Clinical trial NCT03861988
Conditions: Major Depressive Disorder Surgery Orthopedic Disorder
Keywords: depression ketamine anesthesia total joint arthroplasty
Sponsor: Stanford University
Start date: 2019-08-22; Completion date: 2022-09-27
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates whether ketamine, given as part of an anesthetic, improves depression symptoms in depressed patients undergoing non-cardiac surgery. Half of participants will receive a ketamine infusion during surgery, while the other half will receive a placebo (normal saline) during surgery.

Detailed description:
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. 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. The investigators 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.

Arms: arm 1: Patients will receive an intravenous ketamine infusion during surgery. arm 2: Patients will receive an intravenous ketamine infusion during surgery. arm 3: Participants will receive placebo (normal saline infusion) during surgery.
Interventions: intervention 1: Ketamine intervention 2: Normal saline (placebo)
Intervention descriptions: intervention 1: 0.5 mg/kg over 40 minutes, intravenous. intervention 2: Normal saline infusion over 40 minutes, equivalent volume to ketamine infusion.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
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 


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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 
Last edited: 10/22/21 by Theresa Lii 
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. 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Official Title: 
Intraoperative Ketamine Versus Saline in Depressed Patients 
Undergoing Anesthesia for Non-cardiac Surgery 
 
NCT Number: 03861988 
 
Protocol last edited: 10/28/2021 
 
 


Statistical Analysis Plan (SAP) 
 
Section 1: Administrative Information 
 
1. Title and trial registration 
 
1a. Title 
Intraoperative Ketamine Versus Saline in Depressed Patients Undergoing 
Anesthesia for Non-Cardiac Surgery 
 
1b. Trial registration number 
ClinicalTrials.gov Identifier NCT# 03861988 
 
2. SAP version: 2.0 
 
3. Protocol version: Stanford eProtocol ID 49114, last revision submitted 8/9/21 
 
4. SAP revisions 
 
4a. SAP revision history 
10/21/2019 – version 1.0 (originally included in the study protocol) 
10/28/2021 – version 2.0 (created a new, separate SAP document) 
 
4b. Justification for each SAP revision 
Version 1.0 to 2.0:  
1) In our original protocol, recruitment was limited to patients with symptomatic 
depression presenting for hip and knee arthroplasty at Stanford. Patients 
undergoing this type of surgery have a predictable postoperative course, 
which guided our primary endpoint selection. We encountered significant 
difficulties recruiting patients during the COVID-19 pandemic. Therefore, we 
expanded eligibility criteria by including patients presenting for a wider variety 
of surgical procedures, which are described in our updated protocol. To 
account for the likely increased variability of postoperative recovery in this 
broader population, we updated our primary endpoint to include data from the 
first 3 days after surgery, instead of only a single day after surgery.  
2) In our original protocol, the primary outcome measure was defined as the 
sum of scores from a clinician-administered scale and a self-report scale. 
During the recruitment phase of our trial, and prior to unblinding, we 
presented our analysis plan to a panel of statisticians in the Department of 
Biomedical Data Sciences at Stanford University. The panel recommended 
that we could improve the interpretability and reduce the variance in our 
primary outcome by only using one validated measure (rather than a 
composite score) as our primary outcome measure. Based on this 
recommendation, we updated our primary outcome measure to only include 
the clinician-administered scale (the Montgomery-Asberg Depression Rating 
Scale). 


 
4c. Timing of SAP revisions 
This revision (1.0 to 2.0) was made prior to data unblinding and prior to 
completion of data collection (75% of target enrollment). 
 
5. Roles of SAP contributors 
Theresa R. Lii, MD, Stanford University, Primary SAP author 
Boris D. Heifets, MD, PhD, Stanford University, Chief investigator/clinical lead 
 
6. Signatures 
 
6a. Primary SAP author: 
 
 
6b. Chief investigator/clinical lead:  
 
 
 


Section 2: Introduction 
 
7. Background and rationale 
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. 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. 
 
8. Objectives 
We hope to discover whether ketamine has antidepressant efficacy in major depressive 
disorder (MDD) patients 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). 
 
