Postpartum Depression After Cesarean Delivery: Ketamine as a Preventative Intervention: A Feasibility Pilot-study
Phase: PHASE3
Conditions: Postpartum Depression
Sponsor: Washington University School of Medicine

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RESEARCH PROTOCOL 
 
Study Title 
Postpartum depression after Cesarean delivery:  
Ketamine as a preventative intervention.  
A feasibility pilot-study. 
 
Short Title 
The PoCKet pilot. 
 
Principal Investigator Dr David Thomas Monks MBChB FRCA MSc,  
Assistant Professor, Department of Anesthesiology,  
Washington University School of Medicine, 
660 S Euclid Avenue St. Louis. 
314-601-1572 
dmonks@wustl.edu 
 
Co-Investigators 
Dr Arvind Palanisamy, MBBS FRCA MD 
Associate Professor of Anesthesiology and Obstetrics and 
Gynecology, Division Chief of Obstetric Anesthesiology, 
Washington University School of Medicine. 
 
 
Dr Shannon Lenze, PhD 
Assistant Professor of Psychiatry, 
Director of Research, Perinatal Behavioral Health Service, 
Washington University School of Medicine. 
 
 
Dr Michael Avidan, MBBCh FCA(SA) 
Dr Seymour and Rose T. Brown Professor of Anesthesiology, 
Chair of the Department of Anesthesiology, Washington 
University School of Medicine. 
 
Dr Preet Mohinder Singh, MBBS 
Assistant Professor, Department of Anesthesiology, Washington 
University School of Medicine. 
 
 
Version 
v3.4 
Jan 23, 2020 
 
 
 
 
  
 
 

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SYNOPSIS 
Study Title 
Postpartum depression after Cesarean delivery:  
Ketamine as a preventative intervention.  
A feasibility pilot-study (PoCKet Pilot). 
Primary Objective 
To assess the feasibility of the study by establishing:  
a) the incidence of PPD in our cohort; 
b) the acceptability to eligible patients; 
c) the ability of the investigative team to collect the data and; 
d) the tolerability of the interventions.  
Hypothesis 
We hypothesize that ketamine reduces the incidence of 
postpartum depression (PPD) when administered at 
cesarean delivery and that the subcutaneous route is well 
tolerated and has a favorable pharmacokinetic profile.  
Study Period 
Planned enrolment duration: 52 weeks 
Planned study duration: 58 weeks 
Number of Participants 
60 patients  
(20 in each of the subcutaneous [SC], intravenous [IVI] and 
control [P] groups) 
Study Intervention 
Patients in each group will receive both subcutaneous (s/c) 
and intravenous (i.v.) administration of their corresponding 
injectate shortly after delivery of their baby. The injectate will 
consist of either 0.9% Sodium Chloride (N/S) or 50 mg/ml 
ketamine (Ket) depending on their group allocation. The s/c 
injectate will be administered undiluted whereas the i.v. 
injectate will be diluted to make up a 40 ml infusion.  
Groups 
SC: 
IVI: 
P: 
s/c injectate 
Ket 
N/S 
N/S 
i.v. injectate 
N/S 
Ket 
N/S 
Study Design 
A randomised, double-blind, placebo-controlled feasibility 
pilot study 
Eligibility Criteria 
Inclusion criteria 
1. Term pregnancy 
2. Age 18-45 years of age 
3. Scheduled cesarean delivery under neuraxial 
anesthesia 
Exclusion criteria 
1. ASA classification IV or V 
2. History of psychotic episodes 
3. History of allergy to ketamine 
4. Inability to communicate in English or any other 
barrier to providing informed consent 
Measurements 
a) 
Psychosocial stress (Antenatal Risk Questionnaire 
[ANRQ]) 
b) 
Weight (kg) and height (m) 
c) 
Time of delivery of baby 
d) 
Total intraoperative dose of analgesic/sedative 
medication 
e) 
Baseline and intraoperative vital signs 
f) 
Maximum intraoperative pain (NRS) 
g) 
48-hour total opiate consumption (morphine 
equivalents) 
h) 
Apgar scores at 1 and 5 minutes postpartum 
i) 
Admission to NICU 

