Double-blind Trial of Intraoperative Ketamine Versus Saline in Depressed Patients Undergoing Anesthesia for Non-cardiac Surgery
Phase: PHASE4
Conditions: Major Depressive Disorder, Surgery, Orthopedic Disorder
Sponsor: Stanford University

 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
Official Title: 
Intraoperative Ketamine Versus Saline in Depressed Patients 
Undergoing Anesthesia for Non-cardiac Surgery 
 
NCT Number: 03861988 
 
Protocol last edited: 10/22/2021 
 
 

IRB protocol ID: 49114 
Last edited: 10/22/21 by Theresa Lii 
STUDY PROTOCOL: 
Double-blind trial of intraoperative ketamine versus saline in patients with 
major depressive disorder undergoing non-cardiac surgery 
NCT 03861988 
 
 
1. NAME OF STUDY 
Double-blind trial of intraoperative ketamine versus saline in patients with major depressive 
disorder undergoing anesthesia for non-cardiac surgery 
 
2. INVESTIGATORS:   
Principle Investigator: Boris Heifets, MD, PhD 
Sub-Investigators: Theresa Lii, MD, Alan Schatzberg, MD, 
 
3. SOURCE OF INSTITUTIONAL FUNDING:  
Departmental funds from the Stanford Department of Anesthesiology, Perioperative and Pain 
Medicine. This study is not industry sponsored.  
 
4. SOURCES FROM WHOM WE ARE SEEKING FUNDS: 
Pending the results of this trial we will seek NIH or foundation grants. 
 
5. AIMS AND HYPOTHESIS 
 
A. Aims:  
To determine whether intravenous ketamine, when used for its FDA-approved indication to 
supplement anesthesia, is associated with a measurable antidepressant effect in severely 
depressed patients undergoing non-cardiac surgeries when compared to placebo (normal saline 
infusion). 
 
B. Primary Outcome: 
We plan to evaluate the antidepressant superiority of ketamine to placebo by assessing 
postoperative MADRS scores at multiple timepoints. MADRS (Montgomery-Asberg Depression 
Rating Scale) is a validated measure of depression severity used routinely in antidepressant 
trials. 
 
C. Secondary Outcomes: 
● Proportion of participants with clinical response (defined as a 50% reduction in MADRS 
score from baseline) 
● Proportion of participants with remission (defined as a MADRS score of 12 on day 14) 
● Hospital Anxiety and Depression Scale 
● Cumulative inpatient opioid use 
● Hospital length of stay 
● Average inpatient opioid use per day 
● Opioid use at postop day 7 
● Opioid use at postop day 14 
● Postoperative numeric pain scores 
● Postoperative pain interference scores 
● Immunological blood markers 
 
6. GENERAL BACKGROUND 

IRB protocol ID: 49114 
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Major Depressive Disorder (MDD) is widely prevalent among patients preparing to have 
surgery, and it is a known risk factor for complications after surgery, including wound infection, 
myocardial infarction and opioid use disorder. Ketamine has emerged as an effective, rapid-
acting antidepressant therapy for patients with MDD, and may be a useful tool to prevent MDD-
related morbidity in the perioperative period. Ketamine has been well studied for MDD in 
outpatient clinics where it is given as an infusion (0.5 mg/kg over 40 minutes) in awake patients. 
Ketamine is often used as part of an anesthetic cocktail in sedated or anesthetized patients, but 
it is unknown whether ketamine has an antidepressant effect in this context. 
  
We hope to discover whether ketamine has antidepressant efficacy in patients with severe MDD 
when given as an anesthetic adjunct. If ketamine is an effective antidepressant in this 
population under anesthesia, its use could be incorporated into a set of interventions to 
minimize the perioperative complications associated with MDD. While it is more efficient to 
deliver ketamine therapy intraoperatively, if this study finds that ketamine is ineffective in this 
setting, that result establishes a rationale to test treatment prior to the surgical encounter. We 
will also have gained important information on ketamine's antidepressant mechanism (e.g. it is 
blocked by other anesthetics, or it requires that the patient be conscious). 
  