Section 3: Study Methods 
 
9. Trial design 
 
This is a single-site phase IV randomized clinical trial utilizing a quadruple-masked, 
placebo-controlled, parallel arm design. Participants will be randomly allocated in a 1:1 
ratio to one of two groups: Group A (n=20) will receive a ketamine infusion of 0.5 mg/kg 
over 40 min during surgery. Group B (n=20) will receive a saline infusion over 40 min 
during surgery. In both groups, the study drug will be given after anesthetic induction. 
The participants, care providers, investigators, and outcomes assessors will be masked. 
 
10. Randomization 
Participants will be sequentially randomized as they enter the study. We will employ 
block randomization with 5 blocks of 8 patients each. 
 
11. Sample size 
We will enroll a total of 40 participants. Our sample size calculation was derived from an 
a priori power analysis for the primary outcome measure with a 1:1 allocation ratio. In a 
randomized controlled trial of ketamine vs active placebo (midazolam) performed by 


Phillips et al. (2019), participants had a mean decrease of 10.9 points (SD=8.9) in 
MADRS total score relative to pre-infusion scores compared with a mean decrease of 
2.8 points (SD=3.6) with midazolam. Using these results, we computed an estimated 
total sample size of 38 participants at a two-sided alpha level of 0.05 and 80% power. 
An additional 2 participants were added to account for potential attrition, for a total of 40 
participants. Given the increased statistical efficiency of mixed models for repeated 
measures (MMRM) compared to parametric pre-post tests, we assumed that 40 
participants should be sufficient to power our study for MMRM analysis. 
 
12. Framework 
We plan to evaluate the antidepressant superiority of ketamine to placebo by assessing 
the postoperative MADRS scores from postoperative Day 1 through Day 3. Additional 
outcomes collected at postoperative Day 5, 7, and 14 will be used for statistical model 
building and exploratory analyses. 
 
13. Interim data monitoring 
 
13a. Statistical interim analyses planned and time points 
No statistical interim analyses planned. 
 
13b. Any planned adjustment of significance level due to interim analysis 
N/A. 
 
13c. Details of guidance for stopping the trial early 
N/A. 
 
14. Timing of final analysis 
Once all data have been collected at all planned time points from the final (40th) 
participant, all investigators will be unmasked and all outcomes will be analyzed 
together in the final analysis. 
 
15. Timing of outcome assessments 
All patients will have at least one baseline psychiatric assessment prior to Day 0. 
Repeat baseline assessment by questionnaire will occur on the morning of surgery prior 
to any preoperative medication being given. The study assessments will be performed 
at postoperative Day 1, Day 2, Day 3, Day 5, Day 7 and Day 14. Assessments will be 
performed either in hospital or by phone or video. 
 
Section 4: Statistical Principles 
 
16. Level of statistical significance 
We will use an uncorrected two-sided alpha of 0.05 as a cutoff for statistical 
significance. 
 
17. Adjustment for multiplicity and controlling type I error 


The primary outcome (MADRS score) that is measured on postoperative Day 1, 2, and 
3 will be combined and treated as a single timepoint in the mixed model, rather than 
separately testing each day for significance which can inflate type I error rate. 
Postoperative Days 1, 2, and 3 were chosen due to previously published data showing 
that the antidepressant effect of ketamine persists up to 3 days after administration. 
 
18. Confidence intervals to be reported 
We will report 95% confidence intervals for the primary outcome. 
 
19. Adherence and protocol deviations 
 
19a. Adherence to protocol and how this is assessed 
Adherence to protocol is defined as: 1) participant meets eligibility criteria prior to 
randomization; 2) all planned assessments are completed; and 3) the patient 
receives the complete dose of the blinded study drug intravenously over a course 
of 40 minutes, initiated after induction of anesthesia and completed before 
extubation or transfer to the post-anesthetic recovery area. 
 
19b. How adherence to protocol will be presented 
Adherence to protocol will be presented as a proportion. 
 
19c. Protocol deviations 
Emergency protocol deviations are defined as those occurring in an emergency 
situation where departure from the protocol (such as unblinding the study drug) is 
required immediately to protect the life or physical well-being of the participant. 
 
Non-emergent deviations are defined as those that do not occur in an emergency 
situation. Examples potentially encountered in our study include, but are not 
limited to: 1) participant is randomized to a treatment intervention but does not 
meet eligibility criteria, 2) the anesthesiologist administered the study drug 
incorrectly or incompletely, 3) the participant inadvertently received the 
intervention meant for the other trial arm, 4) the participant was not available for 
assessment of the planned outcome either because of loss to follow-up or for 
another reason, 5) study staff were not available for assessment of the planned 
outcome either because of a personal emergency or another reason. 
 
19d. Which protocol deviations will be summarized 
All emergency and non-emergent protocol deviations will be summarized. 
 
20. Analysis populations 
As recommended by CONSORT guidelines for parallel group randomized controlled 
trials, intention-to-treat and per-protocol analyses (if needed) will be performed and 
reported for all planned outcomes to allow readers to interpret the effects of the 
intervention. 
 
Section 5: Trial Population 


 
21. Screening data 
Screening data to be collected and reported in CONSORT flow diagram include: 
 
Patient Health Questionnaire score 
HADS-MADRS composite score 
English-speaking status 
Age 
Body mass index 
History of significant CNS disease or brain surgery 
History of moderate to severe substance use disorder (except nicotine) 
History of schizophrenia, schizoaffective disorder, or psychosis 
Chronic high dose opioid use (>90 morphine milligram equivalents per day) 
High suicide risk 
Other reasons 
 
22. Eligibility 
 
22a. Inclusion criteria 
A subject will be eligible for inclusion only if 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. PHQ-8 score >= 12. 
 
4. Diagnosed with Major Depressive Disorder (MDD), single or recurrent, and 
currently experiencing a Major Depressive Episode (MDE) of at least 4 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. 
 
5. Meet the threshold on the total combined HADS-MADRS score of >/=31 at 
both screening and day of surgery visits. 
 
6. In sufficiently good health to proceed with planned 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. 
 
7. Body mass index between 17-40kg/m2. 


 
8. 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 4 weeks 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. 
 
9. 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. 
 
22b. 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 surgery 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. We will not be 
including pregnant women from other surgical populations as well. 
 
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. 
 
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 that 
conflicts with this trial, 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 
 
23. Recruitment 
Information to be collected and reported in CONSORT flow diagram include: 
 
Patients with a history of depression screened 
Excluded due to PHQ score < 12 
Excluded due to other exclusion criteria 
Declined to participate 
Lost to follow-up during screening 
Excluded after consent 
Withdrew after consent prior to intervention 
Participants consented 
 


24. Withdrawal and follow-up 
 
24a. The following withdrawal/lost to follow-up data will be recorded: 
• Number of participants who withdraw or are lost to follow-up 
• Timing of withdrawal or lost to follow-up 
• Reasons of withdrawal or lost to follow-up 
 
24b. The above withdrawal/lost to follow-up data will be presented as: 
• Percentages (%) of participants who withdraw or are lost to follow-up 
• Kaplan-Meier curves of withdrawal or lost to follow-up (if any) 
• Reasons of withdrawal or lost to follow-up summarized in the Results 
section 
 
25. Baseline patient characteristics 
 
25a. List of baseline characteristics to be reported 
1) Sex (n, %) 
2) Age (years, mean and SD) 
3) Body mass index (mean, SD) 
4) Hispanic/Latino ethnicity (n, %) 
5) Race 
a. White (n, %) 
b. Black/African American (n, %) 
c. Asian (n, %) 
d. Native Hawaiin/Pacific Islander (n, %) 
e. Other (n, %) 
f. Unknown (n, %) 
6) Married (n, %) 
7) Disabled (n, %) 
8) Current smoker (n, %) 
9) PHQ score at screening (points, mean and SD) 
10) HADS at screening (points, mean and SD) 
11) MADRS at screening (points, mean and SD) 
12) HADS-MADRS composite score at screening (points, mean and SD) 
13) Age at first MDD onset (years, mean and SD) 
14) Duration of current episode (months, mean and SD) 
15) Recurrent major depression (n, %) 
16) Previous clinical ketamine exposure (n, %) 
17) Previous recreational ketamine exposure (n, %) 
18) Charlson Comorbidity Index (points, mean and SD) 
19) Maudsley resistance stage (points, mean and SD) 
20) Numerical pain score (points, mean and SD) 
21) Pain interference from BPI (points, mean and SD) 
 
25b. Preoperative psychoactive medications 
1) Opioids (n, %) 


