questions will be answered 
prior to obtaining an informed consent.  
The investigator or research staff 
member obtaining consent will ask the 
participant to provide a brief summary 
of the study to ensure they understand 
what is being asked of them and any 
potential risks and benefits.  Once 
consent is obtained, subjects will 
participate in the following procedures: 
a biopsychosocial interview, psycho-
logical evaluation, a brief cognitive 
evaluation, a physical examination, 
ECG, breathalyzer and a blood sample 
Figure 3. Phase 2 study design. 
 


 
 
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Page 12 
 
for routine testing. A urine sample will be collected for urine toxicology, pregnancy, and 
urinalysis.  
 
In addition, because this is a clinical trial for medications for increased safety pre-cautions, female 
subjects of childbearing age will have a blood sample drawn for a pregnancy test.  If a female 
subject is pregnant, breast-feeding, intending to become pregnant, or does not agree to use an 
approved birth control method (i.e., oral, injectable, or implant birth control, condom, diaphragm 
with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) she will 
be excluded.  
 
After completing the baseline screening and being deemed eligible for participation in the study, 
subjects will be randomized to one of two conditions at Time/Infusion 1 — ketamine+sirolimus 
(with placebo at Time 2) or ketamine+placebo (with sirolimus dose at Time 2).  
 
Day 1 / Infusion 1: 
First, the MADRS assessment will be completed to confirm that the participant continues to have 
significant depressive symptoms (i.e. MADRS ≥ 18) prior to proceeding with Infusion 1. 
Participants will be rescheduled if depression severity was not met‡. If depression severity is 
confirmed, Infusion 1 procedures will be completed as follows: 
• Subjects will present to the VACHS to complete vitals and provide a urine sample for drug 
and pregnancy testing.  
• Subjects will receive a single 6 mg oral dose of sirolimus or placebo, dependent on their 
randomization. They will be monitored for any acute allergic reaction or other adverse 
event. Clinical assessments will be administered throughout the infusion visit, including 
PSWQ, PSQI, MADRS, QIDS-SR, SAFTEE, CGI, HAM-A, CADSS, PANSS** 
(assessment measures are described below). 
• Intravenous lines will be placed.  
• A blood draw for sirolimus level will occur prior to the beginning of the ketamine infusion.  
• Ketamine 0.5 mg/kg will be infused over approximately 40 minutes. Subjects will be 
monitored closely by study physician and nurse.  
• A blood draw for ketamine will occur during the ketamine infusion. 
• One additional blood draw for sirolimus will occur shortly before the participants are 
discharged from their study visit.  
• Subjects may be discharged home after being cleared by a study physician.   
 
‡ Screening procedures will be repeated if participant was not randomized within 60 days of 
screening. *Blood pressure, heart rate, and oxygen saturation will be recorded every 10 minutes 
during infusion (T0-40 minutes). ** Items that could not change within a session, e.g. sleep and 
appetite, will be carried forward from the initial ratings. 
Day 2+ / 24-hour Follow-Up: 
Subjects will present to the VACHS to complete clinical assessments and a brief cognitive 
assessment. They will be asked about any residual side effects of other adverse events (AEs) and 
any appropriate referral for treatment will be made as necessary.  
 


 
 
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Days 3-7+/ Phone Follow-Up: 
A study staff member will contact participants by telephone every other day after the 24-hour 
follow-up until day 7 of the study to track symptom trajectory using QIDS and MADRS. During 
these telephone follow-ups, subjects will also be asked about potential side effects or interaction 
effects they may be experiencing related to the study medications. 
  
Day 8+ / 7-Day Follow-Up:  
The procedures for this visit are identical to those described above for Day 2. For special 
circumstances (e.g., inclement weather, transportation issues, considerable travel burden, etc.) 
this visit may occur over the phone. In the cases where a phone visit is required, we will forego 
the cognitive testing as there is not a way to administer this remotely, but all clinical measures 
and review of AEs will take place.   
 
Day 15+ / 14-Day Follow-Up and Infusion 2:  
First, the MADRS assessment will be completed to confirm that the participant continues to have 
significant depressive symptoms (i.e. within 20% of their baseline MADRS) prior to proceeding 
with Infusion 2. If depression severity is confirmed, Infusion 2 procedures will be identical to 
Infusion 1. As this is a crossover study, those subjects who received sirolimus on Day 1 will receive 
placebo in the second infusion and those who received placebo will receive sirolimus. 
 
Based on several studies, we predict the vast majority of subjects will have returned to within 20% 
of their baseline depressive symptoms within the 2 weeks period. Should a subject not have 
returned to within 20% of their baseline depressive symptoms, Infusion 2 will be rescheduled. We 
will continue to monitor the participant weekly with full assessments identical to Day 2. 
Participants will be discharged from the study should they maintain these benefits for more than 5 
weeks after Infusion 1.  
 
Day 16+ / 24-Hour Follow-Up to Infusion 2:  
The procedures for this visit are identical to those described above for Day 2.  
 
Days 17-21+/ Phone Follow-Up: 
A study staff member will contact participants by telephone every other day after the 24-hour 
follow-up until day 21 of the study to track symptom trajectory using QIDS and MADRS. During 
these telephone follow-ups, subjects will also be asked about potential side effects or interaction 
effects they may be experiencing related to the study medications. 
 
Day 22+ / 7-Day Follow-Up to Infusion 2:  
The procedures for this visit are identical to those described above for Day 2. For special 
circumstances (e.g., inclement weather, transportation issues, considerable travel burden, etc.) 
this visit may occur over the phone. In the cases where a phone visit is required, we will forego 
the cognitive testing as there is not a way to administer this remotely, but all clinical measures 
and review of AEs will take place. 
 
Day 29+ / 14-Day Follow-Up to Infusion 2:  
The procedures for this visit are identical to those described above for Day 2. In addition, 
participants will be discharged from the study with appropriate referral. For special 


 
 
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Page 14 
 
circumstances (e.g., inclement weather, transportation issues, considerable travel burden, etc.) 
this visit may occur over the phone. In the cases where a phone visit is required, we will forego 
the cognitive testing as there is not a way to administer this remotely, but all clinical measures 
and review of AEs will take place. 
 
Day 43+ / 28-Day Telephone Call:  
A telephone call will be made to all subjects to inquire about any potential residual effects of 
ketamine or sirolimus and other AEs. Any additional follow-up and/or referrals will be arranged 
as clinically indicated.  
 
