Clinical trial NCT02669043
Conditions: Depression
Sponsor: Massachusetts General Hospital
Start date: 2016-07-01; Completion date: 2017-02-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Anxious depression is a particularly difficult-to-treat subtype of depression. Patients with anxious depression do not respond as well to currently available antidepressant medications. Nevertheless, in previous studies, low dose IV ketamine, which rapidly decreases symptoms of depression within hours in many patients with "treatment-resistant" depression, has been associated with superior efficacy in those individuals with anxious compared with non-anxious depression. In order to understand this unique effect more fully, the current protocol is aimed at further delineating biomarkers of ketamine's effects among individuals with treatment-resistant anxious depression compared to those with nonanxious depression.

Detailed description:

Arms: arm 1: All participants receive open-label ketamine
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: Intravenous ketamine 0.5mg/kg over 40 minutes

Protocol documents:
Prot_SAP_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychophysiological and Cognitive Biomarkers of Ketamine’s Antidepressant Effects 
(Protocol 2015P002397) 
 
NCT02669043 
 
Version Date: 12/13/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Detailed Protocol: 
 
I. Background and Significance 
 
Establishing remission of major depressive disorder (MDD) often takes weeks to months to achieve on 
traditional monoamine-based antidepressants. Only about one-third of individuals with MDD remit on an initial 
course of treatment, with even lower rates of remission among individuals with certain depressive subtypes, 
such as anxious depression. There is a compelling and widely acknowledged need for antidepressants that 
work more rapidly, that recruit novel, non-monoamine mechanisms, and that target subtypes of depression that 
respond poorly to current antidepressants. Towards this end, single subanesthetic infusions of ketamine (an 
antiglutamatergic medication) have been shown to improve the symptoms of depression in a rapid (within 
hours), robust (across many symptoms), and relatively sustained manner in patients with treatment-resistant 
depression (TRD).(1) Ketamine may have greater efficacy for forms of depression not well treated by current 
agents—especially anxious depression.(2) Low dose parenteral ketamine has now been studied for difficult to 
treat depressive disorders by numerous research groups and off label administration of ketamine is 
increasingly available in some clinical settings.  
 
There is a widely recognized need for developing biomarkers that may predict response to rapidly 
acting antidepressant agents such as ketamine. The identification of biomarkers of treatment response to 
rapidly-acting therapeutics for depression is likely to advance targeted drug development and the goal of 
personalizing depression treatment. The current protocol is aimed at further delineating potential biomarkers of 
ketamine’s effects among individuals with treatment-resistant anxious depression, as well as using putative 
biomarkers to diagnose depression subtypes (i.e., anxious depression).  
 
Background and Preliminary 
Results: Ketamine and Anxious 
Depression. This protocol stems from 
earlier work by the PI with colleagues 
at the NIH/NIMH on the definition,(3) 
neurobiology,(4) and treatment(5) of 
anxious depression. Because anxious 
depression is a common depressive 
subtype, we sought to examine the 
extent to which symptomatically-
diagnosed anxious depression 
predicted response to ketamine. 
Specifically, in our post hoc analysis, 
we found that patients with anxious 
depression (n=15) had significantly 
greater antidepressant responses 
(defined as a ≥50% improvement in 
Montgomery-Asberg Depression Rating 
Scale (MADRS) scores from baseline) 
to ketamine compared to patients with 
nonanxious depression (n=11).(6) This 
effect was observed over the course of 28 days (see Figure 1; * = p<0.05), with the largest effect at Day 2 
(Cohen’s d=0.76)—a clinically relevant finding, given that anxious depression is typically more difficult-to-treat 
than nonanxious depression.(5) In addition, patients with anxious depression had significantly longer median 
days-to-relapse compared to nonanxious depression patients (19.0±17.9 vs 1.0±0.0 days-to-relapse, 
respectively; p=0.002).The two groups did not differ in their experiences with the dissociative (p=0.62) or 
psychotomimetic (p=0.41) side effects of ketamine. These results suggested that symptomatically-diagnosed 
anxious depression may be a clinical predictor of ketamine response, a particularly intriguing finding in the 
context of the majority of clinical trials involving standard antidepressants in which anxious depression is 
related to poorer antidepressant response.  


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Though symptomatically-diagnosed anxious depression appears to predict a better antidepressant 
treatment response to ketamine compared with depression without anxious features, several important aspects 
remain to be elucidated include: 1) the neural mechanisms through which ketamine exerts its superior 
antidepressant effects in anxious depression, 2) the relationship of objective and subjective measures of 
anxiety within mood dysregulated patients (Aim #1), and 3) the extent to which objective physiological 
measures of anxiety might predict patients’ response to ketamine (Aim #2). One theory that may help to 
explain ketamine’s superior antidepressant properties in anxious depression compared to nonanxious 
depression involves the reward/motivation brain circuit. The combination of reward pathway dysfunction 
and hyperactive threat responses has been suggested as a mechanism for the pathophysiology of anxious 
depression.(7, 8) Indeed, anxiety, depression, and dysfunctional reward processing are highly comorbid.(9) 
Furthermore, a recent review of the literature(8) highlighted that chronic stress (a model of anxiety), aversive 
stimuli, and punishment all lead to “stress-induced” clinical symptoms of anhedonia, low motivation, and 
depression through indirect inhibition of the reward circuitry.  
The reward circuitry receives both excitatory (glutamatergic) and inhibitory (GABAergic) inputs from the 
bed nucleus of the stria terminalis (an area of the brain involved in hypervigilant threat monitoring and 
anxiety).(10, 11) Preclinical research has suggested that during aversive events, the reward circuitry is 
indirectly inhibited by increased excitatory (glutamatergic) and decreased inhibitory (GABAergic) neuronal 
activity from the bed nucleus of the stria terminalis.(12) Conversely, a reduction in anxiety-related behaviors 
and an increase in reward-motivated behaviors are observed when this inhibitory tone is increased.(11) 
Altogether, these findings suggest that the bed nucleus of the stria terminalis may have a unique role in 
integrating stress information with reward responses.(13)  
Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, may work in the 
treatment of anxious depression by blocking actions from the excitatory (glutamatergic) neurons in the bed 
nucleus of the stria terminalis, thereby blocking the “stress-induced” inhibition of the reward circuitry. In 
depressed patients, this action may reinstate more normal functioning of the reward circuit. Indeed, in one 
recent mouse study, it was shown that knocking out the glutamatergic receptors within the bed nucleus of the 
stria terminalis mimicked the antidepressant effects of systemic ketamine administration, further implicating the 
bed nucleus’ relationship with ketamine’s antidepressant effects.(14) We propose several noninvasive 
experiments to interrogate these pathways.  
 
Background and Preliminary Results: Psychophysiology and Cognitive Testing. In this protocol, 
several psychophysiological and cognitive experiments will be used to objectively measure anxiety for the 
prediction of ketamine’s antidepressant effects. The startle eye-blink reflex is a well-documented primitive 
defensive/protective reaction that occurs when an individual is exposed to an unexpected, mildly aversive 
stimulus such as a highly annoying but not painful electric shock administered (15). In the literature on the 
startle reflex, a distinction has been made between fear and anxiety. Fear is thought to be associated with 
predictable and phasic administration of an aversive stimulus while anxiety is thought to be associated with an 
unpredictable and sustained aversive stimulus. Despite their clinical similarities, assessing both fear- and 
anxiety-potentiated startle response is critical, as a growing literature suggests that their pathophysiology 
involves distinct brain circuits—specifically, phasic fear-potentiated startle is mediated by the amygdala, 
whereas sustained anxiety-potentiated startle is mediated by the amygdala and the bed nucleus of the stria 
terminalis.(15, 16)  
In previous work, we used the NPU-threat test (No shock, Predictable shock, and Unpredictable shock) 
to examine whether baseline fear- and anxiety-
potentiated startle (as elicited by electric shocks) differed 
between a heterogeneously diagnosed group of patients 
with depression (n=28) and healthy volunteers (HV; 
n=28).(17) Briefly, participants intermittently experienced 
abrupt bilateral auditory stimuli (40-ms duration, 103-dB 
noise burst) through headphones, eliciting a startle 
response. These startle responses were then measured 
during experiments of predictable (signaled by a cue) and 
unpredictable (unsignaled) shock, related to fear and 
anxiety, respectively. Baseline startle responses revealed 


