Clinical trial NCT04227704: Ketamine to Prevent PPD After Cesarean
Official title: Postpartum Depression After Cesarean Delivery: Ketamine as a Preventative Intervention: A Feasibility Pilot-study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Postpartum Depression
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2020-01-14
Enrollment: 25
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomised to one of three groups (two interventional and one control).
Primary purpose: PREVENTION

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.

Eligibility criteria: Inclusion criteria:

* Term pregnancy
* Age 18-45 years of age
* Scheduled cesarean delivery under neuraxial anesthesia

Exclusion criteria:

* ASA classification IV or V
* History of psychotic episodes
* History of allergy to ketamine
* Inability to communicate in English or any other barrier to providing informed consent

Primary outcomes:
measure: The Prevalence of Postpartum Depression in the Study Population, as Defined as EPDS Greater Than 10 Out of 30
timeFrame: 42 days postpartum
measure: Percentage of Eligible Patients Consenting to Participation
timeFrame: Through study completion, approximately 9 months
measure: Percentage of Patients With a Complete Dataset
timeFrame: Through study completion, approximately 9 months
measure: Number of Patients in Study Arms Experiencing One or More Severe Side Effects
timeFrame: Through study completion, approximately 9 months
Secondary outcomes:
measure: Dose of Opiate Analgesics Administered
timeFrame: Intraoperative phase, approximately 2 hours
measure: Dose of Ketorolac Administered (mg)
timeFrame: Intraoperative phase, approximately 2 hours
measure: Prevalence of Intraoperative Hypotension
timeFrame: Intraoperative phase, approximately 2 hours
measure: Maximum Intraoperative Pain (NRS)
timeFrame: Intraoperative phase, approximately 2 hours
measure: Adverse Effects
timeFrame: Intraoperative and 2 and 6 hours postoperatively
measure: Plasma Concentrations of Ketamine
timeFrame: At baseline and approximately 20, 40 and 100 minutes postpartum
measure: Total Opiate Consumption in Morphine Equivalents
timeFrame: In the first 2 days postpartum
measure: Surgical Site Pain: Numerical Rating Scale (NRS 0-10)
timeFrame: At 2, 6, 24 and 48 hours after delivery and on postpartum days 21 and 42
measure: Edinburgh Postpartum Depression Scale (EPDS)
timeFrame: On postpartum days 1, 2, 21 and 42
measure: Apgar Scores
timeFrame: At 1 and 5 minutes after delivery
measure: Admission to NICU
timeFrame: Postpartum day 1
measure: The Number of Participants Achieving Breastfeeding Success
timeFrame: Postpartum days 1 and 2
measure: Prevalence of Intraoperative Hypertension
timeFrame: Intraoperative phase, approximately 2 hours
measure: Prevalence of Intraoperative Bradycardia
timeFrame: Intraoperative phase, approximately 2 hours
measure: Prevalence of Intraoperative Tachycardia
timeFrame: Intraoperative phase, approximately 2 hours
measure: Postpartum Anxiety
timeFrame: On day of surgery, and postpartum days 1, 2, 21 and 42
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
Study officials:
References:
citation: Monks DT, Palanisamy A, Jaffer D, Singh PM, Carter E, Lenze S. A randomized feasibility pilot-study of intravenous and subcutaneous administration of ketamine to prevent postpartum depression after planned cesarean delivery under neuraxial anesthesia. BMC Pregnancy Childbirth. 2022 Oct 21;22(1):786. doi: 10.1186/s12884-022-05118-8.