Phase Three Research Procedures:  
We anticipate recruiting and screening approximately 35 male and female Veterans and non-
Veterans/civilians, between the ages of 21-65 years, in order to meet our target sample of 18 
subjects. Screening, enrollment and discontinuation criteria are identical to Phase 1 and 2. 
Treatment and study procedures are identical to Phase 2, except that participants will have only 1 
treatment day (i.e., Infusion 1) with open-label sirolimus+ketamine (i.e., no Infusion 2 of 
placebo+ketamine). The weekly follow-up post Infusion 1, will be up to Day 29+ (i.e., 4 weeks 
follow-ups instead of 2 weeks). The follow-up period was extended considering the prolonged 
antidepressant effects of the combined sirolimus+ketamine treatment. The collection, processing 
and analysis of peripheral inflammatory biomarkers will be completed under a separate protocol 
and consent (i.e., CA0008). Participants in Phase 2, who consented to be contacted for future 
studies, will be invited to participate in Phase 3. This approach will both facilitate recruitment and 
reduce study risk as these participants who already received and well tolerated the study drug. 
 
Ketamine Administration:  
Subjects will complete two test days separated by at least two weeks. Subjects will receive an 
infusion of ketamine (0.5 mg/kg infusion over approximately 40 minutes). All subjects will receive 
two ketamine infusions—once with a placebo and once with a single dose of sirolimus (6 mg, oral 
administration). The order of placebo and sirolimus is randomized.  Note, the ketamine dose and 
route of administration are similar to that seen in previous investigations and has demonstrated 
high safety and tolerability.  
 
A physician who is trained and has significant experience with both ketamine and infusion studies 
will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout 
the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, 
through to recovery following ketamine infusion. 
Sirolimus or Placebo Dosing:  
Subjects will receive a single 6 mg oral dose via oral solution of sirolimus or a dose of placebo 
approximately two hours prior to the infusions. As above, the order of placebo and sirolimus is 
randomized. The sirolimus dose as well as the placebo solution will be given in 2 ounces of orange 
juice, followed by 4 oz of water. As for the tolerability of single dose of sirolimus, based on data 
in healthy subjects51 and consultation with Dr. Richard Formica, Director of Transplant Medicine, 
Yale University, an expert with sirolimus treatment, it is expected that a single 6 mg oral dose will 
produce minimal adverse effects. 


 
 
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Page 15 
 
 
Screening Measures: 
Assessments that will be used during the psychological evaluation are listed below. 
 
Psychological Evaluation:  
 
1. Alcohol and Consumption Habits: This is a brief measure that documents alcohol, caffeine, 
and nicotine habits.  
2. Beck Suicide Ideation Scale (BSI): The BSI is a 21-item self-report questionnaire that may be 
used to identify the presence and severity of suicidal ideation. Items on this measure also assess 
the respondent's suicidal plans, deterrents to suicide, and the level of openness to revealing 
suicidal thoughts. 
3. Behavioral Inhibition & Activation Scales (BIS/BAS): The BIS/BAS is a self-report scale 
designed to assess dispositional sensitivity to the behavioral inhibition system (BIS) and the 
behavioral activation or behavioral approach system (BAS).  
4. Big Five Inventory (BFI): The BFI measures an individual on the Big Five Factors 
(dimensions) of personality (Goldberg, 1993). Each of the factors is then further divided into 
personality facets.  
5. Brief TBI Screen: The Brief Traumatic Brain Injury Screen, also called the DVBIC TBI 
Screening Tool, is a 3-item instrument used to evaluate the presence of head injury and 
related symptomatology. It was validated in a small, initial study conducted with active 
duty service members who served in Iraq/Afghanistan between January 2004 and January 
2005. 
6. Clinical Global Impressions Scale (CGI) and the Patient Global Impressions Scale (PGI): The 
CGI and PGI are widely used instruments, which assess overall severity of illness on a 1 to 7 
point scale with 1 indicating “normal, not at all ill” and 7 indicating “among the most extremely 
ill patients.” These instruments also assess global improvement on a 1-to-7 point scale with 1 
indicating “very much improved,” 4 indicating “no change” and 7 indicating “very much 
worse.”  
7. Clinician Administered Dissociative States Scale (CADSS): The CADSS has self and 
interviewer-administered items including 5 subscales, generated a priori, evaluating 
dissociation including altered environmental perception, time perception, spatial/body 
perception, derealization and memory impairment.  
8. Cognitive tasks: This will include CogState, a well-validated short computerized cognitive 
tasks. These short computerized tasks along with a brief neuropsychological battery will assess 
cognitive functions.  
9. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a brief clinician 
administered and standardized measure that uniquely assesses essential information about 
suicide behavior, ideation, lethality and severity, and distinguishes between suicidal 
occurrences and non-suicidal self-injury.  
10. Early Trauma Inventory (ETI-SR): The ETI-SR is a self-report instrument to assess childhood 
trauma and includes physical, emotional and sexual abuse as well as general traumas.  
11. Global Perceived Early Life Stress (GPELS): The GPELS is a self-report of perceived stress 
during childhood.  
12. Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a standardized clinician-rated 
instrument to evaluate the severity of anxiety symptoms.  
13. Klein Loss Scale (KLS): The KLS is a self-report of parental loss or separation during 
childhood.  


 
 
