Ketamine to Prevent PPD After Cesarean
Condition: Postpartum Depression
MeSH terms: Depression, Postpartum; Depression
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Ketamine 50 MG/ML; Control
Intervention type(s): Drug; Drug
Intervention description(s): Administration of a 0.5 mg/kg dose of ketamine at cesarean delivery by one of two routes (subcutaneous or 40-minute IV infusion).; Administration of 0.9% Sodium Chloride (N/S)
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomised to one of three groups (two interventional and one control).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention