This randomised controlled trial (n=136) found that a single low-dose esketamine infusion (14mg/70kg) given after fetal delivery during caesarean section, combined with patient-controlled analgesia, reduced postnatal depression scores at days 2 and 7, improved recovery quality, and shortened time to first ambulation, flatus and breastfeeding compared to placebo, with no significant difference in adverse events.
Objective:
To investigate the effects of single low-dose esketamine combined with patient-controlled intravenous analgesia (PCIA) on early postpartum depression symptoms and recovery quality in women undergoing cesarean section.
Methods:
This prospective, randomized, controlled study enrolled 136 women scheduled for elective cesarean section, who were randomly assigned in a 1:1 ratio to the study group (esketamine group, n=68) or the control group (placebo group, n=68). In the study group, esketamine (0.2 mg/kg) was intravenously infused for 40 minutes immediately after fetal delivery. In the control group, an equal volume of normal saline was given. Both groups then received PCIA for pain relief maintenance after the operation. The Edinburgh Postnatal Depression Scale (EPDS) scores, Obstetric Quality of Recovery-10 (ObsQoR-10) scores, and postoperative recovery indicators were compared between groups at different time points after surgery.
Results:
Compared with the control group, the study group showed significantly lower EPDS scores at postoperative days 2 and 7, higher ObsQoR-10 scores, shorter times to first ambulation, flatus, and breastfeeding, as well as increased breastfeeding frequency within 48 hours (all P<0.05). The incidence of adverse reactions revealed no statistically significant difference (P>0.05).
Conclusion:
A single low-dose esketamine combined with PCIA effectively alleviates early postpartum depression symptoms, enhances postoperative recovery in women undergoing cesarean section, and demonstrates good safety and clinical applicability.
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.
A total of 136 women scheduled for elective cesarean section were enrolled in this study and randomly assigned in a 1:1 ratio to the study group (esketamine group, n=68) or the control group (normal saline group, n=68) using a random number table. This prospective, randomized controlled trial (Chinese Clinical Trial Registry: ChiCTR24000-88992) was conducted at Dongguan Maternal and Child Health Hospital between August 2024 and August 2025. The study protocol was approved by the ethics committee of the Dongguan Maternal and Child Health Hospital. Written informed consent was obtained from all participants prior to enrollment. This study was carried out in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines.
Inclusion criteria were: (1) ASA physical status I-II; (2) full-term singleton pregnancy (≥37 weeks); (3) age 18-60 years; (4) body mass index (BMI) between 18 and 35 kg/m 2 ; (5) elective surgery with duration <2 hours; and (6) signed informed consent and voluntary participation. Exclusion criteria were: (1) contraindications to neuraxial puncture or failed neuraxial anesthesia; (2) long-term use of analgesic, sedative, or anxiolytic medications; (3) pre-pregnancy comorbidities such as hypertension, diabetes, or thyroid dysfunction; (4) history of allergy to the involved drug; (5) communication barriers, cognitive impairment, or psychiatric disorders; and (6) any other conditions deemed unsuitable for participation by the investigators.
All study subjects began receiving intravenous infusion immediately after delivery. The study group was administered 0.2 mg/kg of esketamine. Firstly, the esketamine infusion was prepared strictly according to medical orders and introduced via a three-way stopcock into an established peripheral venous access. Subsequently, the drug was continuously infused using a controllable-rate spring pump, and the infusion pump was properly secured to the patient's forearm. During infusion, the patient's vital signs and analgesic effects were closely monitored, and attention was paid to any adverse reactions such as dizziness, nausea, or hallucinations to ensure medication safety and the stability of analgesic effect. The infu-Am J Transl Res 2026;18(2):1287-1297 sion process is shown in Figure. The control group received an equal volume of saline, both infused over 40 minutes. This study employed a single-blind design, where the mothers were unaware of the treatment received, while the attending anesthesiologists were informed of the grouping and carried out the procedure.
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Papers cited by this study that are also in Blossom
Janik, A., Qiu, X., Lane, R. et al. · JAMA Psychiatry (2025)
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.