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significantly greater startle magnitude in the depressed group compared to the HV group (p<0.02; Figure 2), 
extending both to fear- and anxiety-related potentiation. Furthermore, the depressed group exhibited significant 
increases in startle upon the mere placement of the shock electrodes (reflecting contextual anxiety; p<0.005) 
compared to a period prior to shock electrode placement—a difference that was not seen in the HV group. 
In addition to eye-blink startle, we will collect other physiologic measures, including autonomic 
responses to threat stimuli that have a demonstrated link to pathological anxiety in other studies. Specifically, a 
larger heart rate response to loud tones (a threat stimulus) has been shown to be one of the most robust 
physiological findings in patients with current PTSD, and may reflect increased defensive responding to 
threats.(18-21) This increased reactivity appears to be acquired after the onset of the disorder, rather than pre-
existing, further suggesting that this physiological marker is an accurate indicator of disease.(18) Heightened 
heart rate activity has also been observed in patients with obsessive compulsive disorder.(22) It is our 
hypothesis that autonomic responses to threat stimuli will be similarly found as indicators of anxiety within 
depression. 
As described earlier, dysfunction in reward processing may be critical in the pathophysiology of anxious 
depression (7,8). In order to examine the spectrum of reward dysfunction in depressed patients, as well as to 
test the extent to which cognitive deficits in reward processing predict ketamine’s antidepressant effects, we 
will conduct a pre-treatment probabilistic reward task, an objective measurement of participants’ ability to 
modulate behavior as a function of rewards. Clinically, depressed patients have a deficit in reward learning (a 
construct of the so-called RDoC [Research Domain Criteria] positive valence domain), as they have difficulty 
modifying their behavior despite positive reinforcement.(8) In one previous probabilistic reward task study, pre-
treatment inability to modify reward learning in depressed patients predicted continued depressive symptoms 
at 8-weeks after treatment was initiated.(23) In view of ketamine’s effect on the NMDA receptor and its 
relationship to reward processing, we hypothesize that greater reward dysfunction will predict response to 
ketamine.  
In summary, we found that subjectively-diagnosed anxious depression predicts a greater 
antidepressant response to ketamine compared to nonanxious depression. Aberrant brain circuitry between 
the bed nucleus of the stria terminalis and the reward circuitry may contribute to the psychopathology observed 
in the anxious-depression phenotype, and might be the targets that account for ketamine’s superior 
antidepressant efficacy among individuals with this depressive subtype. Therefore, higher pre-treatment 
psychophysiological (i.e., anxiety-potentiated startle magnitude) and cognitive (i.e., reward dysfunction) 
measures of anxiety in depressed patients may serve as biomarkers that can clinically predict better treatment 
response to ketamine and that reflect the activity of specific circuits that could be targeted for future drug 
development. 
 
 
II. Specific Aims 
 
The overall aims of this protocol are to study biomarkers for diagnosis and treatment response in mood 
disorders. Specifically: 
 
Specific Aim #1: Determine the extent to which objective measures of anxiety are related to 
subjective measures of anxiety in patients with mood dysregulation. Our working hypothesis is that 
patients with clinically-diagnosed anxious depression will have higher objective measures of anxiety (anxiety-
potentiated startle responses and lower reward responsiveness) compared to those with nonanxious 
depression. 
 
Specific Aim #2: Determine the extent to which these biomarkers predict response to ketamine. 
Our working hypothesis, based on pilot data and previous work, is that higher pre-treatment 
psychophysiological measures of anxiety-potentiated startle and lower reward responsiveness on cognitive 
measures will correlate with a better antidepressant response to ketamine.  
 
Specific Aim #3: Determine the effect of ketamine on the biomarkers. Our working hypothesis is 
that greater reductions in anxiety-potentiated startle magnitude, and greater improvements in measures of 
reward responsiveness, will be found among ketamine responders compared to nonresponders.  
 
III. Participant Selection 
 
Inclusion Criteria: Patients 


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Patients will:  
1) be 18-64 years old,  
2) read, understand, and provide written informed consent in English,  
3) meet criteria for a primary psychiatric diagnosis of Major Depressive Disorder (MDD) for ≥ 4 weeks, 
according to the Mini International Neuropsychiatric Interview (M.I.N.I.) and have a Hamilton Depression 
Rating Scale (HDRS-28) total score ≥ 20; depression may have started at any time point in their life, and 
certain co-morbid diagnoses (e.g., anxiety disorders) will be allowed,  
4) have a history ≥1 failed medication trial during the current depressive episode (per the MGH 
Antidepressant Treatment History Questionnaire),  
5) be on a stable adequate dose of an FDA-approved antidepressant medication for ≥28 days prior to 
Study Phase II (see medication inclusion/exclusion list),  
6) maintain a treating doctor who is in agreement with study participation,  
7) have a reliable chaperone to accompany them home following the completion of Visit 3 (the 
ketamine infusion day),  
8) be generally healthy, as assessed by medical history, physical examination (including vital signs), 
clinical laboratory evaluations, and electrocardiogram (EKG), 
9) be of non-childbearing potential or use of an acceptable form of birth control (females only). 
 
Exclusion Criteria: Patients  
Patients will be excluded if any of the following criteria are met:  
 
1) delirium or dementia diagnosis,  
 
2) unstable medical illness or clinically significant laboratory results,  
 
3) history of clinically significant cardiovascular disease or electrocardiogram (EKG) findings, or medical 
conditions that put the patient at risk for possible cardiac side effects (e.g., requirement of cardiac pacemaker) 
or alter brain morphology (e.g., recent head trauma, post intracranial surgery, intracranial mass or bleed or 
unstable sleep apnea), or a blood pressure >140/95 mmHg at Screening, 
 
4) history of multiple adverse drug reactions, (e.g., history of hives or anaphylaxis in response to a 
medication, severe intolerance and/or severe side effects to a medication), including hypersensitivity to 
ketamine, 
 
5) current/past history of psychotic disorders, history of out-of-body feelings or derealization, 
 
6) active substance use disorders (except nicotine and caffeine) within the past six months or past 
history of ketamine/PCP abuse (we will confirm this with collateral information from their doctor if necessary), 
 
7) requirement of excluded medications  that may interact with ketamine (see exclusionary medications 
list), 
 
8) caffeine or nicotine use within 1 hour of psychophysiology testing, or alcohol use within 1 day of 
testing, 
 
9) pregnancy, breastfeeding, or unacceptable means of birth control (females only) 
 
10) clinically significant hearing impairment, 
 
11) current serious suicidal or homicidal risk,  
 
12) concurrent participation in other research studies involving medications or other treatments, 
 
13) narrow angle glaucoma, 
 
14) acute intermittent porphyria history, 
 
15) history of seizures in the past 6 months, regardless of seizure type, 
 
16) hyperthyroidism or untreated hypothyroidism,  
 
17) airway instability or pulmonary disease with hypercarbia, or 
 
18) current or past cubital or carpal tunnel syndrome. 
 
IV. Participant Enrollment 
We will enroll 58 depressed patients outpatients into the study. 
Recruitment: 58 outpatients will be enrolled via response to flyers, advertisements, e-mails, 
participation in previous studies with an interest in participating in further research, and letters to providers. The 
DCRP has used these methods for over two decades with considerable success, receiving an average of over 
35 phone calls/week.  


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Retention: All patients are eligible to receive a free consultation at the DCRP immediately following the 
completion of all study materials. This care is supplemental to their ongoing care with their treating 
psychiatrist/doctor. The treating psychiatrist will be informed before any medications changes are considered.  
 
Renumeration: All participants who complete all parts of the study will be paid $200, and parking will be 
validated for the study visits. For patients that come in for the screening visit only, they will be renumerated 
$20; parking will also be validated. The payment schedule for the other three visits is $60 each.  
 
Note, the probabilistic reward task is a monetary reward task. Patients will be told that their payment for 
this task, based on the money they win, will be included in their total payment for study participation.  
 
Procedures for Informed Consent 
Written informed consent will be obtained by a licensed physician from all patients before protocol-
specific procedures begin. The investigator obtaining consent will explain in detail the protocol of the study, its 
purpose, and potential benefits to the society. Participants will be informed that they can choose to terminate 
the study at any time, for any reason.   
 
Treatment Assignment and Randomization (If Applicable) 
 
N/A; All participants will be assigned to open-label ketamine. 
 
V. Study Procedures 
 
Research Design Summary: The proposed research (Aims 1-3) will begin with a screening visit (Visit 1) 
and a medication stabilization period of ≥ 28 days (Phase I). In Phase II, 58 depressed patients meeting 
research criteria (specified above) will undergo baseline biomarker and psychometric assessments (Visit 2). 
One-to-two days later, they will receive an open-label infusion of subanesthetic intravenous ketamine 
(0.5mg/kg over 40 minutes), and will be monitored for 4 hours in the MGH Clinical Research Center (Visit 3). 
Visit 4, which will occur on the day after the ketamine infusion, will consist of the same biomarker and 
psychometric assessments from Visit 2 (see “Schema” for overall study outline): 
 
 
 
 
 
 
 
 
 