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j) 
Pain originating from surgical site (NRS 0-10): 2, 
6, 24 and 48 hours and 21 and 42 days 
postpartum. 
k) 
Edinburgh Postpartum Depression Scale (EPDS) 
and Generalized Anxiety Disorder 7-item (GAD-7) 
Scale: Day of surgery and postpartum days 1, 2, 
21 and 42 
l) 
Plasma concentrations of ketamine at baseline, 
20, 40 and 100 minutes after administration 
m) 
Breastfeeding success (Y/N): postpartum days 1 
and 2 
n) 
Adverse effects, intraoperatively and at 2 and 6 
hours postpartum (absent, mild, moderate or 
severe) 
Statistical Methodology 
Descriptive statistics will be employed to present the 
demographic data. Continuous variables will be summarized 
using means (SD) or medians (IQR), as appropriate. After 
construction of the concentration-time curves for each 
patient, the peak plasma concentration and area under the 
concentration-time curve will be summarized overall and 
associations with both antidepressant effect and incidence of 
adverse symptoms will be explored. 
NONMEM© 7.4 (ICON Development Solutions) software will 
be utilised to assess pharmacokinetic profile of ketamine by 
each route.   
 

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TABLE OF CONTENTS 
SYNOPSIS 
Page  
2 
1 BACKGROUND AND SIGNIFICANCE 
1.1 
Postpartum depression (PPD) 
1.2 
Ketamine’s anti-depressant effect 
1.3 
Ketamine and PPD 
5 
 
2 OBJECTIVES 
7 
3 PATIENT SELECTION 
3.1 
Inclusion criteria 
3.2 
Exclusion Criteria 
3.3 
Inclusion of women and minorities 
7  
4 REGISTRATION PROCEDURES 
4.1 
Confirmation of patient eligibility 
4.2 
Patient registration 
4.3 
Assignment of unique participant identifier 
4.4 
Randomization 
7 
5 STUDY DESIGN 
7 
6 STUDY PROCEDURES 
6.1 
Intervention groups 
6.2 
Measurements 
8 
7 STUDY SCHEDULE 
9 
8 OBSERVATIONS AND MEASUREMENTS 
8.1 
Primary outcome measures 
8.2 
Secondary outcome measures 
10 
9 STATISTICAL METHODS 
9.1 
Sample size 
9.2 
Pharmacokinetic analysis 
10 
10 REGULATORY AND REPORTING REQUIREMENTS 
10.1 
Definitions 
10.2 
Reporting to the Human Research Protection Office 
(HRPO) at Washington University 
10.3 
Timeframe for reporting required events 
11 
11 REFERENCES 
12 
 
 
 

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1. BACKGROUND AND SIGNIFICANCE 
 
1.1 
Postpartum depression (PPD)  
 
PPD is one of the most common perinatal medical complications and can have a detrimental 
effect on both mother and baby. Suicide exceeds hemorrhage and hypertensive disorders as 
a cause of maternal mortality1 and maternal psychopathology interferes with the parent-
infant relationship2. It has been estimated to have a period prevalence of 19.2% in the first 3 
postpartum months. The rapid decline in reproductive hormones is thought to contribute to 
the development of PPD in susceptible women, although the specific pathogenesis is 
unknown. The American College of Obstetricians and Gynecologists3 recommend that all 
women should be routinely screened for depressive symptoms in the perinatal period. The 
strongest risk factor is history of pre-existing mood disorder and Robertson et al.5 list 
additional risk factors (Table 1) for PPD in the postpartum period. 
 
 
Depression during pregnancy 
 
Breastfeeding problems 
 
Preterm birth/infant admission to 
neonatal intensive care (NICU) 
 
Traumatic birth experience 
 
History of depression 
 
Anxiety during pregnancy 
Table 1: Risk factors for PPD 
 
1.2 
Ketamine’s anti-depressant effect 
 
Ketamine, a phencyclidine derivative, is a non-competitive antagonist at the N-methyl-D-
aspartic acid (NMDA) receptor that is commonly used as an anesthetic or sedative agent 
and has proven analgesic effect after a variety of surgeries including CD6, where it has also 
been shown to reduce shivering7. It has been demonstrated to have a rapid anti-depressant 
effect in treatment-resistant depression8 outside of pregnancy. The most commonly 
employed intravenous (IV) dose for this purpose is 0.5 mg/kg over 40 minutes, as single or 
repeated infusions. It has been postulated that prolonged blockade of NMDA receptors 
causes long-term changes in signal transduction leading to sustained clinical improvement, 
some investigators have explored longer term infusions such as those used to treat chronic 
pain9. A recent pilot study assessing the feasibility of a 96-hour (~0.5mg/kg/hr) infusion10 
compared with a single 40-minute (0.5 mg/kg) infusion suggested a trend toward greater 
efficacy in the prolonged infusion but confirmation of a statistically significant result is 
awaited. 
 
1.3 
Ketamine and PPD 
 
This promising anti-depressant effect has prompted investigation of ketamine as a 
preventative measure in patients undergoing CD. There have been 2 studies to date11,12, 
one which failed to demonstrate any benefit from a bolus dose of 0.25 mg/kg and one which 
documented a large reduction (1 and 22% in the treatment and control, respectively) in the 
(6 week) period prevalence of postpartum depression after a 4 mg/kg dose of ketamine over 
50 hours (~0.08 mg/kg/hr). 
 
The prolonged IV infusion, in the Jianxin (2015)12 study, was achieved by adding the 
ketamine to a sufentanil patient-controlled analgesic (PCA) pump with a background 
infusion. This PCA pump is a standard part of their post-cesarean analgesic regimen. In our 
institution, it is standard practice to discontinue IV infusions and to remove IV cannulae as 
early as it is safe to do so. This practice is essential to the attempts to enhance 
postoperative recovery and aid mother’s bonding with their babies and facilitate their early-

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life care. This reflects patients’ expectations and preferences and is in line with other 
maternity units across North America and Europe.  
 
The natural course of PPD varies and, although it may resolve spontaneously within weeks, 
approximately 20% of women with PPD still have depression at 12 months and beyond. As 
many as 13% will still have depressive symptoms at 2 years and 40% will have a relapse13. 
Considering the maternal suffering, disruption to the family, potential impairment of the 
social, emotional, and cognitive development of the child14, and the rare cases of infanticide 
and suicide caused by PPD, the impact on families and society as a whole is difficult to 
overemphasize. An intervention that promises such a large reduction in this devastating 
disease warrants extensive research. In an attempt to achieve the benefit demonstrated by 
Jianxin et al. whilst employing methods more acceptable to our patients we have designed a 
pilot study to assess the feasibility of our study design and collect preliminary tolerability and 
efficacy data on ketamine administered by two alternative routes: 40-minute IV infusion (i.v.) 
and subcutaneous (s.c.) injection. 
 
 

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2 OBJECTIVES 
 
2.1 
To determine the feasibility of performing this study at our institution 
2.2 
To determine the pharmacokinetic profiles of ketamine when administered as a 
subcutaneous injection and an intravenous infusion at cesarean delivery 
2.3 
To obtain preliminary data to inform the design of a randomized controlled trial to 
assess the efficacy of ketamine as a preventive intervention at cesarean delivery 
against PPD 
 
3 PATIENT SELECTION 
 
3.1 
Inclusion criteria: 
3.1.1 Term pregnancy 
3.1.2 Age 18-45 years of age 
3.1.3 Scheduled cesarean delivery under neuraxial anesthesia 
3.2 
Exclusion criteria: 
3.2.1 ASA classification IV or V 
3.2.2 History of psychotic episodes 
3.2.3 History of allergy to ketamine 
3.2.4 Inability to communicate in English or any other barrier to providing 
informed consent 
3.3 
Inclusion of women and minorities: 
3.3.1 Eligible pregnant women of all ethnicities and cultures presenting to the 
Barnes Jewish Hospital Labor & Delivery floor will be invited to participate 
in this research 
 
4 REGISTRATION PROCEDURES 
 
4.1 
Confirmation of patient eligibility 
4.1.1 We will screen all patients scheduled for cesarean delivery and confirm 
their eligibility by assessing their: i) age; ii) gestational age; iii) medical 
history and; iv) allergy history. 
4.2 
Assignment of unique participant number 
4.2.1 Each patient will be identified with a unique participant number (UPN) for 
this study. All data will be recorded with this identification number on the 
appropriate case report form (CRF). 
4.3 
Randomization 
4.3.1 Patients will be randomly assigned to one of the three groups: SC, IVI or 
Control. The randomization will be performed in 1:1:1 ratio in blocks of 6, 
with no stratifications.  
 
5 STUDY DESIGN 
 
5.1 
This will be a double-blinded, placebo-controlled, feasibility pilot study. The primary 
outcomes are related to the ability of the study procedures to gather data on the 
interventions’ efficacy in preventing postpartum depression. Successful attainment of 
the following feasibility milestones (FM) is necessary to justify proceeding with a 
pragmatic clinical trial:  
5.1.1 FM1: Establish that the incidence of PPD in our cohort is >10% 
5.1.2 FM2: Achieve the recruitment of >50% of approached patients to 
demonstrate feasibility for an RCT 
5.1.3 FM3: Ensure that the design of assessments and data collection make it 
possible to achieve a complete dataset in >90% of participants 

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5.1.4 FM4: Ascertain that none of chosen routes of administration of ketamine 
is intolerable to patients, as defined as the incidence of one or more 
severe side effects experienced by >10% of participants in that study arm.  
 
6 STUDY PROCEDURES 
 
6.1 
Participants will be assigned to one of three intervention groups (Table 2).  
 
Groups 
Subcutaneous injectate 
Intravenous injectate* 
SC (n=20) 
50 mg/ml ketamine 
0.9% Sodium Chloride 
IVI (n=20) 
0.9% Sodium Chloride 
50 mg/ml ketamine 
P (n=20) 
0.9% Sodium Chloride 
0.9% Sodium Chloride 
Table 2: Intervention groups. *the i.v. injectate will be diluted up to a 40 ml infusion.  
 
6.2 
Participants will have baseline data (Table 3) recorded on the relevant case report 
form on the day of delivery. This data will include demographics to assess the performance 
of randomization procedures as well as characteristics that have been demonstrated to 
confer an increased risk of PPD. The patient will be prepared for cesarean as per  
institutional protocols. 
 
Measure 
Units/values 
Age 
Years 
Height  
Metres 
Weight (day of surgery) 
Kilograms 
Gestational age  
Weeks 
Ethnicity  
White, Black/African American, Asian, Native 
American/Alaskan natives, Native Hawaiian, Pacific 
Islander, Hispanic/Latino 
Insurance status  
Insured/uninsured 
Psychiatric history 
PPD, major depressive disorder (MDD), anxiety, 
premenstrual syndrome (PMS), premenstrual dysphoric 
disorder (PMDD), mood disorder, personality disorder, 
psychotic disorder 
Current anxiety and 
depressive symptoms 
EPDS and GAD-7 
Psychosocial stress 
ANRQ 
Table 3: Baseline data 
 
Once an adequate sensory block is achieved, surgery will commence. Upon delivery of the 
baby, 0.01 ml/kg of the “subcutaneous injectate” will be injected subcutaneously and the 
“intravenous injectate” will be made up to a 40ml infusion (Table 4) and commenced at 60 
ml/hr. Both injectates will be administered/initiated approximately 0 - 5 minutes after delivery 
by the anesthetic provider via one of the cannulae that they will be using for standard patient 
care. The intravenous study infusion will be prepared by a member of the investigative team, 
who will not be involved in data collection. 
 
Add 0.01 ml/kg of the “IVI study solution” to a 60ml syringe and use 0.9% sodium chloride 
to dilute the solution to 40ml.   
Table 4: Instructions for preparing the “IVI study infusion” 
 
Measurements:  
1. Baseline data 
2. EPDS and GAD-7 scores at baseline and approximately 1, 2, 21 and 42 days 
postpartum 

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3. ANRQ at baseline 
4. Time of delivery of baby 
5. Total intraoperative dose of any analgesic/sedative medication 
6. Incidence of hypo- or hypertension (systolic BP < 80 or > 170 mmHg, respectively) 
and brady- or tachycardia (pulse < 40 or > 120 bpm, respectively) 
7. Maximum intraoperative pain (numerical rating scale [NRS], 0-10) 
8. Incidence of the signs/symptoms in Table 5 will be assessed intraoperatively and 
approximately 2 and 6 hours after delivery. The presence of each adverse effect will 
be assessed using a 4-point scale (absent, mild, moderate, severe). 
 
Nausea 
Shivering 
Blurred vision 
Vomiting 
Anxiety 
Diplopia 
Pruritus 
Euphoria 
Nystagmus 
Dizziness 
Hallucinations 
 
Sedation 
Amnesia 
 
Table 5: Adverse effects 
 
9. Surgical site pain (NRS) at 2, 6, 24 and 48 hours, as well as 21 and 42 days, 
postpartum. 
10. Opiate consumption in the first 48 hours (measured in morphine equivalents) will be 
calculated. 
11. Plasma concentrations of ketamine at baseline and approximately 20, 40 and 100 
minutes postpartum.  
 