Both groups of patients did not use sedatives or analgesics preoperatively. After entering the operating room, a peripheral venous line was established, and routine monitoring of noninvasive blood pressure, heart rate, and pulse oxygen saturation was conducted, with oxygen administered via mask (2 L/min). Anesthesia was performed using combined spinal-epidural anesthesia by an experienced anesthesiologist, with 0.75% ropivacaine injected into the subarachnoid space (dose adjusted according to height) and an epidural catheter left in place 3-5 cm. Postoperative analgesia regimen consisted of butorphanol tartrate 10 mg, flurbiprofen ester 200 mg, and dexamethasone 10 mg, prepared into 100 mL and delivered using a PCIA pump with a regimen of 2 mL/h baseline infusion, with patient-controlled additional 1 mL doses every 20 minutes. If postoperative analgesia was inadequate, flurbiprofen ester 50 mg could be added by intravenous push.
The study drug was administered intravenously immediately after the delivery of the fetus and umbilical cord ligation, with infusion time set uniformly at 40 minutes. The study group received esketamine (0.2 mg/kg), with the specific infusion procedure and medication shown in Figure, while the control group received an equal volume of normal saline. Routine fluid supplementation was administered during surgery, with preloading of 6 mL/kg colloid solution before surgery. If intraoperative systolic blood pressure fell by more than 20% from baseline or <90 mmHg, intravenous phenylephrine 50-100 μg was given; if heart rate <50 beats/min, atropine 0.3-0.5 mg was administered.
The primary endpoints were Edinburgh Postnatal Depression Scale (EPDS) scores on the 2nd and 7th day postpartum. Secondary endpoints include: ① Quality of recovery scores (ObsQoR-10) at 24 h and 48 h postpartum; ② Pain scores at 24 h postpartum at rest and during movement (Visual Analogue Scale, VAS); ③ Length of hospital stay; ④ Discharge satisfaction (total score 10); ⑤ Adverse events within 24 h postoperatively, including tachycardia, hypertension, respiratory depression, nausea, vomiting, dizziness, agitation, hallucinations,
Close monitoring of adverse events within 24 h postoperatively, including heart rate, blood pressure, respiration, and consciousness. All adverse events are recorded with their severity and drug-relatedness. Serious adverse events were reported to the ethics committee within 24 hours and a serious adverse event report form was completed.
Statistical analyses were performed using SPSS 22.0. Continuous variables with normal distribution were expressed as mean ± standard deviation ( _ x ± s) and compared between groups using independent t-tests. Non-normally distributed data are presented as median (IQR) and compared using the Mann-Whitney U test. Categorical data were presented as n (%) and compared between groups using the χ 2 test or Fisher's exact test. For multi-time point or repeated measurement indicators, repeated measures ANOVA or two-way ANOVA were used. Bonferroni post hoc tests were conducted when differences were significant. P<0.05 was considered statistically significant.
No statistically significant differences were observed between the two groups in terms of age, height, weight, body mass index, gestational age, operative time, preoperative leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), preoperative pressure pain threshold, or pain tolerance threshold (all P> 0.05). These findings indicate good baseline comparability between the two groups (Table).
On postoperative days 3, 7, 14, and 30, both the groups showed a decreasing trend in the incidence of PPD. Among them, the difference between the two groups was most significant on postoperative day 3, with 4 cases (5.88%) of PPD in the study group, significantly lower than 15 cases (22.06%) in the control group (χ 2 =7.403, P=0.007). In addition, on postoperative days 7 and 14, the incidence of PPD in the study group was also lower than that in the control group, at 5.08% vs. 22.41% (χ 2 =5.445, P=0.020) and 5.08% vs. 20.69% (χ 2 =5.096, P=0.024), respectively. On postoperative day 30, the difference between the two groups was not statistically significant (χ 2 =1.727, P= 0.189). This suggests that esketamine intervention can significantly reduce the incidence of early postpartum PPD (especially within the first two weeks after surgery) and has a good preventive antidepressant effect. See Figure.