 
Visits and Parameters to be Measured/Data to be Collected and When the Data is Collected 
Study Phase I: Screening: At Visit 1 (“Screening” visit), patients will undergo initial evaluation (i.e., 
physical and psychiatric examination, vital signs, blood genetics and biomarkers collection, neuropsychological 
testing, basic laboratory and pregnancy/urine toxicology testing, EKG, hearing assessed for the ability to detect 
a white noise stimulus at 25dB) following informed consent to evaluate their eligibility based on 
inclusion/exclusion criteria. This will occur at the MGH DCRP. Prior to Study Phase II, patients will remain 
stable on their antidepressant dose for ≥28 days.  
In order to ensure that participants do not have a history of substance abuse or dependence, we will 
perform a structured clinical interview, as well as urine toxicology screen at Visit 1. Furthermore, if necessary, 
we will obtain permission from participants to contact their primary physician or other treaters, to obtain further 
collateral information about substance use problems. 
Study Phase II: Testing and Treatment: Study Phase II consists of three visits (Visits 2-4) over four 
days. At Visit 2, participants will have pre-treatment psychophysiological and cognitive testing assessments in 
the morning. Visit 3 will occur ideally 24 hours after Visit 2, (but within 1-2 days), and will consist of an infusion 
of ketamine (0.5mg/kg over 40 minutes). Prior to ketamine administration, participants will have a urine test for 
pregnancy (females only). Intravenous ketamine will be administered at the Clinical Research Center by a 
medical doctor. Participants will be monitored for 4 hours after the start of the infusion at the CRC trained 
Visit 1: Screening
Visit 2: Baseline biomarker 
and psychometric 
assessments
Visit 3: ketamine infusion
Visit 4: Final  biomarker and 
psych assessments
Phase I: ≥ 28 
Phase II:  ≤4d 


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research nursing staff. Vital signs (Temp, Pulse, Respiration Rate, BP, SpO2 and Sedation level) will be 
measured at +0 minutes, +5, +10, +15, +20, +30, +40, +60, +90, +120, +180 minutes in relationship to the time 
of ketamine infusion.  At the +240 minute mark, participants will have a post-ketamine blood sample drawn for 
genetics and biomarkers. Afterwards, participants will be discharged home into the care of a responsible adult 
escort.  At Visit 4 (which is 24 hours after Visit 3), participants will undergo final psychophysiology and 
cognitive testing, identical to those from Visit 2, as well as have a blood sample drawn for genetics and 
biomarkers. All visits in Phase I and II will include psychometric assessments. 
 
Safety and Monitoring:  
 
Special Case of Sertraline and the Urine Drug Screen  
Sertraline (Zoloft) is known to cause frequent false positives on urine drug screens for benzodiazepines 
(see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728940/).  Over the past several years, the DCRP has 
experienced an increase in false positive urine drug screens for benzos while patients were taking sertraline. In 
the case when a patient (who is taking sertraline for their depression) is screened for the study and tests 
positive for benzodiazepines on urine drug screen (despite denial of benzo use), the following precautions will 
be taken: 1. The patient's physician will be contacted for collateral information pertaining to alcohol and 
substance abuse, including benzodiazepine use; 2. The patient will be checked in the Mass PAT system for 
active benzodiazepine prescriptions within the past year from the screening date. If the patient's physician 
confirms that they are not taking benzos, and there is no evidence of benzo use in Mass PAT, the patient will 
be deemed eligible for the study for this particular criteria. As a precaution, the patient will be informed that if 
they are, in fact, taking benzodiazepines, they may interfere with ketamine's mechanism of 
antidepressant/antisuicidal action, rendering ketamine less effective. Furthermore, the concomitant use of 
benzos and ketamine may lead to more severe side effects (such as increased somnolence) when combined.  
 
Special Case of Medical Marijuana Use   
Ketamine and Cannabis: Marijuana was recently passed for legal medicinal use in the Commonwealth of 
Massachusetts. As a result of this law, the occurrence of medical marijuana prescriptions is likely to increase. 
Subjects who indicate use of medical marijuana will be reviewed on a case-by-case basis by the PI, and will 
not be immediately excluded from the study. The PI will speak with the participant’s physician and confirm that 
the medical marijuana is prescribed for medical purposed; furthermore, the physician will be asked to confirm 
that the subject does not have a history of substance or alcohol misuse. This exception will only be given to 
participants who are currently prescribed marijuana by a medical professional and will not apply to those who 
use marijuana recreationally.  
MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically 
increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. 
MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially 
excessive or prolonged CNS and respiratory depression. Patients will be counseled to avoid hazardous 
activities requiring mental alertness and motor coordination until they know how these agents affect them, and 
to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal 
activities. 
 
Ketamine Administration and Monitoring: A single, open-label infusion of ketamine at a subanesthetic 
dose of 0.5mg/kg over 40 minutes will be administered on the morning of Visit 3 at the MGH Clinical Research 
Center (CRC) by a BLS and ACLS-certified licensed physician, as this dose and procedure has been 
previously used in depression research, (1, 24, 25) including studies completed at the MGH CRC (e.g., 
Protocol 2012P001042). Prior to the infusion, all patients will be fasting since midnight, except for required 
morning medications. Monitoring of oximetry, pulse rate, and blood pressure will be done before, during, and 
after the infusion. Although subanesthetic ketamine has been shown to have a favorable safety profile when 
given to depressed patients in research studies,(1, 24-27) there is a potential risk of adverse psychotomimetic, 
dissociative, and/or sympathomimetic events. Patients will be discontinued from the study if they experience 
serious adverse events during or after the infusion. See below for details on monitoring and rescue 
medications.  


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Psychophysiology Testing: At Visits 2 (“pre-ketamine”) and 4 (“post-ketamine”), psychophysiological 
testing will be used to measure variations in startle responses (elicited by auditory white noise stimuli) during 
three conditions: no-shock (N), predictable (P) shock, and unpredictable (U) shock (“NPU-threat test”).(28) The 
NPU threat test has been approved for the use in several protocols by the Human Subject Committee at the 
National Institute of Mental Health/National Institute of Health. Similar shock experiments have been approved 
by the Partners IRB (e.g., “The Psychophysiology of Delayed Extinction and Reconsolidation in Humans,” PI 
Scott Orr, PhD). First, patients will be seated in the testing room. Second, electromyogram (EMG) of the 
obicularis oculi muscle will be recorded using a BioPac EMG amplifier via two electrodes placed under the left 
eye to assess blink magnitude of the startle response; this is an established reliable measure of startle 
magnitude in humans.(29) Third, skin conductance will be measured directly from the non-dominant hand 
using a BioPac EDA amplifier with a constant value of 0.5 V. Fourth, heart rate will be recorded using standard 
limb EKG leads connecting to a BioPac EKG amplifier. Interbeat interval will be measured from the EKG and 
then converted to heart rate. Next, nine 103-dB auditory white noise stimuli will be delivered biaurally via 
headphones every 25-30 sec for the purpose of habituating the study patient to startle response (Habituation 
1). Following habituation, two disc electrodes will be placed on the left wrist for the purpose of administering 
the shocks. Shocks are an aversive stimulus and are intended to be highly annoying, but not painful, with 
intensity not in excess of 80 mA and of 500ms duration. Prior to starting the NPU-threat test, patients will 
experience up to fifteen “sample” shocks for the purposes of 1) choosing an appropriate subjective level that is 
“highly annoying but not painful” (the “shock work-up”), and 2) allowing for withdraw from the study if the stimuli 
are perceived as excessively unpleasant. 
Prior to testing, (females only) will receive a pregnancy screen. For the NPU-threat test, patients will be 
seated at a computer. Text will appear continuously on the computer screen to indicate the cue for the 
upcoming testing condition as follows: “no shock” (N), “shock only during cue” (P), or “shock at any time” (U). 
The cue (represented by a geometric shape) will then be displayed during the testing condition, with cues 
differing in color between N, P, and U, though they are meaningless in the N and U conditions. Each testing 
condition will last for 150 sec, with four cues presented during each condition (See Figure). Cues will be 
displayed for 8 sec each time. Patients will be presented with two blocks of conditions: 1) P-N-U-N-U-N-P and 
2) U-N-P-N-P-N-U. Two shocks (the aversive stimulus) will be administered during each of the P and U 
conditions, for a total of 8 shocks throughout the entire block. Specifically, shocks will be delivered at the end 
of the cue in the P condition and in the absence of a cue in the U condition. No shocks will be delivered during 
the N condition.  
Each individual condition (N, P, U) will have one auditory startle stimulus during three of the four cues 
(1-4 sec following cue onset), and three auditory startle stimuli during cue-free periods (i.e., the intertrial 
interval, or ITI), for a total of six startle stimuli per condition. The mean intertrial interval will range from 25-30 
sec, and we plan to minimize short-term sensitization of startle 
by delivering the auditory startle stimulus (no less than 8 sec 
after the aversive shock stimulus). Following each block, 
patients will subjectively rate their anxiety levels during the cue 
and intertrial interval for each condition (N, P, U) on a written 
scale of 0 (not anxious) to 10 (extremely anxious). Patients will 
also rate their anxiety on a scale from 0 to 10 during ths task, 
using the computer keyboard. Throughout the experiment 
heart rate and skin conductance will be continuously recorded 
with the BioPac systems during administration of the NPU-
threat test at Visits 2 and 4. The data will be preprocessed and 
scored using AcqKnowledge software.  
Cognitive Testing: Cognitive testing will be carried out 
to measure behavior and self-reports of anhedonia, reward 
processing and pattern separation. Regarding behavior, we 
will use a validated 25-minute computer-based Probabilistic 
Reward Task(30) at Visits 2 (“pre-ketamine”) and again at Visit 4 (“post-ketamine”). Patients will be given 
verbal instructions for the task in that the objective is to win as much money as possible, which will be handed 
out in cash at the end of the task. The task will consist of 3200 trials, divided into 2 blocks of 100 trials, with 