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Page 16 
 
14. Life Events Checklist (LEC): The LEC is a self-report instrument that measures reports of 
traumatic life events.  
15. Perceived Stress Scale (PSS): This is a 10-item self-report questionnaire to assess the 
severity of perceived stress over the past month. 
16. Cumulative Adversity Interview (CAI): A multifaceted semi-structured assessment of 
stressful life events and chronic subjective stress used in research on stress and 
psychopathology. 
17. Massachusetts General Hospital Antidepressant Treatment History Questionnaire (MGH-
ATRQ)-This is a self-rated questionnaire used to determine treatment resistance in major 
depressive disorder.  
18. Montgomery-Asberg Depression Rating Scale (MADRS): The MADRS is a standardized 
instrument to ascertain depressed mood and neurovegetative signs and symptoms of 
depression.  
19. Penn State Worry Questionnaire (PSWQ): The PSWQ is a self-report questionnaire to assess 
for ‘worry’ symptoms that are typical of generalized anxiety.  
20. Pittsburgh Sleep Quality Index (PSQI): The PSQI is a self-report questionnaire to assess sleep 
quality and sleep disturbance.  
21. Positive and Negative Symptom Scale (PANSS): The PANSS is commonly used to measure 
the severity of symptoms in psychotic disorders. It is a clinician- administered scale and 
includes three categories of symptoms: (1) positive symptoms, such as hallucination and 
delusion; (2) negative symptoms, such as flat affect and difficulty in abstract thinking; (3) 
general psychopathology, such as mannerisms and posturing.  
22. PTSD Checklist (PCL): The PCL is used to measure PTSD symptoms and is a self-report 
questionnaire that has high reliability.  
23. Quick Inventory of Depressive Symptoms – Self-Report (QIDS-SR): The QIDS-SR is a 
patient-rated depression instrument.  
24. Sheehan Disability Scale (SDS): The SDS is a brief self-rated measure of disability and 
impairment.  
25. Systematic Assessment for Treatment Emergent Events (SAFTEE): The SAFTEE is a 
commonly used instrument originally developed by NIMH and adapted into a self-report 
instrument. It examines, in systematic fashion, possible treatment-emergent side effects and 
probes for specific adverse symptoms, including suicidal thoughts and behaviors, and self-
injurious behavior.  
26. The Mini International Neuropsychiatric Interview (MINI) will be used to provide current 
and past diagnoses of psychiatric disorders, notably the inclusion/exclusion criteria of a 
current major depressive episode.   
27. Socio-demographic/General Information: At intake, demographic data and medical history 
will be assessed with interviews and self-report forms that provide data on age, race, 
socioeconomic status, marital status, educational and occupational levels, and significant 
medical history.  These are adapted from previous diagnostic and clinical studies at this 
center.  
 
Medical Assessments: 
1. Physical exam by a licensed physician, or Advanced Practice Registered Nurses (APRN’s).  
2. Routine laboratory studies including a complete blood count (CBC) w/ differential, a 
comprehensive metabolic panel, HCG, TSH, fT4, CRP, and ESR, in addition to urinalysis 
and urine toxicology screen. Additional tests will be requested as clinically indicated.  


 
 
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Page 17 
 
3. Urine toxicology screens will be performed at the screening appointment and will be 
administered more frequently if the clinician or research staff becomes concerned about 
possible illicit drug use.  Patients will be informed of random urine drug screens.  
4. An ECG will be performed.  
5. Pregnancy Tests- female subjects will have a blood sample drawn for a pregnancy test.  
 
Audio Recording: 
Clinician administered interviews may be audio recorded for inter-rater reliability and staff 
training purposes. Subject identifying information will not be on the audio recording. Recordings 
will be stored in a locked cabinet when not in use. Subjects will be asked on the consent form to 
indicate whether or not they agree to having their clinical interviews audio recorded. If subjects 
disagree to having their clinical interview audio recorded, it will not affect their eligibility to 
participate in study procedures. 
 
Data Storage:  
Data will be housed at VACHS West Haven campus in Building 1, where the PI’s office is located. 
The computers where data will be stored are password protected and behind the VA firewall. Only 
approved research staff will have access to the screening data.  
 
Table 2. Schedule of Study Events 
Visit 
1- 
Baseline  
2-  
Infusion
** 
3-  
24-hr 
4-  
7-day 
5-  
14-day  
Infusion 
** 
6- 
24-hr 
7-  
7-day 
8-  
14-day 
9- 
28-day 
Day 
-60-0 
1 
2 
8 
15+ 
16+ 
23+ 
30+ 
44+ 
Alcohol & Consumption 
x 
 
 
 
 
 
 
 
 
BFI 
x 
 
 
 
 
 
 
 
 
Blood draw/labs 
x 
 
 
 
 
 
 
 
 
BIS/BAS 
x 
 
 
 
 
 
 
 
 
Breathalyzer 
x 
x 
 
 
x 
 
 
 
 
BSI 
x 
x 
x 
x 
x 
x 
x 
x 
 
B-TBI-S 
x 
 
 
 
 
 
 
 
 
Perceived Stress Scale 
x 
 
 
 
 
 
 
 
 
Cumulative Anxiety Inter. 
x 
 
 
 
 
 
 
 
 
CADSS 
 
x 
 
 
x 
 
 
 
 
CGI-S/I and PGI-S/I  
x 
x 
x 
x 
x 
x 
x 
x 
 
Collect AEs and SAEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Cognitive Tasks 
x 
 
x 
x 
 
x 
x 
 
 
Concomitant Meds 
x 
x 
x 
x 
x 
x 
x 
x 
 
C-SSRS 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
 
 
ETI-SR 
x 
 
 
 
 
 
 
 
 
GPELS 
x 
 
 
 
 
 
 
 
 
HAM-A 
x 
x 
x 
x 
x 
x 
x 
x 
 
*Informed Consent 
x 
 
 
 
 
 
 
 
 
Ketamine Infusion 
 
x 
 
 
x 
 
 
 
 
KLS 
x 
 
 
 
 
 
 
 
 
LEC  
x 
 
 
 
 
 
 
 
 


 
 
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Page 18 
 
MADRS 
x 
x 
x 
x 
x 
x 
x 
x 
 
M-MACE 
x 
 
 
 
 
 
 
 
 
MGH-ATRQ 
x 
 
 
 
 
 
 
 
 
Medical Evaluation 
x 
 
 
 
 
 
 
 
 
PANSS 
 
x 
 
 
x 
 
 
 
 
PCL 
x 
x 
x 
x 
x 
x 
x 
x 
 
PSQI 
x 
x 
x 
x 
x 
x 
x 
x 
 
PSWQ 
x 
x 
x 
x 
x 
x 
x 
x 
 
QIDS-SR 
x 
x 
x 
x 
x 
x 
x 
x 
 
Sirolimus/Placebo Dose 
 
x 
 
 
x 
 
 
 
 
SAFTEE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MINI 
x 
 
 
 
 
 
 
 
 
SDS 
x 
 
 
 
 
 
 
 
 
Serum Pregnancy 
x 
 
 
 
 
 
 
 
 
Urinalysis 
x 
x 
 
 
x 
 
 
 
 
Urine 
Toxicology/Pregnancy 
 
x 
 
 
x 
 
 
 
 
Vital Signs 
x 
x 
 
 
x 
 
 
 
