Single low-dose esketamine improves postpartum depression symptoms and recovery quality in cesarean section women

Perinatal and postpartum depression are common and can have serious consequences for maternal wellbeing, the mother-infant relationship, and infant development. The introduction notes that existing treatments such as psychotherapy and standard antidepressant medication may be too slow or otherwise unsuitable for immediate postoperative mood support after caesarean section. It also highlights growing interest in ketamine and esketamine because of their rapid antidepressant effects, but says that much of the earlier evidence has focused on women at higher risk of depression or on pain-related outcomes rather than the general population of mothers after elective caesarean section. The study therefore aimed to test whether a single low-dose intravenous infusion of esketamine, given immediately after fetal delivery and combined with patient-controlled intravenous analgesia (PCIA), could reduce early postpartum depressive symptoms and improve recovery quality in women undergoing elective caesarean section. The authors frame this as a prospective randomised controlled trial intended to provide clinical evidence for more precise postpartum depression prevention strategies.

This was a prospective, randomised controlled trial conducted at Dongguan Maternal and Child Health Hospital between August 2024 and August 2025 and registered in the Chinese Clinical Trial Registry. The trial enrolled 136 women scheduled for elective caesarean section and randomly assigned them in a 1:1 ratio to an esketamine group or a saline control group, with 68 participants in each arm. The study was approved by the hospital ethics committee and all participants gave written informed consent. Eligibility criteria included ASA physical status I-II, full-term singleton pregnancy, age 18-60 years, body mass index of 18-35 kg/m2, elective surgery lasting less than 2 hours, and informed consent. Exclusions included contraindications to neuraxial puncture or failed neuraxial anaesthesia, long-term use of analgesic or sedative medications, pre-pregnancy hypertension, diabetes or thyroid dysfunction, allergy to the study drug, communication barriers, cognitive impairment or psychiatric disorders, and other investigator-determined unsuitability. Both groups received combined spinal-epidural anaesthesia, routine monitoring and oxygen, and the same postoperative analgesia regimen via PCIA: butorphanol tartrate 10 mg, flurbiprofen ester 200 mg, and dexamethasone 10 mg in 100 mL, delivered with a 2 mL/h basal rate plus 1 mL patient-controlled boluses every 20 minutes. Immediately after delivery and umbilical cord ligation, the study group received esketamine 0.2 mg/kg intravenously over 40 minutes, while the control group received an equal volume of saline. The trial used a single-blind design: mothers were unaware of allocation, but attending anaesthesiologists knew the group assignment. The primary outcomes were Edinburgh Postnatal Depression Scale (EPDS) scores on postpartum day 2 and day 7. Secondary outcomes included Obstetric Quality of Recovery-10 (ObsQoR-10) scores at 24 and 48 hours, pain assessed by visual analogue scale (VAS), length of stay, discharge satisfaction, postpartum recovery milestones such as first ambulation, first flatus and first breastfeeding, breastfeeding frequency within 48 hours, and adverse events within 24 hours. Statistical analysis was performed in SPSS using t-tests, Mann-Whitney U tests, chi-squared or Fisher's exact tests, and repeated-measures or two-way ANOVA where appropriate, with P<0.05 considered statistically significant.

Baseline clinical characteristics were similar between groups, including age, anthropometrics, gestational age, operative time, inflammatory markers and preoperative pain thresholds, suggesting good comparability. For postpartum depression outcomes, the study group had a lower incidence of postpartum depression early after surgery. On postoperative day 3, postpartum depression occurred in 4 women in the esketamine group (5.88%) versus 15 in the control group (22.06%), which was statistically significant. Lower incidence in the esketamine group also persisted on days 7 and 14, with no significant difference by day 30. EPDS scores on postpartum days 2 and 7 were significantly lower in the esketamine group than in the control group. The authors also note lower scores on several depressive-symptom items, including anxiety/worry, unreasonable fear, self-harm thoughts, sleep difficulty and sadness. Recovery quality was better in the esketamine group. ObsQoR-10 scores at 24 and 48 hours were higher in all reported dimensions: emotional state, comfort, psychological support and self-care ability. Pain scores at rest and on movement at 4, 12 and 24 hours were lower with esketamine. Analgesic pump use was also reduced: the number of presses was lower within 24 hours (2.57±0.74 versus 4.15±1.22) and within 48 hours (3.55±1.24 versus 4.75±1.33), although the time to first press did not differ significantly. Postoperative functional recovery was faster with esketamine, with earlier first mobilisation, first breastfeeding and first anal exhaust, plus more breastfeeding sessions within 48 hours. During the infusion period, mean arterial pressure and heart rate did not differ significantly between groups. Adverse events were broadly similar between groups, with no statistically significant differences in reported events such as dizziness, vomiting, nausea, hallucinations, dissociative reactions, hypertension, increased muscle tone, agitation or nystagmus. Dizziness, vomiting and nausea were the most common reactions, and the authors also state that neonatal intensive care unit admission did not differ significantly between groups.

The authors interpret the findings as showing that a single low-dose intravenous infusion of esketamine immediately after delivery, when combined with postoperative PCIA, can rapidly reduce early postpartum depressive symptoms and improve quality of recovery after caesarean section. They argue that the early reduction in EPDS scores and the lower incidence of postpartum depression in the first two postoperative weeks indicate a fast antidepressant effect, while the higher ObsQoR-10 scores and earlier recovery milestones suggest broader benefits for postoperative rehabilitation. They relate these results to earlier research on ketamine and esketamine, noting that ketamine has known rapid antidepressant effects but is limited by concerns about tolerance and addiction. They describe esketamine as acting through NMDA receptor antagonism and related pathways involving AMPA activity, mTOR signalling and BDNF release, which they suggest may explain the rapid mood effects observed. They also propose that the improved recovery profile may reflect both mood improvement and direct analgesic or central pain-modulating effects. The authors state that their findings are consistent with previous studies reporting rapid symptom relief after single low-dose esketamine. The discussion acknowledges several limitations. The study was single-centre, the sample size was relatively small, only one dosing strategy was tested, and mechanistic biomarkers such as BDNF, IL-6 and CRP were not measured. The authors therefore caution that external generalisability and mechanistic interpretation remain limited. They suggest that future research should use larger multicentre designs and incorporate neuropsychological, biochemical and imaging measures to better define the role of esketamine in perinatal mood disorder interventions. They also state that the treatment appeared safe, with no major psychiatric adverse effects and no apparent neonatal safety signal in this study.