2) MME/day, if on opioids (mean, SD) 
3) Anticonvulsants (n, %) 
4) Benzodiazepines (n, %) 
5) Muscle relaxants (n, %) 
6) Antidepressants (n, %) 
7) Antipsychotics (n, %) 
8) Lithium (n, %) 
9) Prescription sleep medications (n, %) 
10) Opioid antagonists (n, %) 
11) Stimulants (n, %) 
 
25c. Surgical characteristics 
1) Type of surgery 
a. ENT/OMF(n, %) 
b. Thoracic (n, %)  
c. Breast (n, %) 
d. Plastic non-breast (n, %) 
e. Spine (n, %) 
f. Major joint (n, %) 
g. Other orthopedic/limb (n, %) 
h. Intraabdominal general surgery (n, %) 
i. Urologic and gynecologic (n, %) 
j. Vascular (n, %) 
k. Transplant (n, %) 
2) Type of anesthesia 
a. General anesthesia (n, %) 
b. Monitored anesthesia care (n, %) 
3) Intraoperative nitrous oxide (n, %) 
4) Intraoperative propofol infusion (n, %) 
5) Intraoperative opioid infusion (n, %) 
6) Length of surgery (hours, mean and SD) 
7) Peripheral or neuraxial catheter placed (n, %) 
 
Section 6: Analysis 
 
26. Outcome definitions 
 
26a. Primary outcome 
Postoperative MADRS scores from postoperative Days 1 through 3. 
 
26b. Main secondary outcomes 
1) Proportion of participants with clinical response (defined as a 50% reduction 
in MADRS score from baseline). 
2) Proportion of participants with remission (defined as a MADRS score of 12 
on day 14). 
 


26c. Other exploratory secondary outcomes 
1) MADRS scores at postoperative Days 5, 7, and 14 
2) Hospital Anxiety and Depression Scale 
3) Cumulative inpatient opioid use 
4) Hospital length of stay 
5) Average inpatient opioid use per day 
6) Opioid use at postop day 7 
7) Opioid use at postop day 14 
8) Postoperative numeric pain scores 
9) Postoperative pain interference scores 
 
27. Analysis methods 
 
27a. Analysis of the primary outcome 
A mixed model for repeated measures (MMRM) will be used to analyze the 
difference in postoperative MADRS score which is our primary outcome. The 
model will include treatment and time as fixed effects, with a treatment*time 
interaction term. The data will be modeled with random intercepts and random 
slopes to account for variation in baseline scores and postoperative trajectories. 
MADRS scores measured on postoperative Day 1, 2, and 3 will be combined and 
treated as a single timepoint in the mixed model, rather than separately testing 
each day for significance which can inflate type I error rate. Postoperative Days 
1, 2, and 3 were chosen due to previously published data showing that the 
antidepressant effect of ketamine persists up to 3 days after administration. 
 
27b. Sensitivity analyses 
Sensitivity analyses will be conducted for the following scenarios: 
 
1) Missing data: See section 28 
2) Intention-to-treat vs per-protocol analysis (if needed) 
3) MMRM analysis using HADS (self-report) as a confirmatory measure 
4) MMRM analysis using the previously proposed primary outcome measure (a 
composite score defined as the sum of scores from MADRS and HADS) 
 
27c. Subgroup analyses 
We will conduct several pre-specified subgroup analyses. While the trial will not 
specifically be powered for these subgroups, we hope to gain further insight into 
sub-populations that may particularly benefit from the intervention. Example 
subgroup analyses to be considered: 
 
1) Preoperative use of antidepressants 
2) Preoperative use of opioids 
3) Intraoperative exposure to nitrous oxide 
4) Intraoperative exposure to opioid infusions 
5) Postoperative use of neuraxial or peripheral nerve catheters 
 


28. Missing data 
For the primary outcome, it will be assumed that the missing data are missing at 
random. Sensitivity analysis will be performed to evaluate the robustness of the MMRM 
to the missing-at-random assumption. 
 
29. Adverse events 
Adverse events will be recorded in the Stanford REDCap database using the Adverse 
Event (AE) Form and Serious Adverse Event (SAE) Form. Refer to document GUI-P13 
(https://researchcompliance.stanford.edu/panels/hs/policies/guidances) for definitions of 
AEs and SAEs. All AEs and SAEs will be summarized. 
 
30. Statistical software 
Statistical analyses will be conducted using R statistical software. Data figures for 
visualization will be generated using either R or Graphpad Prism.