Only one published study addresses whether ketamine given with surgical anesthesia has any 
antidepressant effect in depressed patients (Kudoh et al., 2002). This study found a small 
antidepressant effect of questionable clinical significance, possibly due to studying patients with 
mild symptoms. This work, while promising, does not address whether ketamine has the 
profound antidepressant effect that has been repeatedly documented in nonsurgical psychiatric 
patients with severe MDD. Our proposed study specifically tests ketamine's antidepressant 
efficacy in this high risk group of patients with severe MDD that may particularly stand to benefit 
from remission of their depressive symptoms in the perioperative period. Other previous trials 
involving ketamine as an adjunct to anesthesia have uniformly been conducted in non-
depressed patients and have limited relevance to our research question. 
  
7. PRELIMINARY UNPUBLISHED DATA 
None at present. We have included an open-label, feasibility study as part of this protocol. 
However, there are already many published studies evaluating the antidepressant effect of 
ketamine at the dose used in our study, including one by the principal investigator and co-
investigators (Williams et al., 2018). 
 
8. EXPERIMENTAL DESIGN, SCREENING, STUDY PROCEDURES AND DATA ANALYSIS 
 
A. Design 
We will first conduct an open-label, feasibility study involving 5 participants to identify which 
postoperative day to measure our primary endpoint in order to ensure that patients can 
cooperate with assessment interviews. Once we have determined when to measure our 
primary endpoint, we will modify our registered trial (NCT03861988) on ClinicalTrials.gov 
and submit to the IRB our updated study protocol for a placebo-controlled, double-blind, 
randomized controlled trial. 
 
After registering the trial and updating our protocol, we will conduct a single-center, double-
blind, randomized, placebo-controlled trial involving a total of 40 participants (20 per group). 
 
B. Study Population: Inclusion and Exclusion Criteria 
 
Inclusion Criteria: 

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A subject will be eligible for inclusion when all of the following criteria are met:  
  
1. 
Male or female, 18 to 80 years of age, inclusive, at screen. 
2. 
Able to read, understand, and provide written, dated informed consent prior to screening. 
Participants will be deemed likely to comply with study protocol and communicate with 
study personnel about adverse events and other clinically important information. 
3. 
Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and currently 
experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior 
to screening, according to the criteria defined in the Diagnosis and Statistical Manual of 
Mental Disorders, Fifth Edition. The diagnosis of MDD will be made by a trained study 
staff member and supported by the Mini International Neuropsychiatric Interview - 
Module A. 
4. 
Meet the threshold on the total combined HADS-MADRS score of >/=31 at both 
screening and day of surgery visits. 
5. 
In sufficiently good health to proceed with planned orthopedic surgery, as ascertained 
by a standard preoperative clinic evaluation which includes medical history, physical 
examination (PE), clinical laboratory evaluations, any indicated cardiac testing, and final 
clearance by the attending anesthesiologists on the day of surgery. 
6. 
Body mass index between 17-40kg/m2. 
7. 
Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive 
behavioral, insight-oriented, et al) and frequency (e.g., weekly or monthly) of the 
therapy has been stable for at least three months prior to screening and if the type and 
frequency of the therapy is expected to remain stable during the course of the subject’s 
participation in the study. 
8. 
Concurrent antidepressant therapy (e.g. SSRI or SNRI) and/or hypnotic therapy (e.g. 
zolpidem, zaleplon, melatonin, or trazodone) will be allowed if the therapy has been 
stable for at least 4 weeks prior to screening and if it is expected to remain stable 
during the course of the subject's participation in the study. 
  
Exclusion Criteria: 
A potential participant will NOT be eligible for participation in this study if any of the following 
criteria are met:  
 
1. 
Female that is pregnant or breastfeeding. These women would not be candidates for 
elective total joint replacement under any circumstances, and therefore would be 
screened out from our study population at their routine preoperative evaluation. 
Women of childbearing potential are routinely screened for pregnancy at their 
preoperative visit by urine hCG testing if clinically indicated.  
2. 
Total HADS-MADRS score of <31 at either the screening or day of surgery visits. 
3. 
Current diagnosis of a Substance Use Disorder (SUD; Abuse or Dependence, as 
defined by DSM-V) rated "moderate" or "severe" per criteria of the Mini International 
Neuropsychiatric Interview – Module J (MINI-J), or Alcohol Use Disorder rated 
"moderate" or "severe" per MINI-I criteria. These patients are rarely candidates for 
elective surgery. The following categories of SUD will NOT be excluded: nicotine 
dependence; alcohol or substance use disorder rated "mild"; alcohol or substance use 
disorder of any severity in remission, either early (3-12 months) or sustained (>12 
months) time frames. 
4. 
History of schizophrenia or schizoaffective disorders, or any history of psychotic 
symptoms in the current or previous depressive episodes. 
5. 
In the judgment of the investigator, the subject is at significant risk for suicidal behavior 
during the course of his/her participation in the study. 