 
*Informed consent will be obtained prior to any study procedure. 
Abbreviations: Big Five Inventory (BFI), Behavioral Inhibition & Activation Scales (BIS/BAS), 
Beck Suicide Inventory (BSI), Brief TBI Screen (B-TBI-S), Clinician Administered Dissociative 
States Scale (CADSS), Clinical Global Impression Severity/Improvement (CGI-S/I), Patient 
Global Impression-Severity/Improvement (PGI-S/I), Cogstate and brief neuropsychological 
battery comprises the cognitive testing portion, Columbia-Suicide Severity Rating Scale (C-
SSRS), electrocardiogram (ECG), Early Trauma Inventory – Self Report (ETI-SR), Global 
Perceived Early-Life Stress (GPELS), Hamilton Anxiety Rating Scale (HAM-A), Klein Loss Scale 
(KLS), Life Events Checklist (LEC), Montgomery-Asberg Depression Rating Scale (MADRS), 
Modified Military Acute Concussion Evaluation (M-MACE), MGH Antidepressant Treatment 
Response Questionnaire (MGH-ATRP), Positive and Negative Symptom Scale (PANSS), 
Pittsburgh Sleep Quality Index (PSQI), Penn State Worry Questionnaire (PSWQ), Quick 
Inventory of Depressive Symptomatology – Self Report (QIDS-SR), Systematic Assessment for 
Treatment Emergent Events (SAFTEE), Structured Clinical Interview for DSM (SCID), Sheehan 
Disability Scale (SDS). **Phone call follow-ups will be conducted every other day for five days 
following both infusion days. 
 
Criteria for Discontinuation 
Participants may be discontinued from this proposed study at any time. Specific reasons for 
discontinuing a participant include: 
 
§ Voluntary discontinuation by the participant, who is at any time free to discontinue 
his/her participation in the study without prejudice to further treatment. 
§ Clinical deterioration: The following are objective criteria for clinical deterioration, (1) a 
25% increase in MADRS scores at any time during the study, and (2) the onset of active 
suicidality as assessed by the study physicians or by scoring 5 or more on the item-10 of 
MADRS.  
§ Stopping birth control or positive pregnancy test. 


 
 
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Page 19 
 
§ Safety reasons as judged by the investigator. 
§ Severe non-compliance to protocol as judged by the investigator. 
§ Incorrect enrollment i.e., the subject does not meet the required inclusion/exclusion 
criteria for the study. 
 
A subject that discontinues will always be asked about the reason(s) for discontinuation and the 
presence of any adverse events. If possible, they will be seen and assessed by the investigator. 
Adverse events will be followed up as medically necessary. 
 
Participant Compensation: 
All participants will be compensated for their participation in this study and completion of all study 
visits is not required for receipt compensation. For Phase One, subjects will be paid $10/hour, not 
to exceed $70 for the baseline-screening visit. They will receive $100 for the medication visit, and 
they will receive $50 for the 24-hour follow-up visit. They will also be reimbursed for 
transportation based on mileage or receipts provided up to $50 per visit. At the discretion of the 
investigator, subjects may be reimbursed for additional costs including travel, parking, 
transportation, meals, or other expenses. Subjects will be asked to provide receipts so that they can 
be reimbursed for these expenses, as applicable. For Phase Two, subjects will be paid $10/hour, 
not to exceed $70 for the baseline-screening visit. They will receive $50 per visit for all remaining 
visits for a possible of 7 visits or $350  (i.e., infusion 1, 24-hour follow-up, 7-day follow-up, 14-
day follow-up/infusion 2, 24-hour follow-up, 7-day follow-up, 14-day follow-up) and will be 
reimbursed for transportation based on mileage or receipts provided up to $50 per visit. Payments 
for this study are processed through Yale University.  As such, participants’ names, addresess and 
social security numbers will be provided to the Yale University Accounts Payable department in 
order to process subject payment for participating in this study.  Participants may be asked to 
complete a W-9 form (federal request for taxpayer identification and certification), which allows 
Yale to process their payment and potentially report their earnings to the IRS. Payment may be 
made to participants in cash on the day of each visit, at the discretion of the PI. For any cash 
payments, participants will be asked to sign a receipt acknowledging payment and the amount they 
were given. Most participants will receive payments in the form of a check or through Yale 
University’s debit card system. The debit cards will be offered through the YCCI OnCore 
ePayments system and will be our preferred payment option. Subjects will be informed that they 
will receive payment via a Bank of America pre-paid debit card.  We will provide their name, 
address, and telephone number to the Bank of America for processing and their card will be related 
to their name and number.  Their SSN or other information will not be provided. All compensation 
information will be discussed in the informed consent process.  Yale will also send subjects an 
IRS 1099 form reporting the amount of money paid to them.   
 
For Phase Three, subjects will be paid $10/hour, not to exceed $70 for the baseline-screening visit. 
They will receive $50 per visit for all remaining visits for a possible of 6 visits or $300  (i.e., 
infusion 1, 24-hour follow-up, 7-day follow-up, 14-day follow-up, 21-day follow-up, 28-day 
follow-up). At the principal investigator's discretion, further subject payment may be made for 
travel, parking, lodging, food, or transportation. Payment will be received through the mail in the 
form of a check from the VA, unless participants have arranged for direct deposit through the VA. 
Payment by check may take up to 6 weeks and is subject to withholding for outstanding debts; for 


 
 
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example, defaulted student loans, child support, or back taxes. If participants have any federal 
debt, there is a possibility that they will not receive any money after their participation. 
There will be no charge to participants for any aspects of this study including services, testing, 
evaluation, or medications. However, some Veterans are required to pay a co-payment for medical 
and other services provided by the VA Connecticut Healthcare System that are not part of the 
study. These co-pay requirements will continue to apply to medical care and services provided by 
VA that are not part of this study. 
Data Analysis:  
This study, investigating the impact of sirolimus on ketamine’s rapid antidepressant effects, is the 
first of its kind.  In order to assess study utility and to determine if medication dose adjustments 
may be useful, we plan to do interim analyses after completion of the first 6 subjects, with subjects 
randomized according to block randomization (block of six). We propose to study 30 patients, 
overall.  This sample size is feasible within the funding available for this project and will provide 
80% power for detecting ketamine-sirolimus interaction effects of moderate size (d’=.53), 
assuming a two-tailed alpha=.05. The data analysis plan is provided only for the primary outcome 
variable, the MADRS score.  The normality of the data will be tested initially using probability 
plots and the Kolmogorov-Smirnov tests.  These data are frequently skewed and so we plan to 
analyze them using a non-parametric approach to repeated measures data.51 The data will be first 
ranked and then fitted with a mixed-effects model with an unstructured variance-covariance matrix 
and p values adjusted for ANOVA-type statistics.  In these models sirolimus (active vs. placebo) 
and time will be fitted as within subjects variables.  All interactions will be fitted.  Age and sex 
will be treated as covariates/grouping factors. Post-hoc analyses will be conducted to interpret 
interactive effects significant at the p=0.05 level.  Subject will be used as the clustering variable. 
Plasma ketamine and ketamine metabolite levels will be analyzed using linear mixed models. All 
secondary measures will be assessed using similar methodology. Behavioral measures of Phase 3 
will use similar methodology. The collection, processing and analysis of peripheral inflammatory 
biomarkers will be completed under a separate protocol and consent (i.e., CA0008). 
 