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blocks separated by a 30-sec break. Each trial will start with the presentation of an asterisk for 500 msec in the 
center of the computer screen to serve as a fixation point. Then, a mouthless cartoon face will appear in the 
center of the screen. After a delay of 500 msec, either a short mouth (11.5mm) or a long (13mm) mouth will 
briefly appear on the face for 100 msec, and then will disappear. The mouthless face will remain on the screen 
until the patient chooses a computer key to identify which mouth (long or short) was presented. For each block, 
both stimuli will be shown an equal number of times. Correct responses will be reinforced with monetary 
reward feedback that will be given as follows: “Correct! You won 20 cents.” In order to induce a response bias 
toward one of the mouth lengths, an asymmetrical reinforcer schedule will be used; for example, correct 
responses for 1 mouth (e.g., the long mouth) will be rewarded three times more frequently than correct 
responses for the other mouth (e.g., the short mouth). This designation will be randomized across patients. 
Because of this unequal frequency of reward feedback, patients with high reward responsiveness are predicted 
to favor the stimulus with more reinforced positive feedback, whereas patients with low reward responsiveness 
are expected to have a lower bias, or none at all, towards the positive feedback. As in published work(30-32) 
for the task, the main dependent variables will be response bias across blocks as well as Reward Learning [= 
Response Bias (Block 3) - Response Bias (Block 1)].   
In addition, we will include a computer based pattern separation task at Visits 2 and 4. The pattern 
separation task is a high throughput behavioral task that captures the input-output transformation function 
characteristic of pattern separation processes. (33) For example, if you park your car in the same lot everyday, 
but not the same space, pattern separation is thought to be involved in the process of you finding your car 
everyday despite being in a different space; this may be dysfunctional in people with depression. In this task, 
patients are shown a series of every-day objects (e.g., a car, garden tool, food, etc.) and are asked to identify 
the objects as being indoor or outdoor objects. Immediately after this, a second part of the task is started in 
which the patients are shown another series of objects. They are asked to call the objects as “old” if they have 
seen the objects before in the task, “new,” or “similar.” As previously done by Stark and colleagues,(33) a third 
of the objects in the testing phase are “old”, “similar” and “new”. Identifying a “similar’ object correctly conveys 
pattern separation, whereas, incorrectly identifying it as “old” conveys pattern completion. By plotting 
responses as a function of object similarity, we can generate an input-output transfer curve. This task will serve 
the purpose of rapid assessment of putative changes in pattern separation. 
Psychometric Assessments: Self- and clinician-rated assessments will take place during the study. We 
will administer the following scales to all participants at all visits (Visits 1-4): the Hamilton Depression Rating 
Scale (HDRS) (the primary dependent outcome measure) is a 28-item validated clinician-administered scale 
that is widely used as an observational rating measure of depression presence and severity;(34) the 
Montgomery Asberg Depression Rating Scale (MADRS), a 15-item validated clinical-administered scale widely 
used for the assessment of depression (35); Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) is a 14-
item validated clinician-administered scale that is widely used as an observational rating measure of anxiety 
presence and severity;(36) Clinically Useful Depression Outcome Scale (for the DSM-5 Anxious Distress 
Specifier) (CUDOS-A) is a 22-item self-rated scale for the assessment of DSM-5 anxious distress;(37) Young 
Mania Rating Scale (YMRS) is an 11-item clinician-rated scale for the measurements of hypomanic/manic 
symptoms;(38) MGH Sexual Functioning Questionnaire (SFQ) is a 7-item self-rated scale for the assessment 
of sexual functioning; Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item self-report questionnaire for the 
assessment of anhedonia (please loss to previously pleasurable activities);(39)  
We will administer the following to all participants at Visit 1 only (screening): Mini-International 
Neuropsychiatric interview (M.I.N.I.) to assess for the presence of depression;(40) the MGH Antidepressant 
Treatment History Questionnaire (ATRQ), a clinician-rated scale used to determine treatment resistance in 
depression;(41) the Early Trauma Inventory Self Report-Short Form (ETISR-SF), a 29-item self-report item on 
early trauma history,(42) the EHI (a self-reported measure of dominant handedness), and a demographics 
form.  
We will administer the following scales to all participants during Visit 3 (ketamine administration) only: 
Brief Psychiatric Rating Scale (BPRS) is an 18-item clinician-administered scale for the assessment of 
psychotic symptom constructs;(43) Clinician Administered Dissociative States Scale (CADSS) is a 28-item 
clinician-administered scale for the assessment of dissociative symptoms.(44) BPRS and CADSS will be 
administered at baseline, +40 minutes, +80 minutes, and +120 minutes in reference to the start of the 
ketamine infusion. 


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Study clinicians at the DCRP will be responsible for administering all clinician-administered scales and 
assessments. Clinicians have been extensively trained in the use of the HDRS28 by videotapes and live patient 
interviews.  
Concomitant Medications and Adverse Events: Concomitant medications (dosage, start and stop dates) 
will be reviewed and recorded at all visits in the chart. Adverse events will be recorded at all visits on the 
Adverse Events Form.    
Peripheral Blood Sample Genetics and Biomarkers: At Screening, one 10 mL blood sample, one 8-
10mL blood sample, one 6-8 mL blood sample, and two 10mL blood samples will be collected; two 8-10mL 
blood samples will be collected and at Visits 3 and 4, to obtain DNA for possible pharmacogenetic and 
biomarker (e.g. cytokines, metabolites, etc.) studies. The PI will ensure that appropriate privacy and de-
identification procedures are in place for the collection of biomaterials. 
In order to collect iPS cells for future biomarkers and genetics studies, all subjects will be referred to 
participate in Protocol 2009P000238, “The Use of Human Skin Cells and Blood Derived Cells in the Creation of 
Cellular Models of Neuropsychiatric Disorders” (P.I.: Perlis).” Subjects’ choice as whether or not to participate 
in 2009P000238 will have no bearing on their ability to participate in the current protocol.  
 
Drug to be Used: Ketamine will be the only research drug used as part of the study. 
Ketamine Administration and Monitoring: Ketamine is a glutamatergic receptor antagonist that has been 
administered to millions of patients worldwide as a general anesthetic, though its antidepressant mechanism of 
action (at sub-anesthestic doses) remains largely unknown. Although low-dose ketamine has been shown to 
have a favorable safety profile when given to depressed patients in several studies,(1, 24-27) there is a 
potential risk of adverse psychotomimetic, dissociative, and/or sympathomimetic events. Similar to previous 
studies showing efficacy and safety of intravenous ketamine in adults with mood disorders,(1, 45, 46) including 
studies completed at the MGH CRC (e.g., Protocol 2012P001042),  ketamine will be administered at 0.5mg/kg 
over 40 minutes by a BLS and ACLS-certified, licensed physician at the MGH General Clinical Research 
Center. Patients will be monitored at the General Clinical Research Center by a medical doctor and trained 
nurse for changes in vital signs (i.e., heart rate, blood pressure, respiration, temperature, pulse ox, and 
sedation level) and for treatment-emergent side effects (i.e., as measured by the CADSS and BPRS) during 
administration and post-administration. Rescue medications, including intravenous labetalol, lorazepam, 
ondansetron, and haloperidol will be available in the event that unwanted side effects occur; participants 
requiring such interventions will be withdrawn from the study. PO ibuprofen and acetaminophen will also be 
available. The following parameters are specified in the order set for the CRC: 
 
1. Oxygen 4 to 6 liters/min via face mask or nasal cannula PRN, SpO2 <93% at bedside 
2. Labetolol 2.5 mg IV push over 2 mins PRN BP ≥3 readings in a row of BP ≥ 160/100; may repeat 
every 2 to 5 mins X5. Given by MD/NP. Infusions will be stopped if BP ≥160/00 persists for more than 20 
minutes. PRN for tachycardia >100 bpm; symptomatic tachycardia >100 bpm requires EKG.  
3. Lorazepam 2mg IV push PRN severe agitation, attempting to pull out IV; May repeat every 2-5 
minutes X 3. Given by MD/NP 
4. Haloperidol 1-2mg IV push PRN delirium (not oriented to space and time, hallucinations, attempting 
to pull IV); May repeat every 10 minutes X 5. Given by MD/NP 
5. Glycopyrrolate 0.1mg IV push PRN excessive salivary secretion; May repeat every 2-5 minutes X 3. 
Given by MD/NP 
6. Ondansetron 4mg IV PRN severe nausea, may repeat x1 after 30 min if no effect. 
7. Acetaminophen 325mg tablets, take 1 - 2 tablets PO PRN headache, may repeat x1 after 30 min 
8. Ibuprofen 200mg tablets, take 2 tablets PO PRN headache, may repeat x1 after 30 min 
 
Research staff will be responsible for administering scales and for monitoring side effects.  In order to 
minimize external stimuli, ketamine administration will occur in a room with low lighting and minimal noise 
throughout the administration, as well as during the monitoring period. Participants will be given a small snack 
2 hours after the end of the ketamine infusion.  
 