7 STUDY SCHEDULE 
 
 
Study Event 
Baseline 
Perioperative 
(approximate 
minutes after 
delivery) 
Postoperative 
(approximate hours 
after delivery) 
Outpatient 
(approxim
ate days 
after 
delivery) 
20 
40 
100 
2 
6 
24 
48 
21 
42 
Informed 
consent 
 
 
 
 
 
 
 
 
 
 
Eligibility/ 
Demographics 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
Blood Sample 
Collection 
 
 
 
 
 
 
 
 
 
 
Maximum 
intraoperative 
pain (NRS, 0-
10) score 
 
 
 
 
 
 
 
 
 
 
Adverse Effects 
 
 
 
 
 
 
 
 
 
 
Breastfeeding 
Success 
 
 
 
 
 
 
 
 
 
 
Surgical Site 
Pain (NRS) 
 
 
 
 
 
 
 
 
 
 
EPDS 
 
 
 
 
 
 
 
 
 
 
GAD 7 
 
 
 
 
 
 
 
 
 
 
ANRQ 
 
 
 
 
 
 
 
 
 
 
Table 6: Study schedule 
 
 

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8 OBSERVATIONS AND MEASUREMENTS 
 
8.1 
Primary outcome measures 
8.1.1 FM1: Establish that the incidence of PPD in our cohort is >10% 
8.1.2 FM2: Achieve the recruitment of >50% of approached patients to 
demonstrate feasibility for an RCT 
8.1.3 FM3: Ensure that the design of assessments and data collection make it 
possible to achieve a complete dataset in >90% of participants 
8.1.4 FM4: Ascertain that neither of the chosen routes of administration of 
ketamine are intolerable to patients, as defined as the incidence of one or 
more severe side effects experienced by >10% of participants in that 
study arm.  
 
8.2 
Secondary outcome measures 
8.2.1 Intraoperative supplementary analgesia 
8.2.2 Intraoperative hypo/hypertension and brady-/tachycardia 
8.2.3 Maximum intraoperative pain (NRS) 
8.2.4 Adverse effects intraoperatively and at approximately 2 and 6 hours 
postpartum 
8.2.5 Plasma concentrations of ketamine at baseline and approximately 20, 40 
and 100 minutes postpartum. Samples will be centrifuged and the 
extracted plasma samples will be stored at -80 degrees Celsius before 
transfer to the metabolomics laboratory at Washington University for 
ketamine assay. 
8.2.6 Total opiate consumption in the first 2 days postpartum 
8.2.7 Surgical site pain (NRS 0-10), by face-to-face or telephone interview, at 2, 
6, 24 and 48 hours after delivery and on postpartum days 21 and 42. 
8.2.8 EPDS and GAD-7 on postpartum days 1 and 2, by face to face interview, 
and days 21 and 42, by telephone interview. 
8.2.9 Apgar scores 
8.2.10 Admission to NICU  
8.2.11 Breastfeeding success (Y/N) on post-operative days 1 and 2 
 
9 STATISTICAL METHODS 
 
9.1 
Sample size and analysis  
No formal sample size has been performed as this is a pilot designed to establish the 
feasibility of an RCT. Preliminary data from this study will be used to inform the 
sample size calculation for the subsequent clinical trial. Descriptive statistics will be 
employed to present the demographic data. Continuous variables will be summarized 
using means (SD) or medians (IQR), as appropriate. After construction of the 
concentration-time curves for each patient, the peak plasma concentration and area 
under the concentration-time curve will be summarized overall and associations with 
both antidepressant effect and incidence of adverse symptoms will be explored. 
 
9.2 
Pharmacokinetic analysis  
NONMEM® 7.4 (ICON Development Solutions) software will be utilised to assess 
pharmacokinetic profile of ketamine by each route.   
 
 
 
 

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10 REGULATORY AND REPORTING REQUIREMENTS 
 
10.1 
Definitions 
 
Adverse event (AE): Any unfavorable medical occurrence in a human subject 
including any abnormal sign, symptom, or disease. 
 
Serious adverse event (SAE): Any adverse drug experience occurring at any dose 
that results in any of the following outcomes: 
 
Death 
 
A life-threatening adverse drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability/incapacity (i.e. a substantial disruption of a 
person’s ability to conduct normal life functions). 
 