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6. 
Has dementia, delirium, amnestic, or any other cognitive disorder. 
7. 
Has a clinically significant abnormality on the screening physical examination that 
would otherwise preclude the patient from having surgery. 
8. 
Participation in any clinical trial with an investigational drug or device within the past 
month or concurrent to study participation. 
9. 
Lifetime history of surgical procedures involving the brain or meninges, encephalitis, 
meningitis, degenerative central nervous system disorder (e.g., Alzheimer’s or 
Parkinson’s Disease), epilepsy, mental retardation, or any other 
disease/procedure/accident/intervention associated with significant injury to or 
malfunction of the central nervous system (CNS), or a history of significant head 
trauma within the past two years. 
10. Presents with any of the following lab abnormalities w/in the past 6 months: 
a. 
Thyroid stimulating hormone (TSH) outside of the normal limits and clinically significant 
as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH 
level is high. Subject will be excluded if T4 level is clinically significant. 
b. 
Any other clinically significant abnormal laboratory result at the time of the screening 
exam. 
11. History of hypothyroidism and has been on a stable dosage of thyroid replacement 
medication for less than six months prior to screening.(Subjects on a stable dosage of 
thyroid replacement medication for at least six months or more prior to screening are 
eligible for enrollment.) 
12. History of hyperthyroidism which was treated (medically or surgically) less than six 
months prior to screening. 
13. Any current or past history of any physical condition which in the investigator’s opinion 
might put the subject at risk or interfere with study results interpretation. 
14. Patients currently maintained on high dose opioids (>90 morphine equivalents per day) 
prior to surgery. 
 
C. Statisical Analysis 
 
Sample Size 
Based on published data from other investigators (Zarate et al., 2006) and our own published 
work (Williams et al., 2018), we estimate a sample size of 15 patients per group, alpha=0.05, 
power = 80% to detect a 30% change in depression rating from baseline. We will include an 
additional 5 patients per group to account for participant dropout, for a total of 20 patients per 
group. 
 
Analysis Plan 
1. Statistical analyses will be performed by the investigators using R and GraphPad Prism 
9. 
2. Baseline characteristics and demographics between groups will be compared using t-
tests for continuous and ordinal variables and chi-square tests for categorical variables. 
3. Primary outcome: Significance will be determined with a mixed model for repeated 
measures. MADRS scores obtained on postoperative Day 1, 2, and 3 will be combined 
and treated as a single timepoint in a mixed model, rather than separately testing each 
day for significance which can inflate type I error rate. We will use an uncorrected two-
sided alpha of 0.05 as a cutoff for statistical significance. 
4. Secondary outcomes will be compared using t-tests for continuous and ordinal variables 
and chi-squared tests for categorical variables. No correction for multiple comparisons 
needed due to the exploratory nature of these outcomes. 
 

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D. Study Procedures from Screening to Closeout 
 
Screening 
Patients may be informed about the study if they are contacted as part of a perioperative mental 
health screening service (IRB-54043, approved as not clinical research and not requiring IRB 
oversight), at which time they may be offered psychiatric care referrals, counseling and 
information about multiple ongoing clinical trials. Potential subjects may also be introduced to 
the study through handouts and brochures placed in surgical and pre-anesthesia clinics. Patient 
identified through Epic as likely to be depressed may also be approached at pre-op 
appointments and study staff will describe the study and consent if appropriate. Surgery 
schedulers will ask surgery patients if they are interested in the study and give them a letter or 
by reading/sending a phone script. Specific procedures for introducing patients to the study and 
which patient data will be assessed to identify depression are described in detail in section 8g.  
 
Informed consent will be obtained prior to full evaluation of inclusion and exclusion criteria. 
 
Informed consent may be obtained in one of two ways: in-person or over the phone.  
 
In-person consent: 
If the patient has an already scheduled preoperative appointment at Stanford, research 
staff may meet the patient before or after this appointment to obtain informed consent. 
Alternatively, the patient may choose to make a separate visit to Stanford Medical 
Center for the consenting process.  
 