IX. POTENTIAL RISKS: 
Although precautions will be taken to minimize risk to participants, some risks and inconveniences 
remain. The risks and inconveniences involved with this study include those associated with: (a) 
ketamine administration, (b) sirolimus administration, (c) phlebotomy and intravenous line 
placement, (d) psychiatric and cognitive evaluation to include clinical and neuropsychological 
assessments, (e) clinical deterioration, (f) ECG, (g) HIV and Hepatitis testing, and (h) pregnancy 
and breast-feeding.  
 
Ketamine Administration:  
Ketamine is a dissociative anesthetic that has been used clinically since the late 1960s. Despite 
extensive experience, there is no clear and compelling evidence of long-term toxicity associated 
with ketamine administration in medically supervised settings. However, there are acute medical 
and neuropsychiatric sequelae that deserve special consideration. The ketamine doses employed 
in this study have been specifically selected to produce behavioral effects without significant 
sedation. At these doses, ketamine produces a transient alteration of consciousness including 
altered sensory processing, and thought processes. Initially, subjects frequently feel “drunk” and 
giddiness is common. As blood levels increase, blood pressure and heart rate increase moderately. 


 
 
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Page 21 
 
This increase is transient. Subjects report differences in complex problem solving evident on 
frontal lobe and delayed memory tasks, some subjects may report a narrowing of their 
concentration, feeling distant from surroundings, and enhanced perception of some sensory 
stimuli. Subjects sometimes report blurred vision and nystagmus. Alterations in the perception of 
time, body boundaries, and illusions occur. Subjects may experience visual distortions, altered 
perception of orientation in space, and inability to control thought processes. Subjects may report 
feeling quite distanced from their surroundings, describe altered awareness of their bodies, and 
they may close their eyes. During this period, they are still oriented to time and place. They can 
complete ratings scales testing memory without impairment, their rate of finger tapping is 
unchanged and the latency of their response on continuous performance tasks of attention is not 
increased. However, some individuals feel that they cannot control the experience and find it 
frightening. Vivid dreams and poor sleep quality after infusion of ketamine has also been reported, 
although dream content was not necessarily unusual and alterations in sleep were not reported on 
subsequent nights. The doses used in this protocol produce blood levels that are 1/6 to 1/3 of those 
produced clinically when ketamine is used as an anesthetic. Short-term safety data showed that 
adverse events in response to ketamine infusion have been mild and transient, with no evidence of 
any clinically significant or persistent adverse effects. Adverse events included nausea and 
vomiting, sedation, anxiety, hypotension, insomnia and nightmares and transient pain in the 
infusion arm. 
 
Sirolimus Administration:  
Sirolimus is a commonly prescribed immunosuppressant (maximum daily dose is 40 mg); FDA 
approved for prophylaxis of renal transplant rejection.  The limited administration and low dose 
proposed in this study was selected to yield efficacy but minimize side effects.51, 52 Short-term 
administration (i.e., a single 6 mg dose) is anticipated to have limited, if any, side effects. Potential 
side effects include nausea, vomiting, diarrhea, constipation, stomach pain, headache, skin rash, 
and joint pain. Other adverse reactions related to treatment with sirolimus include: peripheral 
edema, 
hypertriglyceridemia, hypertension, 
hypercholesterolemia, 
increased 
creatinine, 
fever, urinary 
tract 
infection, anemia, 
pain, 
thrombocytopenia, 
susceptibility 
to 
infection, lymphoma, and malignancy, hypersensitivity reactions, exfoliative dermatitis, 
angioedema, fluid accumulation and wound healing, proteinuria, interstitial lung disease, and 
increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic 
thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA). 
 
Also uncommon, but possible, is an allergic reaction to sirolimus. Signs of such a reaction include 
the acute onset of hives, difficulty breathing, swelling of the face lips, tongue, or throat. As 
described above, a trained physician and nurse will be in attendance throughout the drug 
administration and infusion to monitor subjects for any side effects or other adverse events.  
 
Blood drawing & intravenous line placement:   
For the intake appointment, a butterfly needle will be inserted into a vein to retrieve blood samples. 
The placement of a butterfly needle in the vein can be associated with bruising, infection, or clot 
formation. These risks are minimized by proper techniques. Sometimes people also experience a 
feeling of lightheadedness during or following blood withdrawal.  Subjects will have no more than 
8 ounces of blood drawn. Blood samples are drawn for routine labs and drug screening. 
 


 
 
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During the intravenous line placement for the ketamine administration, a bruise may occur at the 
puncture site, and very rarely, an infection may develop. If this occurs, appropriate treatment will 
be instituted immediately. To reduce any risk of large amount of air bubbles getting into the veins, 
all air bubbles are out of the IV tubing before connecting the tubing to the IV lines. Also, the 
infusion pumps used automatically detect air bubbles going through the pump and stops infusion.   
 
Risks associated with blood loss are minimal. Less than 200 mL will be drawn, and this represents 
40% of a 500 mL blood donation. 
 
Psychiatric Screening and evaluation: The risks and discomforts of the screening and 
evaluations are minimal. The discomfort associated with the physical examination or intake 
interview with the study clinician includes the possible stress of answering personal questions. 
Subjects will be answering questions about their symptoms and filling out questionnaires. They 
may find this process to be inconvenient, uncomfortable or upsetting. The psychological testing 
may include personal questions about previous experiences. The questions will be asked in a 
private room. Subjects will be informed that they do not have to answer any question that they do 
not want to answer. Subjects will also have the option to discuss their concerns with someone on 
the research staff. One or more individuals will be available to talk to the subjects should they 
become distressed during an interview or while filling out questionnaires. The cognitive testing 
portion may be frustrating or boring for some subjects, yet it shown to be well tolerated.   
 