A congenital anomaly/birth defect 
 
Any other experience which, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to 
prevent on of the outcomes listed above 
 
 
Unanticipated problem: Unexpected (in terms of nature, severity, or frequency) given 
(a) the research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent document, and 
(b) the characteristics of the subject population being studied; related or possibly 
related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and suggests that the research 
places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
Noncompliance: Failure to follow any applicable regulations or institutional policies 
that govern human subject’s research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice 
to ignore regulations, institutional policies, or determinations of the IRB. 
 
10.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 
Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
 
Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 
Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
10.3 
Timeframe for reporting required events 
 
These events must be reported to the IRB within 10 working days of the occurrence 
of the event or notification to the PI of the event.  The death of a research participant 
that qualifies as a reportable event should be reported within 1 working day of the 
occurrence of the event or notification to the PI of the event. 

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Adverse events: The investigator will closely monitor subjects for evidence of 
adverse events.  We review data on a regular basis.  All adverse events will be 
reported and followed until satisfactory resolution. The description of the adverse 
experience will include the time of onset, duration, intensity, etiology, relationship to 
the study drug (none, unlikely, possible, probable, highly probable), and any 
treatment required. 
 
11 REFERENCES 
 
1 
Palladino CL, Singh V, Campbell J, Flynn H, Gold KJ. Homicide and suicide 
during the perinatal period: findings from the National Violent Death Reporting 
System. Obstet Gynecol 2011; 118: 1056–63.  
2 
Parsons CE, Young KS, Rochat TJ, Kringelbach ML, Stein A. Postnatal 
depression and its effects on child development: a review of evidence from low- 
and middle-income countries. Br Med Bull. 2012; 101: 57-79.  
3 
Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. 
Perinatal depression: a systematic review of prevalence and incidence. Obstet 
Gynecol. 2005 Nov; 106(5 Pt 1): 1071-83. Review.  
4 
Committee on Obstetric Practice. The American College of Obstetricians and 
Gynecologists Committee Opinion no. 630. Screening for perinatal depression. 
Obstet Gynecol. 2015 May; 125(5): 1268-71. 
5 
Robertson E, Grace S, Wallington T, Stewart DE. Antenatal risk factors for 
postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry 
2004; 26: 289-95.  
6 
Heesen M, Böhmer J, Brinck EC, Kontinen VK, Klöhr S, Rossaint R, Straube S. 
Intravenous ketamine during spinal and general anaesthesia for caesarean 
section: systematic review and meta-analysis. Acta Anaesthesiol Scand. 2015 
Apr; 59(4): 414-26.  
7 
Liu J, Wang Y, Ma W. Shivering prevention and treatment during cesarean 
delivery under neuraxial anesthesia: a systematic review. Minerva Anestesiol. 
2018 Jun 26. 
8 
Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, 
Summergrad P, Nemeroff CB. American Psychiatric Association (APA) Council of 
Research Task Force on Novel Biomarkers and Treatments. A consensus 
statement on the use of ketamine in the treatment of mood disorders. JAMA 
Psychiatry. 2017; 74(4): 399-405.  
9 
Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br 
J Clin Pharmacol. 2014; 77: 357–367. 
10 Lenze EJ, Farber NB, Kharasch E, Schweiger J, Yingling M, Olney J, Newcomer 
JW. Ninety-six-hour ketamine infusion with co-administered clonidine for 
treatment-resistant depression: A pilot randomised controlled trial. World J Biol 
Psychiatry. 2016 Apr; 17(3): 230-8  
11 Xu Y, Li Y, Huang X, Chen D, She B, Ma D. Single bolus low-dose of ketamine 
does not prevent postpartum depression: a randomized, double-blind, placebo-
controlled, prospective clinical trial. Arch Gynecol Obstet. 2017 May; 295(5): 
1167-1174.  
12 Jianxin G, Junmei X. Efficacy of ketamine in preventing postpartum depression. 
Chin J Anesthesiol 2015; 35(6): 674 - 676 16. 
13 Goodman JH. Postpartum depression beyond the early postpartum period. J 
Obstet Gynecol Neonatal Nurs 2004; 33: 410-20.  
14 Stein A, Pearson RM, Goodman SH, Rapa E, Rahman A, McCallum M, Howard 
LM, Pariante CM. Effects of perinatal mental disorders on the fetus and child. 
Lancet 2014; 384: 1800-19