Reply to: prophylactic esketamine to reduce postpartum depression in primiparae: A multicentre, double-blind, randomised clinical trial

Editor, We thank Drs Du and Liu for their interest in our work and for their insightful comments regarding breastfeeding safety, postpartum recovery, and the clinical meaningfulness of our findings. Their letter1 raises important considerations that we would like to address point by point. To ensure the safety of breastfeeding, we fully agree that direct measurement of esketamine concentrations in breast milk would provide the highest level of evidence for neonatal safety. While our study did not include such pharmacokinetic sampling, several lines of evidence support the safety profile of our regimen. First, previous studies investigating perinatal esketamine administration have consistently reported no significant differences in neonatal outcomes, including ICU admission rates, between treatment and control groups.2,3 Second, the dose of esketamine used in our trial [(0.25 mg kg−1 bolus intravenously followed by 80 mg over 24 h via patient-controlled intravenous analgesia (PCIA)] belongs to lower to moderate range compared to published literature.4,5 To further minimise potential neonatal exposure, the PCIA infusion was deliberately limited to 24 h, whereas several previous studies used 48-hour regimens.2,4,5 Importantly, a pharmacokinetic study investigating ketamine in lactating women demonstrated that even at doses of 0.5–1.0 mg/kg, the concentrations in breast milk were consistently low, with mean relative infant doses <1%, and did not lead to clinically relevant effects in breastfed infants.6 Third, given that our primary outcome was the incidence of postpartum depression (PPD), and considering the logistical challenges of systematic breast milk sampling in a multicentre setting, we prioritised rigorous clinical monitoring of neonates for 72 hours post-delivery. Of particular concern are the central nervous system (CNS) side effects of esketamine and their potential impact on early postoperative recovery. We did not systematically assess functional outcomes such as time to first ambulation, falls, or maternal-infant interaction, which is a limitation of our manuscript. However, emerging evidence suggests that esketamine may actually facilitate postoperative recovery after caesarean section.7 A recent study demonstrated that esketamine significantly improved time to first ambulation, first flatus, and initiation of lactation compared with controls. Besides, several points merit consideration when interpreting the clinical relevance of CNS effects noted by Drs Du and Liu. First, the 31.7% incidence of CNS adverse events in the esketamine group refers specifically to those occurring within one hour after drug administration. These, including dizziness, hallucinations, and dissociation, were transient and resolved spontaneously before the end of surgery, with no intervention required. Importantly, they did not persist into the postoperative period. Second, during 24 h after surgery, dizziness was the predominant CNS symptom that remained significantly more frequent in the esketamine group (12.80% vs. 5.70%). We prospectively graded the severity of dizziness using a clinically adopted classification scale: 90.5% of affected patients were Grade I, meaning that symptoms did not interfere with daily activities, including ambulation and maternal-infant interaction. Only one patient experienced Grade III dizziness, which did not require additional treatment and resolved spontaneously. Third, a previous study by Wang et al.3 reported a 45.1% incidence of neuropsychiatric adverse events in parturients receiving esketamine. However, it is important to note that the control group in that study also had a 22% incidence of similar events, which may reflect the differences in assessment methods or anaesthesia regimens. Moreover, there were no significant between-group differences in adverse events at 2 or 24 h post-administration, consistent with the transient nature of these side effects observed in our study. Regarding the IMPAKT Enhanced Recovery After Caesarean (ERAS) trial, there are two important distinctions to be made. First, racemic ketamine was studied in the trial, not esketamine. Esketamine has approximately twofold higher affinity for N-methyl-d-aspartic (NMDA) receptor and a different pharmacokinetic profile, which may influence both efficacy and side effects. Second, the ketamine regimen in IMPAKT ERAS trial was a continuous infusion of 2.5 μg kg−1 min−1 for 48 h, resulting in a total dose of approximately 504 mg for a 70 kg patient. This cumulative dose far exceeds those used in perinatal depression studies (typically 0.2–0.25 mg kg−1 as a single bolus, with or without 50–140 mg of esketamine as an adjuvant in PCIA).2,3,4 Prolonged continuous exposure to ketamine and its metabolites may explain the more severe recovery impacts observed in IMPAKT trial, which cannot be directly extended to other low-dose studies. We thank Drs Du and Liu for their thoughtful consideration of whether the short-term benefit in PPD reduction might be offset by the intervention's impact on postpartum recovery. We appreciate this viewpoint and propose the following considerations. First, the number needed to treat (NNT) for PPD prevention at 7 days was approximately 10, based on an absolute risk reduction of 10.3%. In the context of PPD, a condition with potentially severe and lasting consequences for both mother and infant, this may represent a clinically meaningful benefit, even if the effect is short-term. Second, we fully acknowledge that the usage of PCIA deviates from ERAC principles, and have explicitly noted this in our limitations section. Future studies should explore combining esketamine with neuraxial opioids to align with ERAC protocols while preserving the prophylactic benefit against PPD. Third, the CNS effects observed were transient, predominantly mild, and without serious sequelae, a finding consistent with most studies of esketamine use in the perinatal setting. Moreover, 70.6% of patients experiencing hallucinations described them as euphoric, which may reflect a different subjective experience than the distressing symptoms sometimes associated with ketamine. This distinction may have important implications for patient tolerability and acceptance. Taken together, we believe that the short-term prophylactic benefit of eskatamine, quantified by an NNT of 10, coupled with the mild and transient nature of its CNS effects, supports a favourable risk-benefit profile. Nevertheless, we strongly concur with Drs Du and Liu that future trials should incorporate ERAC-compliant regimens and systematically assess functional recovery and maternal-infant outcomes to further refine the balance between benefit and risk.