Clinical Deterioration: There is a risk of increasing depressive symptoms due to the natural 
history of the illness and/or poor response to ketamine and sirolimus administration. 
ECG: Sometimes the adhesive pads used to attach the leads for recording the electrical activity of 
the heart (ECG) can cause skin irritation. Such irritation usually clears without treatment. 
HIV, Hepatitis B and C testing: as part of the screening assessment, may yield information that 
we are legally required to disclose to the State of Connecticut and/or CDC as reportable infections. 
Any identifiable information obtained in connection with this protocol remains confidential. 
Information is disclosed only with the subject's prior authorization or as required by U.S. and State 
law. Information that we are legally required to disclose includes abuse of a child or elderly person, 
or certain reportable infectious disease. 
 
Pregnancy and Breast Feeding:  Women will be tested for pregnancy as part of the routine 
laboratory tests the day of the screening appointment.  If the test is positive, the woman will not 
be included in the study. Before starting the study, we will ask women to avoid becoming pregnant 
and ask what precautions will be taken. We will ask that participants use contraception throughout 
the duration of the study and for 12 weeks following the study. We ask that they agree to use an 
approved birth control method including oral, injectable, or implant birth control, condom, 
diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with 
vasectomy) or if post-menopausal for at least 1 year, or surgically sterile. If they are taking a 
contraceptive medication, we ask that they also use (or ask that their partner use) a barrier method 
contraceptive (e.g, condom, diaphragm with spermicide).  If the participant changes her mind 
about becoming pregnant or how to avoid becoming pregnant, we ask that she tell us immediately.  


 
 
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In addition, women who are breastfeeding will be excluded. Urine pregnancy testing will be 
completed prior to each infusion.  
 
MINIMIZING RISKS 
 
General risk-minimizing strategies: (1) Effective screening to exclude subjects who would be 
placed at a greater risk. This includes a comprehensive psychiatric and medical evaluation, 
physical examination, and the screening studies performed before starting studies (see above). 
Trained staff, under the supervision of the PI, will conduct all screening procedures. (2) The 
investigator or a designated person will explain the benefits and risks of participation in the study 
to each subject. Subjects will be asked to verbalize their understanding of all aspects of the consent, 
including risks, benefit and alternatives. The voluntary nature of research studies is always 
emphasized. (3) All subject information will be kept confidential and only members of the 
investigative team with appropriate IRB/HIC and HIPAA training will have access to the study 
data. Data will be maintained and secured in locked file cabinets or password protected electronic 
media. A numbering code will be used to assign a unique identifier to each subject. (4) A Data and 
Safety Monitoring Plan is described below. 
Ketamine Effects: As noted above, our group here at the VACHS and Yale pioneered ketamine 
studies in healthy subjects and in depression, and has been performing these studies since early 
1990s. Before participating, subjects undergo careful psychiatric and medical evaluation. A 
research nurse and study physician are available at all times during test sessions to provide support 
and consistent “reality testing” for individuals experiencing confusion or transient psychosis. If a 
subject reports that symptoms cannot be tolerated, the ketamine infusion will be stopped. Subjects 
will be observed for at least an hour after the termination of testing, and if intolerable physical or 
behavioral symptoms persist, subjects may be admitted to the inpatient Clinical Neuroscience 
Research Unit at the Connecticut Mental Health Center for further observation and overnight if 
necessary. Participants will be informed that they may not drive or operate machinery for 24 hours 
after end of test day procedures, and study staff will ensure that they are picked up by a responsible 
adult or safely reach their home on alternate transportation. Subjects will be provided a number to 
call to reach an on-call research psychiatrist (24 hours/day) should unpleasant effects occur after 
subjects have left the testing facility. Medication effects will be reviewed and “debriefed” with 
subjects following each test day by a study clinician. If necessary, subjects will be administered 
oral diazepam to reduce residual symptoms and their participation in the study will be terminated 
if necessary. Such subjects will be monitored as found appropriate by the study physicians. 
We are also taking a number of precautions to help reduce the chance of having an unpleasant 
response to ketamine or to reduce the severity of any lingering medication effects. These 
precautions include: 
1) A research clinician will be present throughout the study to offer support and to help 
clarify the progress of the test day in case the medication causes feelings of confusion.  
2) Medications are available (IV lorazepam) to relieve distress related to the behavioral 
effects of ketamine.  
3) We will ask the subject to remain at the VACHCS in a recovery room for several 


 
 
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hours after the behavioral effects of ketamine should have worn off to further evaluate 
side effects and ensure the subject is feeling well before discharge to home.  
4) We will review the test day with the subject to deal with their feelings and reactions to 
each test day before they leave.  
5) We will ask the subject to contact us at any time if any unpleasant effects occur.  
6) We will ask the subject not to engage in demanding work in the day following the test 
sessions and we will work with the subject to schedule your test days accordingly.  
7) If the subject has any lingering medication effects, such as sedation, we will terminate 
the remaining test days and work with him/her until these side effects have resolved.  
8)  If the subject develops psychiatric symptoms, we may admit him/her to the hospital. 
This may be involuntary if he/her are in danger of harming self or others.  
9) We will conduct 24-hour, 7-day, 14-day, and 28-day follow-up assessments for residual 
effects.   
Clinical Deterioration: Subjects will be closely monitored with serial depression rating scales. In 
the event of clinical deterioration, the subject will be discharged from the study protocols and the 
study physicians will initiate treatment as clinically recommended. As noted above, the following 
are objective criteria for acute decompensation: (1) a 25% increase in MADRS scores at any time 
during the study, or (2) the onset of active suicidality as assessed by the study physicians or by 
scoring 5 or more on the item-10 of MADRS. Study participants will be informed that a decision 
to initiate standardized psychotropic and/or psychotherapeutic regimens will not adversely affect 
their ability to participate in future protocols or receive treatment at VACHS, Yale Depression 
Research Program (YDRP), CMHC, or private psychiatric practice in the community. All 
participants will be treated by a study physician until appropriate referral is arranged. 
IV Irritation:  
If there is irritation due to IV blood sampling, the physician present during the study will examine 
the subject, and the study will be terminated if the subject is in pain. 
Data Safety Monitoring Plan:  
An independent data and safety monitoring board (DSMB) will be established for the clinical trial 
(i.e., phase 1 & 2, not the mechanistic phase 3 study). 
The investigator’s assessment of the overall risk for subjects participating in this study is moderate. 
Moderate Risk DSMP 
1. Personnel responsible for the safety review and its frequency: 