On the 2nd and 7th days postpartum, the EPDS scores of the mothers in the study group were lower than those of the control group (all P<0.05), suggesting that the intervention had benefits in alleviating early postpartum depression moods. On the 2nd day postpartum, the scores of both groups were high in sub-items such as "feeling happy", "feeling optimistic about the future", "feeling anxious or worried", "feeling self-blame", and "feeling sad or distressed", but the overall score of the study group was significantly lower than that of the control group. Particularly in core emotional items such as "feeling anxious or worried", "feeling fear without reason", and "having thoughts of self-harm", "the study group scored lower", indicating that the intervention helped relieve negative emotions. By the 7th day postpartum, EPDS scores in both groups had decreased compared with those on the 2nd day, showing a gradual recovery of maternal moods over time. However, the study group still maintained lower scores in multiple sub-items, such as "difficulty sleeping" and "feeling sad", indicating a more significant effect in improving sleep disturbances and alleviating depression. See Tables.
In the comparison of ObsQo-R-10 scores at 24 and 48 hours postoperatively, the study group had significantly higher scores than the control group in the four dimensions of emotional state, comfort, psychological support, and self-care ability (all P<0.05). See Figure.
VAS scores at each time point: The resting and movement VAS scores at 4 h, 12 h and 24 h postoperatively in the study group were significantly lower than those in the control group (all P<0.05). See Figure.
The time to first press of the analgesic pump in the study group was slightly shorter than that in the control group (5.63±0.81 h vs. 5.79±0.72 h, P>0.05). Within 24 hours postoperatively, the number of presses of the analgesic pump in the study group was significantly lower than that in the control group (2.57±0.74 times vs. 4.15±1.22 times), and within 48 hours postoperatively, the number of presses was also lower than that in the control group (3.55±1.24 times vs. 4.75±1.33 times, all P<0.05). This indicates that patients in the study group had lower postoperative analgesic requirements and better pain relief. See Table.
There were no statistically significant differences in the mean arterial pressure and heart rate between the two groups of patients at all Am J Transl Res 2026;18(2):1287-1297 observation time points during the intervention (P>0.05). See Table.
The study group had more breastfeeding sessions within 48 hours after surgery, with earlier first mobilization, first breastfeeding, and first anal exhaust times than the control group (all P<0.05). See Figure.
During intraoperative adverse reactions, the most common adverse events in the study group were dizziness (20.6%), vomiting (17.6%) and nausea (7.4%), while in the control group they were vomiting (17.6%), nausea (10.3%) and dizziness (16.2%). Although the incidence of dizziness was high in both groups, it was slightly higher in the study group. Additionally, a few parturients in both groups experienced mild central nervous system-related reactions such as hallucinations, dissociative reactions, hypertension, increased muscle tone, agitation, and nystagmus, with no statistically significant differences between the groups (all P>0.05). See Table.
This study focused on women undergoing caesarean section and investigated the effects of immediate intravenous infusion of low-dose esketamine (0.2 mg/kg over 40 min) after fetal delivery on postpartum depression symptoms and the quality of postoperative recovery. The results demonstrated that compared to the control group, the study group had significantly lower EPDS scores at multiple postoperative time points -a marked reduction in the incidence of postpartum depression on the third postoperative day, significantly improved ObsQoR-10 scores, and better post- operative functional recovery indicators. This indicates that low-dose esketamine has excellent effects in alleviating postpartum depression and promoting postoperative rehabilitation, with good safety. Intravenous infusion of 0.5 mg/kg ketamine is the most commonly used dose for treating depression, with mood improvement lasting about a week, and increasing the frequency of treatment can extend the antidepressant effect. Unfortunately, the risk of addiction and tolerance to ketamine leads many practitioners to be cautious about repeated injections. Esketamine, as a new anesthetic drug, has recently been shown to have significant antidepressant effects. Additionally, the drug exhibits certain analgesic potential, which may be related to its non-competitive blockade of NMDA receptors, thereby inhibiting receptor activation, reducing neuronal excitability, and producing both anesthetic and analgesic effects. Furthermore, esketamine can also participate in pain relief by activating opioid receptors. Regarding