Single bolus low-dose of ketamine does not prevent postpartum depression: a randomized, double-blind, placebo-controlled, prospective clinical trial

This randomized-controlled trial (n=330) assessed the efficacy of low-dose ketamine (17.5mg/70kg diluted to 10 mL with 0.9% saline) administered during caesarean section in preventing postpartum depression (PPD). No significant differences were found in the prevalence of PPD between the active group and the placebo group at 3 days and 6 weeks after delivery. Pain scores were significantly different at 6 weeks only.

Abstract

“Purpose: Postpartum depression is a common complication of childbirth. In the last decade, it has been suggested that subdissociative-dose ketamine is a fast-acting antidepressant. We aimed to investigate the efficacy of low-dose ketamine administered during caesarean section in preventing postpartum depression.

Methods: Using a randomized, double-blind, placebo-controlled design, 330 parturients who were scheduled to undergo caesarean section were enrolled in this trial. The parturients were randomly assigned to receive intravenous ketamine (0.25 mg/kg diluted to 10 mL with 0.9% saline) or placebo (10 mL of 0.9% saline) within 5 min following clamping of the neonatal umbilical cord. The primary outcome was the degree of depression, which was evaluated using the Edinburgh Postnatal Depression Scale (EPDS) (a threshold of 9/10 was used) at 3 days and 6 weeks after delivery. The secondary outcome was the numeric rating scale score of pain at 3 days and 6 weeks postpartum.

Results: No significant differences were found in the prevalence of postpartum depression between the two groups at 3 days and 6 weeks after delivery. The pain scores measured at 3 days postoperatively were not significantly different between the groups, whereas the scores measured at 6 weeks postpartum were significantly reduced in the treatment group compared with the saline group (P = 0.014).

Conclusions: Intra-operative low-dose ketamine (0.25 mg/kg) does not have a preventive effect on postpartum depression.”

Authors: Yang Xu, Yuantao Li Xiaolei Huang, Daili Chen, Baozuan She & Daqing Ma

Summary

Introduction

Postpartum depression is a common complication of childbirth, and subdissociative-dose ketamine is a fast-acting antidepressant with long-lasting effects. It is also an important public health burden, as mothers with postpartum depression are more likely to harm themselves, impair mother-infant interactions, and adversely affect the children’s emotional, behavioural, and cognitive development.

Abstract

330 parturients who were scheduled to undergo caesarean section were enrolled in this trial. Ketamine or placebo was administered intravenously within 5 min following clamping of the neonatal umbilical cord.

A prospective, randomized, double-blind clinical trial was conducted to evaluate whether low-dose ketamine administrated during caesarean section could prevent the development of postpartum depression. The results revealed that low-dose ketamine did not significantly reduce postpartum depression.

Subjects

The study was conducted in the Shenzhen Maternity and Child Healthcare Hospital and included women with BMI less than 40 kg/m2 and elective caesarean delivery with spinal anaesthesia.

Study design

The study was a randomized, double-blind, placebo-controlled, prospective clinical trial in which subjects were randomly assigned into the ketamine or saline group. The anaesthesiologist performed a spinal block at the level of L3 – L4.

The anaesthesiologist slowly injected 10 mL of 0.25 mg/kg classical ketamine or an equal volume of saline into the neonatal circulation within 5 min after clamping the neonatal umbilical cord.

Randomization and blinding

The random number sequence was generated using Excel and the investigational drug protocol was concealed in sequentially numbered, sealed, opaque envelopes. The subjects, anaesthesiologists, and follow-up investigators were blind to the group assignments.

General data collection

The investigator collected baseline data and intra-operative data from the subjects, including age, BMI, history of the present pregnancy, and concurrent obstetric diseases.

Safety

After the investigational drug was administered, the anaesthesiologist recorded the subject’s vital signs and rated her sedation status (anxiety, irritability, cooperative, quiet, with good orientation, responsive to commands, drowsy, unresponsive).

Outcome measures

The Edinburgh Postnatal Depression Scale (EPDS) was used to assess postpartum depression at 3 day and 6 week postpartum. The pain intensity was assessed with the numeric rating scale (NRS) at 3 day and 6 week postpartum.

Sample size calculation and statistical analysis

According to the literature, 22% of women in China experience postpartum depression. A single intravenous infusion of ketamine was associated with a two-fold response to a general population in depression when compared to that of midazolam.

A statistical analysis was performed on continuous variables and categorical variables using SPSS 20.0 software. A value of P 0.05 was considered statistically significant.

Results

A total of 330 patients were enrolled in this study, and 325 were lost to follow-up. No significant differences were observed between the two groups in terms of demographics or intra-operative maternal and neonatal general parameters.

Ketamine-induced side effects included headache, hallucinations, dizziness, drowsiness, and diplopia, as well as a Ramsay sedation score >3. There was no significant difference in postpartum depression prevalence between the two groups at 3 day and 6 week postpartum.

Discussion

Postpartum depression is a common neurologic disorder after childbirth, and several risk factors are involved in its development.

Ketamine can decrease pain intensity by reducing NMDA receptor-mediated hyperalgesia, the wind-up phenomenon, and the hyperalgesia elicited by opioids. However, ketamine did not reduce postoperative pain scores on postpartum day 3. A review of previous studies of ketamine used in caesarean sections to reduce postoperative opioid use or pain scores revealed that the data from these studies were not consistent. The current study used fully multimodal analgesia to control post-operative acute pain, which covered up the advantages of low-dose ketamine.

A meta-analysis of clinical studies indicated that ketamine may be a good treatment choice for chronic pain following caesarean section.

In our study, a single bolus dose of 0.25 mg/kg of ketamine had no effect on postpartum depression. However, the potential neurotoxic effects of ketamine on the newborn and psychological side effects for the mother are still obstacles to its wide use in the clinic.

This study has several limitations, such as the fact that postpartum depression was not assessed by psychiatrists, and that ketamine-related side effects were not fully documented after the subjects left the operating room. However, the results show that ketamine can reduce postoperative chronic pain. The difference in pain scores between the ketamine and placebo groups may be only statistical, and hence, its clinical significance is unknown yet.

Ketamine administered during caesarean section does not prevent postpartum depression, but may attenuate pain up to 6 weeks after caesarean section.