Phone consent: 
If the patient gave permission for research research staff to contact them about the study 
(see Section 8g), research staff will call the patient to introduce the study. If the patient 
agrees to consent, research staff will mail, fax, or email a PDF of the consent form to the 
patient. Research staff will confirm receipt of the consent form, and then obtain informed 
consent over the phone. The participant will bring the signed consent form with them 
during an in-person screening visit, or on the day of surgery or will sign the consent 
through Redcap.  Research staff will verify signatures and sign the researcher signature 
line at that time. 
 
After providing informed consent, the participant will be offered the option to complete 
SCREENING in the following ways: 
 
1. During a preoperative visit to Stanford Medicine Outpatient Center. 
2. By phone or video interview (using Facetime or Zoom, which is PHI compliant)prior to 
surgery. 
3. In-person visit to Stanford Medical Center. 
4. On the day of surgery, prior to surgery at Stanford Hospital; patients will be asked to 
check in 30-45 minutes early to allow time for screening. 
 
Participants will have the standard preoperative workup and management for surgery, including 
diagnostic labs/studies and perioperative medication adjustment as needed. 
 
During screening, investigators must document a patient history of Major Depressive Disorder 
(MDD), single or recurrent. The patient must be currently experiencing a Major Depressive 
Episode (MDE) of at least eight weeks in duration prior to screening, according to the criteria 
defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition. The diagnosis 

IRB protocol ID: 49114 
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of MDD will be made by a trained study staff member and supported by the Mini International 
Neuropsychiatric Interview (MINI) - Module A. Patients with a current diagnosis of Alcohol or 
Substance Use Disorder (Abuse or Dependence, as defined by DSM-V), with the exception of 
nicotine dependence, at screening or within six months prior to screening will be excluded. The 
diagnosis of Alcohol or Substance Abuse Disorder will be made by a trained study staff member 
and supported by the Mini International Neuropsychiatric Interview – Modules I and J. 
  
Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, 
insight-oriented, etc.) and frequency (e.g., weekly or monthly) of the therapy has been stable for 
at least 3 months prior to screening and if the type and frequency of the therapy is expected to 
remain stable during the course of the subject's participation in the study. 
  
Concurrent antidepressant therapy (e.g. SSRI or SNRI) and/or hypnotic therapy (e.g. zolpidem, 
zaleplon, melatonin, or trazodone) will be allowed if the therapy has been stable for at least 4 
weeks prior to screening and if it is expected to remain stable during the course of the subject's 
participation in the study. 
  
Once patients agree to participate in the study and have signed the informed consent 
document, the following screening procedures will be performed: 
 
By Physician or Study Staff: 
● Concomitant Medication Review 
● Medical and Psychiatric History 
● Review of preoperative evaluation data including physical exam, vital signs, any lab work 
(including a pregnancy test, if applicable) or cardiac testing performed in the course of 
standard preoperative medical clearance 
● Urine toxicology screen test for drugs of abuse 
● Mini International Neuropsychiatric Interview (MINI) - Modules A, I & J 
● Columbia Suicidality Severity Rating Scale - short screen 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
● Maudsley Staging Method (MSM) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
Participant Compensation: 
● $50 after completion of Screening and $50 upon completion of study at day 14. If 
patients come to Stanford Hospital for the purpose of screening, they will be reimbursed 
an additional $50 for their time and transportation costs. 
 
Safety Plan for Patients Who Endorse Active Suicidality 
A patient may be identified to be at risk for suicidal behavior after consent and during our extended 
screening process. The Columbia Suicide Severity Rating Scale (CSSRS) – Short Screen is 
administered face to face, by phone, or by video call (Stanford Zoom) by a study staff member. A 
patient may be identified as “low”, “moderate” or “high” risk. For any patient scoring “moderate” 
or “high” risk, the study staff will immediately contact Dr. Boris Heifets or Ms. Robin Okada (RN 
and study coordinator). 
 
If Dr. Heifets or Ms. Okada are notified of a patient at risk for suicidal behavior, Dr. Heifets will 
contact that patient, verify their response and decide if a wellness check from police is needed 
or other interventions. That patient will be offered immediate assistance, including calling an 

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ambulance for transport to the Emergency Department, and their primary physician will be 
informed. 
 