clinical dose selection, research has indicated that in the context of caesarean section, a dose of 1 mg/kg esketamine has been proven to be safe and feasible. In this study, we adopted an innovative administration strategy: low dose esketamine (0.2 mg/kg, 40 min) was administered intravenously immediately after delivery, combined with postoperative PCIA analgesia maintenance. This regimen effectively overcomes the limita tion of the short duration of effect of a single intravenous infusion while also addressing the issue of insufficient blood drug concentration that may occur with standalone PCIA. In addition, this administration method can significantly reduce the occurrence of common postoperative adverse reactions. Thus this study offers a promising intervention strategy that may optimize the risk-benefit ratio in the management of postpartum depression syndrome. Am J Transl Res 2026;18(2):1287-1297 Esketamine is the right-handed enantiomer of ketamine, and its mechanism of action mainly involves non-competitive antagonism of NMDA receptors, blocking the neurotoxicity of glutamate, enhancing AMPA receptor activity, activating the mTOR signaling pathway, and increasing presynaptic release of BDNF, thereby improving synaptic plasticity, regulatingfunc-tional connectivity in emotionrelated brain regions, and exerting rapid antidepressant effects. Studies have confirmed that a single low dose of esketamine can take effect within 24 hours, continuously alleviating depressive symptoms, with some studies indicating effects lasting up to 7 days or even more than 2 weeks, and with mild adverse reactions and good patient compliance. The results of this study are consistent with the aforementioned literature, with the study group showing a significant decrease in EPDS scores on the third day postoperatively, suggesting rapid antidepressant effects of esketamine. On the 14th and 28th postoperative days, the study group maintained lower EPDS scores, indicating some persistence of the antidepressant effect. In addition, ObsQoR-10 scores in the study group were significantly higher than those of the control group, especially in terms of emotional state, comfort, emotional support, and independence, indicating that esketamine may not only indirectly promote postoperative recovery through mood improvement but also directly enhance the postoperative experience by affecting central pain modu-Am J Transl Res 2026;18(2):1287-1297 lation and alleviating postoperative discomfort. The study group showed significantly earlier times for first ambulation, first anal exhaust, and first breastfeeding compared to the control group, and the number of breastfeedings within 48 hours post-surgery was also significantly increased, suggesting that the intervention can accelerate the functional recovery of postpartum women. This may be due to improved patient cooperation with recovery behaviors following better emotional status, or the multidimensional alleviating effects of esketamine on postoperative fatigue, pain, and anxiety. Notably, although esketamine has psychoactive properties, it did not induce common psychiatric side effects such as agitation, hallucinations, or dissociation in this study; patients remained awake and cooperative, demonstrating good safety. Regarding the newborns, there was no statistically significant difference in neonatal intensive care unit admission rates between groups, further supporting that esketamine has minimal impact on neonatal safety, consistent with its pharmacological characteristics of weak placental transfer and rapid metabolism. Despite the positive conclusions of this study, certain limitations still remain. Firstly, the study was conducted at a single clinical center, and the sample size was relatively small due to restrictions on sample availability and follow-up management, which may affect external generalizability. Secondly, only the effects of a single postoperative medication were observed, and multiple or staged dosing strategies were not evaluated. Thirdly, monitoring of relevant biomarkers (such as BDNF, IL-6, CRP, etc.) was lacking, so mechanistic inferences still require experimental data support. Future research is recommended to expand the sample size, adopt a multicenter design, and combine neuropsychological assessments, biochemical tests, and brain imaging techniques to systematically evaluate the application value and mechanisms of esketamine in perinatal mood disorder interventions, providing theoretical support for more precise and individualized clinical intervention programs. In summary, immediate intravenous infusion of low-dose esketamine after fetal delivery, and it being combined with postoperative PCIA for pain management maintenance, can effectively alleviate postpartum depression symptoms, improve recovery quality, promote functional restoration following caesarean section, and it is safe. It has a broad application prospect in perioperative rapid recovery and mood interventions.