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

Postpartum depression is a common complication of childbirth and represents a substantial public‑health burden because it can harm mothers, disrupt mother–infant interaction and adversely affect children's emotional, behavioural and cognitive development. Reported prevalence varies by setting; the authors note rates of approximately 14.5% in developed countries and up to 22% in China. Conventional antidepressants act slowly and have limited efficacy for many patients, while more recent clinical evidence indicates that subdissociative doses of ketamine (commonly 0.5 mg/kg) can produce rapid antidepressant effects lasting up to about a week despite ketamine’s short plasma half‑life. Xu and colleagues framed two mechanistic rationales for testing perioperative ketamine to prevent postpartum depression: its rapid antidepressant actions and its potential to reduce acute and chronic postoperative pain via NMDA receptor antagonism, because perinatal acute and chronic pain are risk factors for postpartum depression. The study therefore aimed to test whether a single intra‑operative bolus of low‑dose ketamine (0.25 mg/kg) given during caesarean section reduces the subsequent incidence of postpartum depression, with pain intensity as a secondary outcome.

This was a prospective, randomised, double‑blind, placebo‑controlled clinical trial conducted at Shenzhen Maternity and Child Healthcare Hospital between October 2015 and March 2016. The protocol received local ethical approval and the trial was registered in the Chinese Clinical Trial Registry; written informed consent was obtained from all participants. Eligible participants were ASA grade 1–2 parturients scheduled for elective caesarean section under spinal anaesthesia. Exclusion criteria included BMI ≥40 kg/m2, contraindications or allergy to ketamine, history of hallucinations, drug abuse or psychiatric disease, chronic pain, and contraindications to spinal anaesthesia. The investigators screened 448 women, and 330 were enrolled; 325 completed follow‑up and were included in the final analysis. Participants were randomised 1:1 to receive either intravenous ketamine 0.25 mg/kg diluted to 10 mL or 10 mL of 0.9% saline. The investigational drug was administered slowly intravenously within 5 minutes after clamping the neonatal umbilical cord to avoid neonatal exposure through breastfeeding; if administration was delayed the dose was withheld. Spinal anaesthesia comprised 15 mg 0.5% ropivacaine plus 0.1 mg intrathecal morphine, targeted to a sensory block level of T4–T6. Postoperative analgesia used a patient‑controlled intravenous analgesia (PCIA) device delivering sufentanil (continuous 0.5 µg/h, bolus 3 µg, lock‑out 15 minutes, maximum 12.5 µg/h). Randomisation sequence was generated with equal allocation and concealed in sequentially numbered opaque envelopes. An unblinded anaesthesia nurse prepared the syringes; participants, anaesthesiologists and follow‑up investigators were blinded to assignment. Baseline demographic and obstetric data and intra‑operative variables were collected by designated investigators. Vital signs and acute side effects were recorded at 5 and 15 minutes after dosing and prior to leaving the operating room, and sedation was rated using the Ramsay Sedation Scale. The primary outcome was postpartum depressive symptoms measured by the Edinburgh Postnatal Depression Scale (EPDS) at 3 days and 6 weeks postpartum, with a screening cut‑off of EPDS ≥10. The EPDS is a 10‑item questionnaire with scores 0–30; the Chinese translation has reported sensitivity and specificity in screening contexts. The secondary outcome was pain intensity assessed by the numeric rating scale (NRS, 0–10) at 3 days and 6 weeks. Follow‑up at 3 days was by direct visit and at 6 weeks by telephone interview. Sample size was calculated on the assumption of reducing postpartum depression prevalence from 22% to 10% with ketamine, yielding 300 participants for 80% power and α = 0.05; allowing 10% loss to follow‑up, the planned enrolment was 330. Between‑group comparisons used t tests or Mann–Whitney U tests for continuous variables and χ2 or Fisher’s exact tests for categorical variables; P < 0.05 was considered statistically significant.

Of 448 eligible women, 330 were randomised and 325 were analysed (162 in the ketamine group and 163 in the saline group); 1 participant declined the 3‑day visit and 4 were lost by 6 weeks. Baseline demographic, obstetric and intra‑operative maternal and neonatal parameters did not differ significantly between groups. The primary outcome showed no significant difference in the prevalence of postpartum depression between the ketamine and saline groups at either 3 days or 6 weeks postpartum using the EPDS ≥10 threshold. In terms of the secondary outcome, NRS pain scores at 3 days postoperatively did not differ between groups, but at 6 weeks the ketamine group had significantly lower NRS scores. The authors also report that the proportion of patients with moderate‑to‑strong pain (NRS >3) at 6 weeks was higher in the saline group than in the ketamine group, whereas the proportion with mild pain (NRS ≤3) differed accordingly. Acute ketamine‑related adverse effects were more frequent shortly after dosing. At 5 minutes after administration, the ketamine group had higher incidences of headache, hallucinations, dizziness, drowsiness, diplopia and of a Ramsay sedation score >3 compared with saline. At 15 minutes, vomiting, hallucinations, dizziness, drowsiness and diplopia remained more common in the ketamine group, but there was no longer a significant difference in Ramsay sedation score >3. By the time subjects left the operating room, ketamine‑related side effects did not differ significantly between groups. No ketamine‑related adverse events were reported during postoperative follow‑up in the extracted text.

Xu and colleagues interpret their findings to mean that a single intra‑operative bolus of low‑dose ketamine (0.25 mg/kg) administered during caesarean section does not prevent postpartum depression at 3 days or 6 weeks postpartum, although it was associated with reduced pain scores at 6 weeks. The authors note mechanistic plausibility for both hypotheses: ketamine has rapid antidepressant effects and can modulate synaptic plasticity, and NMDA antagonism can reduce acute and chronic pain and central sensitisation. The investigators suggest several reasons their primary hypothesis was not confirmed. First, the administered dose (0.25 mg/kg) was lower than typical antidepressant infusion doses (commonly 0.5 mg/kg) and lower than doses reported in one study (4 mg/kg) that observed reduced postoperative depression, raising the possibility of a dose‑response relationship. Second, early analgesic benefits of ketamine may have been masked by multimodal analgesia in this trial—intrathecal morphine plus postoperative sufentanil PCIA—which has been associated with inconsistent findings regarding ketamine’s analgesic effect in caesarean cohorts. Safety considerations are emphasised: higher ketamine doses raise concerns about neonatal exposure to ketamine metabolites via breastmilk and potential neurotoxic effects, as well as transient maternal psychological and perceptual side effects such as dissociation, dizziness and hallucinations. The authors acknowledge several limitations: postpartum depression was screened using the EPDS rather than assessed by psychiatrists, which could miss cases or lack sensitivity; ketamine‑related side effects after leaving the operating room were not fully documented; the study did not follow participants beyond 6 weeks for formal assessment of chronic pain (commonly defined as pain >3 months); and the sample size may be insufficient to detect differences in longer‑term pain outcomes. Finally, while the reduction in pain at 6 weeks reached statistical significance, the authors state its clinical significance is uncertain. In conclusion, the study team concludes that 0.25 mg/kg ketamine during caesarean section did not prevent postpartum depression but may attenuate pain up to 6 weeks. Given potential neonatal and maternal risks associated with higher ketamine doses, they advise caution about using ketamine to prevent postpartum depression and call for further research to develop safe and effective preventive strategies.