Randomization 
Only Investigational Drug Services (IDS) Pharmacy will be aware of drug allocation prior to 
completion of data collection for the randomized, placebo-controlled study. A computer-
generated randomization scheme will be used to randomize participants to receive either 
ketamine or saline (allocation ratio 1:1, blocks of 4). The study participants, intraoperative 
anesthesiologists, and study staff conducting postoperative assessments will be blinded to drug 
allocation until data collection is completed. 
 
Infusions 
The study intervention will occur during surgery (Study Day 0). Participants will be randomized 
to one of two groups: Group A (n=20) will receive a ketamine infusion of 0.5 mg/kg over 40 min 
during surgery, beginning after anesthetic induction with propofol. Group B (n=20) will receive a 
saline infusion over 40 min during surgery, beginning after anesthetic induction with propofol. 
Infusion (instead of bolus) dosing of ketamine was chosen since infusions have demonstrated 
antidepressant efficacy in outpatient psychiatric populations, as well as theoretically lower risk of 
adverse events due to lower peak serum concentrations compared to bolus dosing. A patient 
who is not enrolled in the study has a reasonable chance of receiving the same treatments 
(ketamine or saline) at comparable doses as those tested in the study. 
 
Monitoring 
Routine vital signs will be collected before and after surgery by the participant’s nurse and 
reviewed by investigators. Each participant will have continuous physiological monitoring during 
their anesthetic. A SedLine® Brain Function Monitor will be used to evaluate depth of 
anesthesia/sedation. If the participant experiences an adverse event temporally related to the 
infusion where corrective action by the intraoperative anesthesiologist requires unblinding, then 
the study infusion drug will be revealed to the anesthesiologist.  
  
Data Collection Procedures 
The first 5 patients that meet inclusion/exclusion criteria will be entered into the open-label 
feasibility study; all will receive a ketamine infusion. All other patients enrolled thereafter will be 
entered into the double-blind, randomized, placebo-controlled study. The day of surgery will be 
considered Day 0 of the study. Baseline assessments must be performed before the patient 
receives any psychoactive premedication (e.g. midazolam, fentanyl, gabapentin, oxycodone). 
Assessments will be performed either in the hospital or, if the patient has been discharged 
(typically on postoperative Day 2), by phone. 
 
Participants who remain in the hospital for at least 24 hours post-surgery will be asked to give 
blood samples for immunological analyses. Two blood samples (10mL for each draw) will be 
collected from each participant. 
  
Day 0 (Baseline Assessments): 
By Physician or Study Staff: 
● Vital Signs 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
● Collect breath sample #1 
By the Participant, reviewed by Investigators: 

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● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
  
Day 0 (During Surgery): 
By the Intraoperative Anesthesiologist: 
● Ketamine infusion or placebo (saline) infusion 
● Continuous physiological monitoring 
● SedLine® Brain Function Monitor to evaluate depth of anesthesia/sedation 
● Collect breath sample #2, after infusion is complete 
  
Day 1: 
By Physician or Study Staff: 
● Vital Signs 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
 
Day 2: 
By Physician or Study Staff: 
● Vital Signs (inpatient only) 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
 
Day 3 (inpatient or via phone): 
By Physician or Study Staff: 
● Vital Signs (inpatient only) 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
  
Day 5 (inpatient or via phone): 
By Physician or Study Staff: 
● Vital Signs (inpatient only) 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
  
Day 7 (inpatient or via phone): 

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By Physician or Study Staff: 
● Vital Signs (inpatient only) 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
  
Day 14 (inpatient or via phone): 
By Physician or Study Staff: 
● Ask participants what treatment they believe they received 
● Reveal treatment to participant 
● Vital Signs (inpatient only) 
● Concomitant Medication Review 
● Adverse Events Review 
● Montgomery-Asberg Depression Rating Scale (MADRS) 
By the Participant, reviewed by Investigators: 
● Hospital Anxiety and Depression Scale (HADS) 
● Brief Pain Inventory (BPI) 
Participant Compensation: 
● $50 after completion of all study assessments 
 
  
 
 

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Study Procedures Matrix 
  
Screen-
ing 
Day 0 
(Baseline) 
Day 0 
(Intraop) 
Day 1 
Day 2 
Day 3 
Day 5 
Day 7 
Day 
14 
PHQ-8 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
 
X 
X 
X 
X 
X 
X 
Medical and Psychiatric 
History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
X 
O 
O 
O 
O 
Continuous physiological 
monitoring 
 
 
X 
 
 
 
 
 
 
Urine toxicology screen 
test 
X 
 
 
 
 
 
 
 
 
Labs and studies as 
warranted by standard 
preoperative medical 
clearance (includes 
pregnancy test) 
X 
 
 
 
 
 
 
 
 
Mini International 
Neuropsychiatric Interview 
(MINI) - A , I & J 
X 
 
 
 
 
 
 
 
 

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Hospital Anxiety and 
Depression Scale (HADS) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Montgomery Asberg 
Depression Rating Scale 
(MADRS) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Columbia Suicide Severity 
Rating Scale (CSSRS) – 
Short  Screen 
X 
 
 
 
 
 
 
 
 
Maudsley Staging Method 
(MSM) 
X 
 
 
 
 
 
 
 
 
Brief Pain Inventory 
X 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
Ketamine infusion or 
Placebo (saline) infusion 
 
 
X 
 
 
 
 
 
 
SedLine® Brain Function 
Monitor 
 
 
X 
 
 
 
 
 
 
Ask participants what 
treatment they believe they 
received 
 
 
 
 
 
 
 
 
X 
Treatment revealed  to 
participant 
 
 
 
 
 
 
 
 
X 
Participant compensation 
X 
 
 
 
 
 
 
 
X 
X – required 
O - inpatient only 
  
  
  
  
 
  
  
  
  
 
9. SIGNIFICANCE 
Major Depressive Disorder (MDD) is widely prevalent among patients preparing to have 
surgery, and is a known risk factor for complications after surgery, including wound infection, 
myocardial infarction and opioid use disorder. Ketamine has emerged as an effective, rapid-
acting antidepressant therapy for patients with MDD, and may be a useful tool to prevent MDD-
related morbidity in the perioperative period. Ketamine has been well studied for MDD in 
outpatient clinics where it is given as an infusion (0.5 mg/kg over 40 minutes) in awake patients. 

IRB protocol ID: 49114 
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Ketamine is often used as part of an anesthetic cocktail in sedated or anesthetized patients, but 
it is unknown whether ketamine has an antidepressant effect in this context. We will determine 
whether a ketamine infusion, compared to placebo (normal saline infusion), has an 
antidepressant effect when given during surgical anesthesia. If ketamine is an effective 
antidepressant in this population under anesthesia, its use could be incorporated into a set  
of interventions to minimize the perioperative complications associated with MDD.  
 
 
10. REFERENCES 
  
aan het Rot M, Collins KA, Murrough JW, et al. Safety and Efficacy of Repeated-Dose Intravenous 
Ketamine for Treatment-Resistant Depression. Biological Psychiatry. 2010;67(2):139-145. 
 
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. 
Biological Psychiatry. 2000;47(4):351-354. 
 
Etcheson JI, Gwam CU, George NE, Virani S, Mont MA, Delanois RE. Patients With Major 
Depressive Disorder Experience Increased Perception of Pain and Opioid Consumption 
Following Total Joint Arthroplasty. J Arthroplasty. 2018;33(4):997-1002. 
 
Kudoh A, Takahira Y, Katagai H, Takazawa T. Small-Dose Ketamine Improves the Postoperative 
State of Depressed Patients. Anesthesia & Analgesia. 2002;95(1):114. 
 
Luckenbaugh DA, Niciu MJ, Ionescu DF, Nolan NM, Richards EM, Brutsche NE, Guevara S, 
Zarate CA: Do the dissociative side effects of ketamine mediate its antidepressant effects? 
Journal of Affective Disorders 2014,159:56-61. 
 
Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant Efficacy of Ketamine in Treatment-
Resistant Major Depression: A Two-Site Randomized Controlled Trial. American Journal of 
Psychiatry. 2013;170(10):1134-1142. 
 
Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of 
repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 
2013;74(4):250-256. 
 
Price RB, Nock MK, Charney DS, Mathew SJ. Effects of Intravenous Ketamine on Explicit and 
Implicit Measures of Suicidality in Treatment-Resistant Depression. Biol Psychiatry. 
2009;66(5):522-526. 
 
Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by 
Opioid Receptor Antagonism. American Journal of Psychiatry. 2018;175(12):1205-1215. 
 
Zarate CA, Singh JB, Carlson PJ, et al. A Randomized Trial of an N-methyl-D-aspartate Antagonist 
in Treatment-Resistant Major Depression. Arch Gen Psychiatry. 2006;63(8):856-864.