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Discharge: After the ketamine infusion, if medically stable (as deemed by a board-certified physician 
study investigator), participants will be discharged home with a responsible family member or other adult 
caretaker. Discharge home will be based on criteria established by the MGH Department of Anesthesia 
practices for discharge from the hospital following ambulatory surgery. The participant must have stable vital 
signs, be able to respond appropriately to normal commands, be pain free, be free from any nausea and 
vomiting, and have no bleeding from the intravenous sites. Participants must be able to walk unassisted and 
have an accompanying adult to escort them home. Participants will be advised not to return to work and 
against driving or operating heavy equipment for 24 hours.  
 
Medication Transport and Storage 
 
The MGH Research Pharmacy and MGH CRC will store medications, including ancillary medications.  
 
Devices to be Used 
N/A 
 
Procedures/Surgical Intervention 
N/A 
 
VI. Biostatistical Analysis 
Specific Data Variables to be Collected 
As described above, we will administer the following scales at all visits (Visits 1-4): HDRS, MADRS, 
HAM-A, CUDOS-A, YMRS, SFQ, and SHAPS.  
We will administer the following at Visit 1 only (screening): M.I.N.I., ATRQ, and ETISR-SF.  
We will administer the following scales during Visit 3 only (ketamine): BPRS and CADSS at baseline, 
+40 minutes, +80 minutes, and +120 minutes in relationship to the time of ketamine infusion. 
Vital Signs will be recorded once at Visit 1 (the screening visit), and again at Visit 3 at baseline, +0 
minutes, +5, +10, +15, +20, +30, +40, +60, +90, +120, +180 minutes in relationship to the time of ketamine 
infusion.  
 
Study Endpoint 
 
Primary clinical endpoint is change in the HDRS28 total score. Scores that decrease by ≥ 50% from 
baseline will be considered “response.”  
 
Specific Statistical Methods 
Testing of Hypotheses: Statistics and Data Analysis 
 
Specific Aim #1: Objective and subjective measures of anxiety will be positively correlated with 
each other. A primary analysis will examine Pearson correlations between subjective measures of anxiety 
(i.e., the HDRS Anxiety-Somatization Factor Scale, HAM-A, and CUDOS-A) and eye-blink startle response. 
Similarly, we will examine correlations between subjective anxiety and reward responsiveness. We will analyze 
the data to ensure that linearity exists. If linearity does not exist, we will conduct comprehensive sub-analyses 
to find the best way to characterize the relationship of all data. For example, we will use covariates (e.g., 
clinical descriptors such as treatment failures) to determine their role in creating non-linearity. 
 
Specific Aim #2: Greater psychophysiological and cognitive objective measures of anxiety will 
predict better antidepressant response to ketamine, regardless of subjective depression symptoms. 
We will use a nonlogitudinal linear regression model to assess the extent to which the combination of pre-
treatment psychophysiological (e.g., anxiety-potentiated eye-blink startle) and cognitive reward processing 
(high versus low reward responsiveness) predict the antidepressant treatment response to ketamine (Visits 3 
and 4). Antidepressant response to ketamine will be defined as a ≥50% improvement in HDRS scores (primary 
dependent outcome measure). 
 
Specific Aim #3: In ketamine responders, psychophysiological measurements will show a 
significantly larger decreases in magnitude compared to ketamine nonresponders; greater 
improvements will be seen in cognitive reward processing measures in ketamine responders. We will 
use longitudinal analyses (linear mixed effects random regression models) to analyze the effect of ketamine on 


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the biomarkers. These models account for the correlation of observations from the same individual. For the 
change in startle magnitude post-ketamine, the model will include the change in startle magnitude as the 
outcome, and time (Visit 2 and 4) as the predictor. For the change in reward processing post-ketamine, the 
model will include the change in reward processing as the outcome, and time (Visit 2 and 4) as the predictor. 
The coefficient for the correlations in this model quantifies the rate of change in the psychophysiological and 
cognitive measures associated with a change in depressive symptoms. A coefficient significantly different from 
zero indicates that changes in the clinical measures of depression are associated with changes in 
psychophysiological and/or cognitive measures. We will also perform between-group comparisons of 
measurements for responders vs. nonresponders. All models will be fit using SAS software, α=0.05, two-tailed.  
 
Sample Size Determination:  
 
The sample size for Aims #1 and #2 was calculated using the G*Power Sample Size calculator 
(Version 3.9.1.2; downloaded from http://www.gpower.hhu.de) and was based on findings from a post-hoc 
analysis of the antidepressant treatment response to ketamine in anxious versus nonanxious depressed 
patients, where anxious depression predicted a better response to open-labeled ketamine.(6) The anxious 
depression effect size (Cohen’s d) reached its maximum of d=0.76 on Day 2 post-infusion. With this, for Aims 
#1 and #2, we estimate requiring 58 patients with power >0.8, r=0.35 and an α=0.05, two-tailed, in order to 
reject the null hypothesis that there will be no correlations with baseline psychophysiological and cognitive 
measures between ketamine responders and nonresponders. For Aim #3, a sample size of 58 would allow us 
to detect a moderately-large effect size (Cohen’s d≥0.75) for between-group comparisons. In order to account 
for potential drop-outs, we will recruit 70.  
Expected Outcomes/Results:  We expect that subjective and objective measures of anxiety will be at 
least moderately correlated in patients with mood dysregulation. Further, we predict that patients with higher 
pre-treatment levels of objective anxiety, as measured by psychophysiological and cognitive assessments, will 
have significantly greater antidepressant responses to ketamine, compared to patients with lower pre-
treatment objective anxiety. These results will significantly contribute to the paucity of information regarding 
biomarkers of diagnosis and antidepressant response and provide insight into the anxiety and reward 
neurocircuitry that could contribute to the pathophysiology of anxious depression. 
 
VII: Risks and Discomforts 
Complications of Procedures 
Safety: At any time during the study, participants, family members, and treating psychiatrist will be 
encouraged to contact the principal investigator via phone or pager in the case of adverse events or worsening 
symptoms. The treating psychiatrist will be immediately notified of any concerns.  
 
 
Drug Side Effects and Toxicities 
Ketamine: Ketamine is a relatively commonly used anesthetic in both veterinary and human medicine. 
Although it has a good safety profile overall, ketamine has documented sympathomimetic activity that may 
result in mild to moderate increases in heart rate, blood pressure, and cardiac output, though this activity is 
generally short-lived.(47) Findings from previous research on single- and repeated-dose intravenous ketamine 
for treating depression have provided evidence that the autonomic changes that may occur during the active 
administration (i.e., elevated blood pressure, pulse) return to normal shortly after the infusion stops, with no 
clinically significant sequelae.(48, 49) Other possible side effects reported during ketamine infusion include 
arrhythmia, increased salivation, increased bronchial secretions, horizontal nystagmus, euphoria and 
hallucinations. Nystagmus may persist for a period after the ketamine infusion has terminated. 
Rare side effects are allergic reactions (skin rash), pain at site of injection, increased intraocular 
pressure, ulcerations and inflammation in the bladder (reported in ketamine abusers). Ketamine is a controlled 
substance and has the potential for abuse and dependence, in particular in participants with history of drug 
abuse. Participants with history of substance abuse or dependence in the previous year will be excluded.  
In light of ketamine’s relatively good safety profile, all participants will be medically screened (including 
EKG and vital signs) prior to entering the active treatment portion of the study, to ensure healthy baseline 
general and cardiac functioning. In addition, as ketamine is an anesthetic that may result in respiratory 
depression, participants will be excluded from the study if they require sedatives or opiates. During the 


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administration, a medical doctor will remain in the room with a research nurse, the research assistant, and the 
patient, and vital signs will be monitored every 5 minutes during the 40 minutes of administration. Any 
concerning changes will be managed by the physicians. Criteria for discontinuation include ≥3 readings in a 
row of systolic BP ≥180 mmHg or diastolic BP ≥110 mmHg, HR ≥110 bpm, or symptomatic elevations in blood 
pressure (i.e., new onset headache, chest pain, or shortness of breath). Furthermore, the physician may 
choose to stop the infusion at any time if he/she believes it is in the best interest of the participant, based upon 
his/her clinical judgment.  
Participants will stay at the General Clinical Research Center (GCRC) for up to 4 hours following the 
start of the administration, and will be monitored for psychotomimetic, dissociative, and sympathomimetic side 
effects during this time.  Afterwards, they will be discharged home in the care of a responsible adult family 
member or caretaker after completing rating scales with the study physicians. If participants experience 
adverse events at home, they will be referred for evaluation at the nearest emergency department. These 
instructions will also be provided to the responsible adult escort prior to discharge. The participant’s individual 
insurance plan will be responsible for covering this visit.  
Prior to informed consent, potential participants will be informed of alternatives to research, and will be 
provided with the option to seek further psychopharmacological or psychotherapy-based interventions. 
 
Electric Shocks 
The electric shocks that participants receive will be self-selected to be highly annoying, but not painful. 
Subjects may stop the electric shocks at any time. The stimulator is manufactured by Digitimer. It is inspected 
annually by biomedical engineering under the auspices of Partners Human Research Committee (PHRC), who 
have affirmed compliance with safety regulation. The stimulator has been used in similar experiments across 
institutions, including the National Institute of Mental Health (NIMH), and has been approved by their IRB for 
use in humans.  
 