 
 
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The principal investigator, Chadi Abdallah, M.D., will be responsible for monitoring the data, 
assuring protocol compliance, and conducting the safety reviews at the specified frequency, which 
must be conducted at a minimum of every 6 months (including when reapproval of the protocol is 
sought). During the review process, the principal investigator (monitor) will evaluate whether the 
study should continue unchanged, require modification/amendment, continue or close to 
enrollment. Furthermore, a data and safety monitoring committee (DSMC) of independent 
researchers/clinicians (including an ethicist and statistician) will review adverse advents. The 
DSMC committee will review the study prior to the initiation of Phase One subject enrollment. 
The DSMC will be consulted again prior to Phase Two of the study, at which point the committee 
members will determine whether this study can be safely conducted on an outpatient basis. In 
addition, the DSMC will conduct a safety assessment twice yearly. Either the principal 
investigator, the DSMB  (Phase 1 & 2), or the VA IRB have the authority to stop or suspend the 
study or require modifications. 
2. The risks associated with the current study are deemed moderate for the following reasons:  
1. We do not view the risks associated with ketamine infusion and sirolimus dosing as 
minimal.  
2. Given the established safety and validity of the use of ketamine and sirolimus, we do not 
view the proposed study as high risk. 
Although we have assessed the proposed study as one of moderate risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not 
possible to predict with certainty the absolute risk in any given individual or in advance of first-
hand experience with the proposed study methods. In order to assess safety in this patient group, 
we will conduct an interim data analysis after the first 5 subjects are completed. 
Therefore, we provide a plan for monitoring the data and safety of the proposed study as follows: 
 
3. Attribution of Adverse Events: 
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design according to the following categories: 
a. Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b. Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c. Possible: Adverse event may be related to investigational procedures(s)/agent(s). 
d. Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e. Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s). 
4. Plan for Grading Adverse Events: 
The following scale will be used in grading the severity of adverse events noted during the study: 
1. Mild adverse event 
2. Moderate adverse event 
3. Severe 
 


 
 
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5. Plan for Determining Seriousness of Adverse Events:  
Serious Adverse Events: 
In addition to grading the adverse event, adverse events are evaluated to determine whether they 
meet the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it: 
1. is life-threatening 
2. results in in-patient hospitalization or prolongation of existing hospitalization 
3. results in persistent or significant disability or incapacity 
4. results in a congenital anomaly or birth defect OR 
5. results in death 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition, or 
7. adversely affects the risk/benefit ratio of the study 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event. Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
SAE. It is important for the PI to consider the grade of the event as well as its “seriousness” when 
determining whether reporting to the IRBs is necessary. 
6. Plan for reporting serious AND unanticipated AND related adverse events, anticipated 
adverse events occurring at a greater frequency than expected, and other unanticipated 
problems involving risks to subjects or others to the IRBs 
The investigator will report the following types of adverse events to the IRBs: a) serious AND 
unanticipated events; b) adverse events occurring with a greater frequency than expected; and c) 
other unanticipated problems involving risks to subjects or others. 
These adverse events or unanticipated problems involving risks to subjects or others will be 
reported to the IRBs and DSMB (Phase 1 & 2) within 48 hours of it becoming known to the 
investigator, using the appropriate forms.  
7. Plan for reporting adverse events to co-investigators on the study, funding and regulatory 
agencies 
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified: 
• All Co-Investigators listed on the protocol. 
• DSMB (Phase 1 & 2) 
The principal investigator, Chadi Abdallah M.D., will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 
severity of the adverse events and determine if modifications to the protocol or consent form are 
required. 


 
 
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Funding Sources: 
 
National Center for PTSD (NCPTSD) 
Yale University  
Gustavo and Louise Pfeiffer Foundation – “Discovering a New Class of Antidepressants” 


 
                                     
Ver. 01/09/19 
 
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Abdallah, C., et al. 2018. Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, 
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Appendix 1: Initial Phone Pre-screen  
 
Sirolimus and Ketamine Phone Interview 
 
Introduce yourself to all candidates. For candidates who call for information about the Sirolimus and 
Ketamine study, follow the script below: 
 


 
 
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If you call someone back and speak with them directly: 
 
“Hello, my name is: ______________. I am calling from the National Center for PTSD at the VA in West Haven. 
I am returning your call indicating that you may be interested in participating in our research study”.  
(Follow with script from the next section). 
 
If you answer a call from someone interested in the Sirolimus and Ketamine study, start here: 
“Thank you for your interest in our study. May I tell you a little about the study? We are currently 
enrolling eligible Veterans and civilians in a research project to study the impact of sirolimus on 
ketamine’s antidepressant effects.  Sirolimus is an FDA-approved drug commonly used in cancer 
treatment and following organ transplants.  Ketamine is an FDA-approved anesthetic drug shown to 
have rapid antidepressant effects.  As this study is exploring the interaction between these two 
medications and their impact on depressive symptoms, we will be recruiting individuals who have 
current depression and have tried at least one antidepressant in the past with little to no success at 
improving symptoms.  This study is a randomized, controlled trial in which it is expected most 
participants will receive two ketamine infusions, one with sirolimus and one with placebo, an inactive 
“sugar pill.” The order in which you receive these will be based on the way you are randomized into the 
study. The infusion days will happen here at the VA and will be separated by approximately two-weeks. 
There will be follow-up assessments after each infusion to assess any changes in symptoms you may 
experience and to address any question or concerns you may have.   
Does this sound like something you may be interested in?  If yes, continue.   
 
If the candidate does not want to pursue the interview, thank them for their time and end the phone 
call. 
May I ask you some questions about your physical and mental health, to determine if you may be eligible 
for the study? Some of these questions may be of a confidential nature. Is this an appropriate time for 
you to talk? We expect these questions to take approximately 10 minutes to complete.” 
 
If the candidate agrees: “Thank you. Please understand that your participation is voluntary and it is 
optional to answer these questions. You do not have to answer any question that makes you 
uncomfortable. Your decision to participate in this research will not affect your medical care or 
benefits.” 
 
