Ketamine to Prevent PPD After Cesarean

Phase 3

Completed

Conditions: Postpartum Depression

Interventions: Drug: Control
Drug: Ketamine 50 MG/ML

Registration Number: NCT04227704

Lead Sponsor: Washington University School of Medicine

Brief Summary: The investigators plan to randomise participants to receive ketamine or placebo control subcutaneously or by 40-minute intravenous infusions and will follow them up for 42 days to assess the incidence of postpartum depression. This feasibility pilot study is designed to explore the adequacy of the study procedures and tolerability of the interventions.

Detailed Description: 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 mortality and maternal psychopathology interferes with the parent-infant relationship. 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 Gynecologists recommend that all women should be routinely screened for depressive symptoms in the perinatal period.

Risk factors for PPD include:

* Depression during pregnancy • Breastfeeding problems

* Preterm birth/infant admission to neonatal intensive care (NICU)

* Traumatic birth experience

* History of depression

* Anxiety during pregnancy

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 CD, where it has also been shown to reduce shivering. It has been demonstrated to have a rapid anti-depressant effect in treatment-resistant depression 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 pain. A recent pilot study assessing the feasibility of a 96-hour (\~0.5mg/kg/hr) infusion 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.

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 date, 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, 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-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 relapse. Considering the maternal suffering, disruption to the family, potential impairment of the social, emotional, and cognitive development of the child, 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 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 25

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control	Control	Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection and 40-minute intravenous infusion of 0.9% sodium chloride.
Ketamine SC	Ketamine 50 MG/ML	Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride.
Ketamine SC	Control	Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.5 mg/kg of ketamine and a 40-minute intravenous infusion of 0.9% sodium chloride.
Ketamine IVI	Control	Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine.
Ketamine IVI	Ketamine 50 MG/ML	Shortly after cesarean delivery of their baby, participants will receive a subcutaneous injection of 0.9% sodium chloride and a 40-minute intravenous infusion of 0.5 mg/kg ketamine.

Primary Outcome Measures

Name	Time	Method
The Prevalence of Postpartum Depression in the Study Population, as Defined as EPDS Greater Than 10 Out of 30	42 days postpartum	Establish a sufficient burden of disease (\>10%) in our population to warrant a full RCT
Percentage of Eligible Patients Consenting to Participation	Through study completion, approximately 9 months	Establish a recruitment rate of greater than 50% to confirm the feasibility of conducting an RCT in our population Twenty-five (20.7%) out of 121 women who were approached consented to participation. 2 were withdrawn with 23 completing participation.
Percentage of Patients With a Complete Dataset	Through study completion, approximately 9 months	Ensure that the design of assessments and data collection make it possible to achieve a complete dataset in \>90% of participants
Number of Patients in Study Arms Experiencing One or More Severe Side Effects	Through study completion, approximately 9 months	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.

Secondary Outcome Measures

Name	Time	Method
Dose of Opiate Analgesics Administered	Intraoperative phase, approximately 2 hours	Intraoperative supplementary analgesia in morphine milligram equivalents
Dose of Ketorolac Administered (mg)	Intraoperative phase, approximately 2 hours	Intraoperative supplementary analgesia
Maximum Intraoperative Pain (NRS)	Intraoperative phase, approximately 2 hours	Reported maximal level of intraoperative pain on the numerical rating scale 0 - 10, where 0 is no pain and 10 is the worst pain imaginable
Adverse Effects	Intraoperative and 2 and 6 hours postoperatively	Incidence and severity (mild, moderate or severe) of nausea, vomiting, pruritus, dizziness, sedation, shivering, anxiety, euphoria, hallucinations, amnesia, blurred vision, diplopia, nystagmus
Plasma Concentrations of Ketamine	At baseline and approximately 20, 40 and 100 minutes postpartum	Assays of venous blood samples
Total Opiate Consumption in Morphine Equivalents	In the first 2 days postpartum	Morphine equivalents
Prevalence of Intraoperative Hypotension	Intraoperative phase, approximately 2 hours	Prevalence of participants with intraoperative hypotension of a systolic BP of less than 90
Surgical Site Pain: Numerical Rating Scale (NRS 0-10)	At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42	Surgical site pain on a numerical rating scale of 0-10, where 0 is no pain and 10 is the worst pain imaginable.
Edinburgh Postpartum Depression Scale (EPDS)	On postpartum days 1, 2, 21 and 42	The EPDS is a validated measure of depressive symptoms in the postpartum period. The scale is scored between 0 - 30, a higher score represents greater depressive symptomatology. We report the study mean of each participant's mean EPDS score for their postpartum assessments
Apgar Scores	At 1 and 5 minutes after delivery	Apgar score (0-10) comprised of an assessment of neonatal color, tone and crying. A higher score indicates healthier color, tone and crying.
Admission to NICU	Postpartum day 1	Incidence of admission
The Number of Participants Achieving Breastfeeding Success	Postpartum days 1 and 2	An indication of whether breastfeeding has been successfully established (Yes or No).
Prevalence of Intraoperative Hypertension	Intraoperative phase, approximately 2 hours	Prevalence of intraoperative hypertension as defined by number of participants with a systolic blood pressure greater than 140 mmHg
Prevalence of Intraoperative Bradycardia	Intraoperative phase, approximately 2 hours	Prevalence of intraoperative bradycardia, defined as number of participants with a heart rate of less than 40 bpm
Prevalence of Intraoperative Tachycardia	Intraoperative phase, approximately 2 hours	Prevalence of intraoperative tachycardia as defined by the number of participants with a heart rate greater than 110 bpm
Postpartum Anxiety	On day of surgery, and postpartum days 1, 2, 21 and 42	Mean Anxiety in the postpartum. General Anxiety Disorder 7-item Scale (GAD-7), ranges from 0 to 21. Higher scores indicate more severe anxiety.