Psychosocial (non-medical) Risks 
Privacy: As per standard DCRP procedures, study data is recorded using standard forms.  All data will 
be stored in locked cabinets. For statistical analysis, only study IDs will be used as identifiers. Separate folders 
with unblinded information (e.g., patient name) will be kept in a locked cabinet in a separate office to ensure 
the blind.   
 
Safety Risk 
 
Though patients with severe suicidal ideation will be excluded from the study at screening, any patient 
who, based on the investigator’s judgment, is judged to present with an imminent risk of suicide will be 
discontinued from the study and referred to a local emergency room for further evaluation. 
 
VIII: Potential Benefits 
To Participating Individuals and Society 
 
The patients participating to the study may feel better, if for only a brief period of time. Some may not 
receive any direct benefit. The results of this study may lead to improved understanding of the neurobiology of 
depression, as well as the biomarkers for diagnosis and treating depression. Furthermore, the results from this 
study may lay the groundwork for future studies into the mechanism of action of ketamine’s antidepressant 
effects, as well as using neurobiology to subtype depression. 
 
IX: Monitoring and Quality Assurance 
 
Because this study is a physiological study of biomarkers, as opposed to a clinical trial, the principal 
investigator and co-investigators will be responsible for monitoring and quality assurance of the study. In 
conjunction with the research assistants, weekly meetings will be held and documented. Current participants in 
the study will be discussed at each meeting, and charts will be reviewed for completeness. 
 
Serious Adverse Events:  Expedited review will occur for all events meeting the FDA definition of SAEs 
– i.e., any fatal event, immediately life-threatening event, permanently or substantially disabling event, event 
requiring or prolonging inpatient hospitalization, or any congenital anomaly. This also includes any event that a 


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study investigator judges to impose a significant hazard, contraindication, side effect, or precaution.  Reporting 
to the IRB will be done within 24 hours of the SAE. 
 
Study Stopping Rules:  If at any time during the course of the study, the PI or CO-Is judge that risk to 
participants outweighs the potential benefits, the PI/CO-Is shall have the discretion and responsibility to 
recommend that the study be terminated.  
 
 
AE Reporting Guidelines 
Concomitant Medications and Adverse Events: Concomitant medications (dosage, start and stop dates) 
will be reviewed and recorded at each visit. The study doctor will document and side effect or adverse event 
during Phase II.  
In case of serious adverse cognitive side effects (delirium or confusion of clinical concern, with or 
without other symptoms like hallucinations, paranoia) or other serious side effects (e.g., cardiac, neurologic), 
patients will be discontinued from the study and immediately treated with the appropriate pharmacologic 
management (e.g., haloperidol, as needed, for delirium and psychotic symptoms). 
 
 
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ICF_003.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychophysiological and Cognitive Biomarkers of Ketamine’s Antidepressant Effects 
(Protocol 2015P002397) 
 
NCT02669043 
 
Version Date: 12/13/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Partners HealthCare System 
Research Consent Form 
Page 2 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
 
 
 
General Template 
Version Date:  October 2014 
Subject Identification 
 
 
Protocol Title: Psychophysiological  and Cognitive Biomarkers of Ketamine’s 
Antidepressant Effects 
 
Principal Investigator: Dawn F. Ionescu, M.D. 
 
Site Principal Investigator: 
 
Description of Subject Population: Adults with Treatment-Resistant  Depression 
 
 
 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study. 
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
We are doing this research to study ways to predict who will have an antidepressant  response to 
ketamine. We will use different types of tests before and after giving ketamine in order to answer 
this question. 
 
One of the tests utilizes a brief electric shock, which is applied to your fingers. The shock is 
highly annoying but not painful. The purpose of the electric shock is to help us to measure your 
startle response, which might be a helpful predictor for ketamine’s antidepressant  effects. 


Page 3 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
This is a pilot study. Pilot studies are done on a small group of subjects to learn if a larger study 
would be useful. 
 
Ketamine is approved by the U.S. Food and Drug Administration (FDA) to be used with other 
drugs for anesthesia and as a pain reliever during procedures.   However, ketamine is not 
approved by the FDA to treat depression. 
 
We are asking you to take part in this research study because you have treatment-resistant 
depression (TRD) with or without anxiety.  This means you have tried an antidepressant  in the 
past that has not helped your depression. 
 
Subjects in this study will receive one dose of ketamine in addition to your current 
antidepressant medication(s).  It is very important that you take your medications exactly as your 
doctor has prescribed them. 
 
We hope to enroll about 70 patients with depression in this study at Massachusetts General 
Hospital (MGH). 
 
The National Institute of Mental Health is paying for this research to be done. 
 
How long will I take part in this research study? 
 
It will take you about 4-5 weeks, at most, to complete this research study. During this time, we 
will ask you to make 4 study visits. All of these visits will be at MGH. 
 
What will happen in this research study? 
 
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures. 
 
Screening - Visit 1 
The screening visit will take up to 3 hours. This visit will take place at the MGH Depression 
Clinical and Research Program. During this visit, we will do some tests and procedures to see if 
you qualify to take part in this research study. The study doctor will review the results of these 
tests and procedures. If you don’t qualify, the study doctor will tell you why. 
 
At this visit, we will: 
Ask about your medical history 
Give you a physical exam, including height, weight and “vital signs” (blood 
pressure, temperature, and heart rate) 


Page 4 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
Ask you about your age, sex, and ethnic origin 
Ask you to take a brief hearing test 
Draw a blood sample 
Test your urine for certain drugs 
Test your urine for pregnancy, if you are a female able to become pregnant.  Note: 
pregnant women cannot take part in this research study 
Give you an ECG (electrocardiogram) 
Give you some questionnaires to fill out about your general health and well-being, 
quality of life, mental health, emotional health, and mood. 
   We may ask for your permission to contact the physician who currently prescribes 
your antidepressants 
 
Urine Drug Screen 
During this study, we will test your urine for certain drugs, including illegal drugs such as 
cocaine and marijuana. If your urine shows you have taken any of these drugs, you can’t be in 
this study.  The results of the urine drug test will not become part of your hospital medical 
record.  These test results will, however, remain part of your research study record. 
 
Blood Sample 
 
Will my blood sample be used for genetic research? 
 
Yes. We plan to do genetic research on the DNA in your blood sample.  DNA is the material that 
makes up your genes.  All living things are made of cells.  Genes are the part of cells that contain 
the instructions that tell our bodies how to grow and work, and determine physical characteristics 
(such as hair and eye color).  Genes are passed from parent to child. Genetic research is an 
important part of the investigation into the causes of depression and individual responses to 
antidepressant  medications.   The causes of depression are believed to be the result of 
combinations of inherited genes and possible various exposures to the environment.  You may 
still participate in this study even if you choose not to provide blood samples for future genetic 
research. 
 
Your samples may be used to create a living sample (called a “cell line”) that can be grown in 
the laboratory.  This allows researchers to have an unlimited supply of your cells in the future 
without asking for more samples from you. 
 
Do you agree to let us store your samples for future genetic research related to depression and 
other health disorders? 
 
Yes 
No 
Initials  
 


Page 5 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
 
 
 
Metabolic and Serum Biomarkers for Future Use 
 
We would like to store some of your samples to study metabolic and serum biomarkers. 
Metabolites and biomarkers are naturally occurring substances found in blood.  One component 
of blood is serum, which stores these substances.  Future research may lead to new methods of 
diagnosing disease by measuring levels of metabolites and/or biomarkers in a person’s blood, 
tissue, or urine.  You may still participate in this study even if you choose not to provide blood 
samples for future metabolic and serum biomarker research. 
 
Your samples may be used to create a living sample (called a “cell line”) that can be grown in 
the laboratory.  This allows researchers to have an unlimited supply of your cells in the future 
without asking for more samples from you. 
 
Do you agree to let us store your blood samples for future research related to metabolic and 
biomarkers? 
 
Yes 
No 
Initials  
 
 
How long will my samples be kept? 
 
The researchers will keep your sample until it is all gone, becomes unusable, or until the 
researchers or sponsor decide to discard the sample. 
 
How much blood will be drawn during this study? 
 
A total of 76-88 mL (5-6 tablespoons) of blood will be taken throughout the entire study. 
 
ECG (electrocardiogram) 
This test checks the electrical activity of your heart.  We will place several small, sticky pads on 
your chest, arms, and legs.  Each pad has a wire attached.  The wires connect to a machine that 
makes a recording of your heart rhythm.  This painless test takes about 15 minutes. 
 
Pre-Ketamine and Post-Ketamine  Testing Visit - Visit 2 and Visit 4 
At this visit, we will ask you to complete baseline testing. Specifically, we will be asking you to 
complete computer-based  behavioral tasks and a task that involves a brief electric shock on your left 
wrist. 
 
Do not consume caffeine or nicotine within 1 hour of the experiments; do not consume alcohol 
within 24 hours of the experiments. 