Document Subject Assent: 
Subject Agrees       q                                 Subject Disagrees       q 
 
Date: _______________________________                                                                                    Subject Id #:____________________                    
 
Screened by: ________________________________ 
 
Are you available for weekly appointments during the day?       Yes  q      No q 
 
Are you available for appointments on more than one day?      Yes  q      No q 
 
  
  
                                                                                           Demographics 
    
 
 
  


 
 
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Page 32 
 
 
1. What is your primary language? ___________________________ 
 
 
 
 
 
 
 
 
 
2.  What is your age? ___________________________ 
 
                                                                                         Physical Health  
 
 
 
 
 
 
3.  Do you have any current or ongoing medical problems? 
qYes    q  No   
 
                    If yes, what are they: ______________________________________________________________________________________ 
                   
__________________________________________________________________________________________________________________________ 
 
4. Have you ever had an organ transplant? qYes    q  No    
 
 
If yes, what and when: ______________________________________________________________________________________ 
                      
_________________________________________________________________________________________________________________________ 
 
5. Have you had any recent vaccines? (e.g., flu shot, MMR, small pox, typhoid, etc.) qYes    q  No   
 
If yes, what and when: ______________________________________________________________________________________ 
                
  __________________________________________________________________________________________________________________________ 
 
6. Have you ever taken a medication called ketamine? qYes    q  No  
 
If yes, when, what was it for, did you have any adverse reaction: _____________________________________ 
                
  ____________________________________________________________________________________________________________________________ 
 
7. Have you ever taken a medication called sirolimus? qYes    q  No  
 
If yes, when, what was it for, did you have any adverse reaction: _____________________________________ 
                
______________________________________________________________________________________________________________________________ 
 
8. Do you have a history of heparin sensitivity or heparin-related thrombocytopenia? qYes    q  No  
 
If yes, when, what was it for, did you have any adverse reaction: _____________________________________ 
                
______________________________________________________________________________________________________________________________ 
 
9.  If female, are you currently pregnant or breastfeeding?   qYes   q  No   q N/A male subject 
 
 
 
 
10. Are you currently taking any medications, vitamins, herbal or dietary supplements?   
 
 
Name of Medication, 
Vitamin, etc. 
 
Reason 
 
Dose 
 
Regimen/length of time on 
medication/% improvement of 
symptoms 


 
 
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Page 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11. Have you smoked marijuana (cannabis) at any time during the last 30 days? ___________   If yes, when 
was the last time you smoked marijuana?  ___________ 
 
12. Have you participated in any research studies that involved taking any medications, even if just for one 
day? ______________________  If yes, when were those studies and what medications may have been 
involved?_____________________________________________________________________________________ 
 
 
 
MDD Symptom Screening  
 
IN THE PAST 2 WEEKS … 
13. Have you been feeling down, depressed, or hopeless?  qYes   q  No     
 
14. Have you experienced decreased interest or pleasure in doing things?     qYes   q  No     
 
15. Have you had trouble falling or staying asleep, or sleeping too much? qYes   q  No  
 
16. Have you been feeling tired or having low energy?  qYes   q  No     
 
17. Have you had a poor appetite or been over eating?  qYes   q  No     
 
18. Have you been feeling bad about yourself (e.g., like a failure, like you’ve let yourself or others 
down, etc.)?   qYes   q  No     
 
19. Have you had problems with concentration?   qYes   q  No     
 
20. Have you been moving or speaking so slowly that others may have noticed? Or on the other hand, 
been so restless that you were moving around much more than usual.   qYes   q  No     
 
21. How have the symptoms you reported above have affected your functioning over the last two 
weeks?  ____________________________________________________________________________________________________________ 
 
Other Disorders Screening 
22.   Have you been diagnosed with bipolar disorder or schizophrenia?  qYes   q  No    
 
23. Have you experienced a traumatic event in your life that continues to bother you (e.g., you think 
about it, dream about it, feel anxious when reminded of it, etc.)  qYes   q  No    
 
24. Have you been having trouble in your personal life, or at school/work, because of problems with 
alcohol within the past 3 months? qYes   q  No  
 
25. Have you been having trouble in your personal life, or at school/work, because of problems with 
drugs within the past 3 months? qYes   q  No  
 
Treatment 


 
 
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If prior questions regarding psychological symptoms were answered affirmatively ask the following: 
 
26. Are you currently receiving psychotherapy for depression?  
qYes   q  No    
(If yes, how long have you been in treatment? :_______________________________________) 
 
 
27. (you may know this already from above)  
Are you currently receiving medication for MDD or another psychological condition?  qYes   q  No 
 If yes, what is it (name & dose) and how long have you been taking the medication? _____________________ 
 
 
28. If you are eligible for the study and have symptoms of MDD:  Would you be willing to take 
medication as part of this study?  qYes   q  No    
 
 
 
29. Do you have a medical chart at the VA?    q Yes        q No  
 
30. If yes, may we have permission to access your chart to look at your laboratory tests and other 
medical records?  
 
Document Subject’s verbal consent: 
Subject Agrees       q                                 Subject Disagrees       q 
 
 
At the conclusion of the phone interview: “Thank you for answering my questions.  If you have given us 
permission to do so, we will review your medical records. I will also review your responses to my 
questions with the study physician, and call you back.  If it appears that you may be eligible for our 
research, we will also schedule an in-person screening evaluation at that time.  Do you have any 
questions for me?” 
 
Document Participant Disposition  
 
Candidate is eligible for a face-to-face screening for the study based on phone screen: q Yes        q No  
 
Candidate’s medical records have been reviewed: q Yes        q No  
 
If the candidate is not eligible for the study list the reason(s) why: ___________________________________________ 
 
 
_____________________________________________________________________________________________________________________ 
 
Contact the candidate following review and confirmation of available material and either schedule a 
face-to-face interview and review of the informed consent and HIPAA or inform him/her of 
ineligibility. 
 
CONTINUE ON TO NEXT PAGE à 
 
Appendix 2: Phone Pre-screen Identification Page 
 
 
Phone Pre-Screen Identifier Page (if participant agrees to us review their medical records) 
(to be stored separately from the telephone pre-screening form)  
 


 
 
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1.  What is your full name: _____________________________________________________________________ 
 
2.  What are the last four digits of your social security number? ________________________ 
 
3.  What is your date of birth?  _________________________________________________________________ 
 
4. What is the best contact number for us to reach you regarding scheduling and reminder calls?  
 
________________________________________________________________