Page 6 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
 
At this visit, we will: 
Ask you questions about side effects or health problems since your last visit 
Give you some questionnaires to fill out about your general health and well-being, 
quality of life, mental health, emotional health, and mood 
Test your urine for pregnancy, if you are a female able to become pregnant 
Complete computer-based  behavioral tasks (cognitive reward task and task that 
involves differentiating patterns of objects). 
Complete a startle task that involves electric shock 
Draw a blood sample at the last visit 
 
Electric Shocks 
We will use a half-second annoying (but not painful) electric shock, administered on your left 
wrist. Two small electrodes will be attached to your left wrist The electrodes are made of a small 
piece of metal that is attached to a cable. The cable is connected to a battery-powered  stimulator. 
The electric shock feels like an annoying tingling sensation. 
 
We will first find the level of shock that you consider highly annoying, but not painful. To do 
this, we will begin at a low level that you will not be able to feel very much, if at all.  We will 
slowly increase the shock levels with your permission. We will ask you to tell us when you find 
the level of the current to be highly annoying, but not painful. During the rest of the research 
study, the level of current that you will experience will not be higher than this level. 
 
Electric shock is used to create a startle response. We will be measuring how hard your eye 
blinks (“startle”) after the shocks. You will also be sitting in front of a computer screen, and we 
will ask you to complete tasks while under the threat of shock. 
 
During the experiment, we will be monitoring how your body responds to the threat of shock. In 
order to do this, we will place small stick-on recording electrodes to the surface of your chest 
(near your right collar bone), your left arm, and to the surface of your hands. Each electrode has 
a wire attached. The wires connect to a computer that will measure your emotional reaction to 
the videos you see. 
 
Ketamine Infusion - Visit 3 
You will receive a single, low dose (0.5mg/kg over 40 minutes) of ketamine at this visit. We will 
do the infusion at the Clinical Research Center at MGH. This visit will happen 1-2 days after 
Visit 2. 
 
For safety reasons, you must have nothing to eat or drink for 8 hours before this study visit. 
At this visit, we will: 


Page 7 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
Ask you questions about side effects or health problems since your last visit 
Record your vital signs 
Test your urine for pregnancy, if you are a female able to become pregnant 
Give you some questionnaires to fill out about your general health and well-being, 
quality of life, mental health, emotional health, and mood 
   Insert an IV catheter (small, flexible tube) into an arm vein with a needle.  We 
will use the catheter to give you the ketamine 
   Place an oxygen monitor on your fingertip (to measure the amount of oxygen in 
your blood) during the ketamine infusion 
   Do an electrocardiogram  (ECG). An ECG checks the electrical activity of your 
heart. We will place several small, sticky pads your chest. Each pad has a wire 
attached. The wires connect to a machine that records your heartbeat 
Give you a ketamine infusion 
Draw a blood sample after ketamine 
Ask you questions from questionnaires 
 
 
 
Ketamine Administration  Procedures 
 
Before the study visit, we will ask you to fast (have nothing to eat or drink, except water) after 
midnight before the day of the ketamine. 
 
Do not consume alcohol or opiates/narcotic  analgesics (such as morphine, hydromorphone, 
oxycodone, fentanyl)  the night before the ketamine infusion or the day of the infusion. 
Benzodiazepines  (such as lorazepam, alprazolam, clonazepam)  should be avoided the night 
before the ketamine infusion and the day of the infusion. Do not consume caffeine or nicotine 
that morning. 
 
Ketamine will be dosed based on your weight, at a dose of 0.5 mg/kg (a mg/kg is a unit of drug 
dosage). An experienced medical doctor will administer your infusion (about 40 minutes). To do 
this, we will place an intravenous (IV) line into a vein in your forearm. An IV is a flexible plastic 
tube that is connected to a needle.  You may relax comfortably in bed while we give you an 
infusion of study drug through the IV.  Your IV will stay in place for 1 hour after the infusion in 
case we need to give you other medications. 
 
The medical doctor will stay with you for the entire infusion, along with a research nurse and a 
trained research assistant.  A trained research staff member will be asking you a series of 
questions about how you are feeling.  We will record your vital signs, your mood and anxiety 
levels, and any side effects you experience for up to 4 hours after the start of the infusion. 


Page 8 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
To record your vital signs during the ketamine infusion, you will need to wear: 
 
A blood pressure cuff (to monitor your blood pressure at regular intervals) 
A 3 or 5-lead electrocardiogram  (ECG).  An ECG checks the electrical activity of 
your heart.  We will place several small, sticky pads your chest.  Each pad has a wire 
attached.  The wires connect to a machine that records your heartbeat. 
   An oxygen monitor on your fingertip (to measure the amount of oxygen in your 
blood) 
   We can use an oxygen face mask (fits over your nose and mouth) or nasal cannula 
(two small plastic tubes that are placed in both nostrils) to deliver oxygen therapy at 4 
to 6 liters per minute, as needed.  Oxygen therapy is a treatment that provides you 
with extra oxygen, a gas that your body needs to work well. 
 
We will also get a blood sample for post-ketamine genetics and biomarkers.   After we give you 
the ketamine and the up to 4 hour monitoring period is over, we will make sure that the effects of 
the study drug have worn off enough for you to go home. You must have a responsible adult 
available to escort you home when you have completed the study. This responsible adult 
escort must be present regardless of the mode of transportation you choose (i.e., even if you take 
a cab or the bus). If you do not know anyone who can help you, and you are not able to work 
with a medical escort service to take you home, then you cannot take part in this study. 
 
Stopping the Study Early 
 
You may withdraw from this study at any time, even in the middle of an experiment. We will 
make sure you stop the study safely. The study doctor will speak to you about follow-up care, if 
needed. 
 
The study doctor may have to take you out of the study. This may happen because of several 
different reasons, such as a decline in your physical or mental health (“worsening of your 
condition”) or missing too many study visits. 
 
What Study Information May Become Part of Your Electronic Medical Record? 
A notation that you are taking part in this research study may be made in your electronic medical 
record.  Information from the research that relates to your general medical care may be included 
in the record (for example: list of allergies, results of standard blood tests done at the hospital 
labs, vital signs). 
 
Please ask your study doctor if you have any questions about what information will be included 
in your electronic medical record. 
 
Will I be contacted about future studies? 


Page 9 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
We have a particular interest in studying depression. We may want to contact you again in the 
future by letter or telephone if the researchers think you may qualify for a follow-up study. Is it 
okay to contact you in the future? Please indicate your choice with your initials next to the 
appropriate answer. 
 
Yes:  
 
No:  
 
 
 
 
Best way to contact you: 
 
 
 
 
 
 
 
 
What are the risks and possible discomforts from being in this research 
study? 
 
Risks of Taking Ketamine 
Taking ketamine may cause you to have one or more of the side effects listed below. 
Common side effects of ketamine are: 
fast, irregular heartbeat 
increased blood pressure 
clear dreams that may seem real 
confusion 
irritated feeling when waking up 
floating sensation (feeling “out-of-body”)  lasting from minutes to hours 
breathing problems, coughing 
nausea, vomiting 
twitching, muscle jerks, and muscle tension 
increased saliva (spit) 
increased thirst 
headaches 
metallic taste 
constipation 
blurry or double vision 


Page 10 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
Rare side effects of ketamine are: 
allergic reactions, like skin rash 
pain at infusion site 
ulcerations (open sores) and inflammation (swelling or irritation) in the bladder 
hallucinations (seeing or hearing things that are not really there) 
euphoria (a feeling of extreme happiness) 
involuntary eye movements 
low mood or suicidal thoughts 
 
In one published review of ketamine’s safety and tolerability in depression research, four out of 
204 ketamine administrations  had to be discontinued because of new or worsening physical or 
psychiatric symptoms (including the sensation of being “out of body,” confusion, agitation, and 
paranoia) within the first 10 to 80 minutes after receiving ketamine.  In all studies these 
symptoms disappeared within 110 to 240 minutes (about 2 to 4 hours).  Three of t he six studies 
also reported mild increases in blood pressure and heart rate, but this was only for 1 out of 10 or 
fewer of the subjects.  All of the subjects’ blood pressures and heart rates returned to normal 
within minutes. 
 
We do not know the risk of side effects due to drug interactions between ketamine and the drugs 
that you are already taking is. There may be risks of ketamine that are currently unknown. 
 
In the published studies there were no reports of severe or long-lasting side effects.  If you 
experience any severe side effects or need to stay in the General Clinical Research Center for 
longer than 4-5 hours, the study doctors will send you to the Emergency Department where the 
emergency doctors will evaluate you. 
 
We may give you medications to help with side effects during the administration.  These 
medications are: labetalol for blood pressure or high pulse; lorazepam for agitation; haloperidol 
for delirium; glycopyrrolate  for excessive spit or arrhythmia; ondansetron for severe nausea; 
acetaminophen  for headache; and ibuprofen for headache. We will only give these medications if 
deemed medically necessary in the clinical judgment of the medical doctor. 
 
If you experience any side effects once you are at home, please call the doctor in charge of this 
study, or the covering psychiatrist.  She/he may instruct you to take a dose of your medications 
to help with the side effects, or may tell you to go to your local Emergency Room. 
 
 
 
 
 
Risk of Allergic Reaction 


Page 11 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
 
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, 
and can even result in death.  Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing. An allergic reaction would 
typically occur shortly after receiving the ketamine, before you go home. However, if you think 
you are having an allergic reaction at home, call the study doctor right away.  If you are having 
trouble breathing, call 911 immediately. 
 
Risks of Electric Shocks 
 
The electric shocks that you will receive will be uncomfortable  but not painful or dangerous. 
You may stop the electric shocks at any time. 
 
 
Risks of the IV 
 
The risks of having an IV placed in your vein include: 
mild discomfort where the IV is placed 
bruising (black and blue marks at the site of puncture) where the IV is placed 
bleeding (usually less than a tablespoon of blood) where the IV is placed 
dizziness 
fainting (rare) 
 
Risks of Blood Draws 
 
You may have a bruise (a black and blue mark) or pain where we take the blood samples.  There 
is also a small risk of infection, lightheadedness,  and/or fainting. 
 
Risks of Genetic Testing 
 
Genetic information that results from this study does not have medical or treatment importance at 
this time.  However, there is a risk that information about taking part in a genetic study may 
influence insurance companies and/or employers regarding your health.  To further safeguard 
your privacy, genetic information obtained in this study will not be placed in your medical 
record. 
 
Taking part in a genetic study may also have a negative impact on family or other relationships. 
If you do not share information about taking part in this study, you will reduce this risk. 
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 


Page 12 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
The effect of ketamine on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding  infant, are unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are: 
Pregnant 
Trying to become pregnant 
Breastfeeding 
 
If you are a menopausal woman and have not had a period for the past 12 months or more, you 
will not need to have a pregnancy test.  Also, if you have had any well-documented  method of 
surgical sterilization, you will not need to have a pregnancy test.  The documented methods of 
surgical sterilization include having had a hysterectomy (removal of the uterus with or without 
the ovaries), bilateral oophorectomy (removal of both ovaries), a tubal ligation (having your 
tubes tied), or transvaginal occlusion (plugging the opening of the tubes with a coil). 
 
If you are a menopausal woman and have not had a period for the past 12 months or more, you 
will not need to have a pregnancy test.  Also, you will not need to have a pregnancy test if you 
have had a hysterectomy (surgical removal of your uterus and/or ovaries).  All other female 
subjects must have a negative pregnancy test before starting the study medication. 
 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below.  You must use birth control for the entire study. 
 
Acceptable birth control methods for use in this study are: 
   hormonal methods, such as birth control pills, patches, injections, vaginal 
ring, or implants 
   barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm) 
intrauterine device (IUD) 
abstinence (no sex) 
 
If you miss a period, or think you or your partner might be pregnant during the study, you must 
tell the study doctor immediately.   If you become pregnant, you must stop taking part in the 
study.  The study doctor may ask for your permission to collect information about the outcome 
of your pregnancy and the condition of your newborn. 
 
 
 
Risks of Receiving Ketamine While Taking Other Medications 
 
For your safety during this study, call your study doctor BEFORE you take any: 
   new medications prescribed by your own doctor 


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Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
other medications sold over-the-counter  without a prescription 
dietary or herbal supplements 
 
Protection Against Risk 
 
Since your depression puts you at risk for suicidal thoughts or behaviors, we will ask you to 
provide information about a friend, family member, or primary doctor who will be your 
emergency contact. 
 
If at any time during the study, you develop serious thoughts about suicide or harming yourself, 
you should immediately contact Dawn Ionescu, M.D.  You can reach Dr. Ionescu directly at 617- 
643-0491. Dr. Ionescu (or her physician coverage if she is away) can be paged by calling the 
MGH page operator at 617-726-2000. 
 
In some cases, you may be referred for emergency psychiatric evaluation and treatment with 
the MGH Acute Psychiatric Service or the nearest emergency department. You may be 
withdrawn from the study if emergency treatment is necessary. 
 
If we learn information from you during this study that indicates intent to seriously harm 
others or yourself, we may share that information with third parties, including public safety 
or law enforcement authorities, and may take other precautions to protect against such harm. 
 
Safety Caution 
 
If you need to seek medical care for any reason during the study (between the screening visit and 
Visit 2), we ask that you inform your study doctor.  There may be possible treatment interactions 
if you are prescribed other medications.   Generally, we recommend patients inform their doctors 
regarding the study immediately upon deciding to participate in this study. 
 
Discomforts 
 
Some of the questions on the questionnaires  may make you feel uncomfortable.  You can skip the 
questions that make you feel uncomfortable. 
 
 
 
 
Loss of Confidentiality 
 
Any time information is collected about you there is a potential risk for loss of confidentiality. 
Every effort will be made to keep your information confidential. However, this cannot be 


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Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
guaranteed. Some answers you give in the study might put you at risk if other people find out. To 
keep what you say private, your study records will be coded; in other words, we will assign you a 
number to identify your information, instead of using your name. We will protect your records 
by keeping all your materials in locked file cabinets or secure password-protected computer files. 
Only research staff will have access to your private information. Any information kept on the 
computers is only available to research staff. 
 
Other Risks 
 
There may be other side effects that are unknown at this time. 
 
 
 
What are the possible benefits from being in this research study? 
 
You will not benefit from taking part to the study. The study may benefit other people with 
depression by furthering our understanding of depression and predictors of ketamine. 
 
 
 
What other treatments or procedures are available for my condition? 
 
 
There are approved treatments available for your depression, including psychotherapy, 
antidepressant  medications, and electroconvulsive  therapy (ECT). 
 
 
 
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part? 
 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future. 
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
 
 
What should I do if I want to stop taking part in the study? 


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Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
Will the results of research tests be reported to me? 
 
No.  The research tests are being done for research purposes only.  You will not receive the 
results of these research tests.  The information created by this study will not usually become 
part of your hospital record. 
 
 
Will I be paid to take part in this research study? 
 
If you complete all parts of the study, you will be paid up to $200. The payment Schedule is as 
follows: $20 for the Screening Visit (Visit 1), and up to $60 for the remaining 3 visits. At Visits 
2 and 4, you will be asked to participate in a task that involes the ability to make money based on 
your responses.  The money you make from this task will be calculated into your total payment. 
We will also pay for the cost of your parking during the study visits; in the case of Visit 3 (the 
ketamine administration visit), we will pay for the parking for your chaperone. 
 
What will I have to pay for if I take part in this research study? 
 
Study funds will pay for the study drug and other study-related procedures. 
 
Charges for any ongoing or routine medical care you receive outside this study will be billed to 
you or to your insurance company in the usual way. You will be responsible  for any deductibles 
or copayments required by your insurer for your routine medical care. 
 
What happens if I am injured as a result of taking part in this research 
study? 
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 


Page 16 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
 
 
General Template 
Version Date:  October 2014 
Subject Identification 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
 
 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want. 
 
Dawn F. Ionescu, M.D. is the person in charge of this research study.  You can call her at 617- 
643-0491 M-F 9-5, or you can page her 24/7 by calling the MGH page operator at 617-726-2000 
with questions about this research study. 
 
If you have questions about the scheduling of appointments or study visits, call Chelsea Dale at 
617-724-2936 M-F 9-5. 
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 617-424-4100. 
 
You can talk to them about: 

 Your rights as a research subject 

 Your concerns about the research 

 A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
 
 
If I take part in this research study, how will you protect my privacy? 
 
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”   In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so. 


Page 17 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
 
In this study, we may collect health information about you from: 
Past, present, and future medical records 
Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable health information and why they may 
need to do so: 
Partners research staff involved in this study 
The sponsor(s) of this study, and the people or groups it hires to help perform this 
research 
Other researchers and medical centers that are part of this study and their ethics boards 
A group that oversees the data (study information) and safety of this research 
Non-research staff within Partners who need this information to do their jobs (such as for 
treatment, payment (billing), or health care operations) 
   The Partners ethics board that oversees the research and the Partners research quality 
improvement  programs. 
   People from organizations that provide independent accreditation and oversight of 
hospitals and research 
   People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
   Federal and state agencies (such as the Food and Drug Administration,  the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research) 
   Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
   Other: 
 
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.   We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 


Page 18 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  October 2014 
 
 
 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study. 
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished. 
 
 
 
Informed Consent and Authorization 
 
 
Statement of Person Giving Informed Consent and Authorization 
 

 I have read this consent form. 

 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 

 I have had the opportunity to ask questions. 

 I understand the information given to me. 


Page 19 of 18 
Consent Form Title: Consent Form_Clean 7-5-16 
IRB Protocol No: 2015P002397 
Sponsor Protocol No: N/A 
Consent Form Valid Date: 12/13/2016 
Sponsor AME No: N/A 
IRB Expiration Date: 12/1/2017 
IRB AME No: N/A 
Partners HealthCare System 
Research Consent Form 
Subject Identification 
General Template 
Version Date:  December 2008 
 
 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
Subject  
Date 
Time (optional) 
 
 
 
 
 
 
Signature  
Date 
Time (optional) 
 
 
 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 

 I have explained the research to the study subject. 

 I have answered all questions about this research study to the best of my ability. 
 
 
 
 
Study Doctor or Person Obtaining Consent  
Date 
Time (optional) 
 
 
 
 
 
Consent Form Version:  07/05/2016