Perioperative Adjunctive Esketamine for Postpartum Depression Among Women Undergoing Elective Cesarean Delivery

Key Points Question Does perioperative administration of adjunctive esketamine during cesarean delivery prevent postpartum depression? Findings In this randomized clinical trial of 298 pregnant women who underwent elective cesarean delivery, intravenous administration of esketamine significantly decreased the incidence of screened positivity for postpartum depression and improved depressive symptoms during the early postpartum period. Meaning This study suggests that perioperative adjunctive esketamine during cesarean delivery mitigates depressive symptoms, although the effect is transient and preoperative assessment of the mental status of patients should be a concern.


Background
Postpartum depression (PPD) refers to the depression disorder that occurs during the puerperium, which is a puerperal psychiatric syndrome along with postpartum dysphoria and postpartum psychosis, and it is a relatively common postpartum psychological disorder for women, with an incidence rate as high as 15% to 30%.It mainly manifests symptoms such as depressed mood, reduced interest in activities, sadness, irritability, insomnia, tiredness, decreased concentration, and even recurring suicidal thoughts, seriously affecting postpartum women's physical and mental health 1,2 .
Tragically, it can even lead to suicidal thoughts, accounting for about 20% of postnatal maternal deaths 3 .In addition, PPD also adversely affects infants' behavioral, emotional, and cognitive development, causing a significant burden on families.With the increasing incidence of PPD, there has been growing interest in understanding the pathogenesis of PPD 4,5 .
N-methyl-D-aspartate (NMDA) receptor antagonists have significant analgesic and sedative effects, and its classical representative drug, ketamine, is one of the critical components of clinical anesthesia and multimodal analgesia [6][7][8] .As the newest NMDA receptor antagonist, Esketamine is the S-enantiomer of ketamine, which has a stronger affinity for NMDA receptors and has a more potent anesthetic and analgesic activity as well as a more precise antidepressant effect compared with ketamine 9 .Therefore, in recent years, the clinical research on esketamine in the treatment of depression has been deepening, and the study by Singh et al. found that the treatment of esketamine nasal spray is a novel and reliable option for patients with refractory depression who do not respond well to standard treatment approaches 10,11 .Recent reviews have also highlighted that the introduction of esketamine is a new hope for patients with refractory depression and holds a unique and indispensable role in combating this challenging condition 12 .
However, the effect of esketamine on postpartum pain-depression co-morbidity has not been definitively established.Given its dual therapeutic potential in pain management and antidepressant effects, our research team intends to conduct a prospective RCT study, taking the mothers who have undergone cesarean section to terminate pregnancy in our hospital as the research participants, and observing the effect of intravenous administration of esketamine on the analgesic effect and the occurrence of PPD after cesarean section, by collecting the perinatal data and the data from the follow-up visit in the postnatal clinic of our hospital in the 6 weeks after the delivery.We will employ statistical methods, including univariate analysis and multifactorial logistic regression analysis, to assess the effects of intravenous esketamine on the analgesic effect after cesarean section and the occurrence of PPD.This study is expected to provides clinical evidence for the prevention and treatment of postpartum depression.

Study purpose
To explore the effect of intravenous administration of esketamine on both the incidence of PPD and its analgesic efficacy following cesarean section.

Type of the study
The research is a single-center, double-blind, placebo-controlled, randomized clinical trial.The flow chart of the study is shown in Figure 1 Figure 1

Sample size calculation
This was based on our preliminary study, in which the incidence of screened positivity for PPD on postpartum day 7, was 35% for patients who underwent cesarean deliveries.
The expected effect size was subsequently calculated to detect a 50% prevalence reduction in PPD after surgery, with a 2-sided α = .05and 90% power.The sample size required was determined to be 128 patients.Considering the possibility of loss to follow-up and consent withdrawals, 150 patients were selected for inclusion in each arm of this trial.

Randomization and blinding
In the study, an independent researcher who otherwise were not involved in the trial's execution or statistical analysis, generated a numerical random sequence using a computer.This sequence was distributed discreetly through sealed envelopes.When eligible patients were enrolled in the study, the envelopes were handed over to a nurse anesthetist, who opened them and prepared medication based on the information contained within.

Control group:
The equivalent volume of normal saline was administered intravenously after fetus delivery.Moreover, sufentanil (100 μg) and palonosetron hydrochloride (0.25 mg) in 100 ml saline were also given using a PCIA pump.

3.6.3
The above measures will be recorded.

Baseline data
Age, height, weight, pregestational comorbidity, number of gravidity and parturitions, duration of gestation, ASA classification, and Baseline EPDS score.

Intraoperative data
Duration of surgery, estimated blood loss, dosage of oxytocin, and use of vasopressors

Neonatal outcomes
Birth weight, APGAR scores at 1 min, 5 min, 10 min, Umbilical artery blood gas.The level of significance will be established at α < 0.05 with a two-sided test.

1 3 . 6 . 2
When the subarachnoid block fails, local anesthetic solution is incrementally added through the epidural catheter in the extradural space until the block level reaches T6.Postoperatively, if the NRS pain score exceeds 5 points, patients may selfadminister a bolus dose.If the NRS score remains above 4 points after 5 minutes, 50 mg of flurbiprofen axetil is administered intravenously until the NRS score is ≤3 points.

1 4 . 4 . 2
Assessment of postpartum depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) at the following time points: day 7, 14, 28, and 42 following delivery.Evaluation of postoperative pain intensity at rest and during movement assessed with NRS pain score at designated time points: 12, 24, 48, and 72 h after surgery.

4. 4 . 3
Analysis of postoperative pain sensitivity assessed with pain sensitivity questionnaire scores (PSQ-C) 7 days after surgery.score as a covariate, and treatment, day, and day-by-treatment interaction as fixed effects.Random intercepts and unstructured covariance structures were used to model the within-patient errors.An exploratory analysis was conducted to evaluate disparities in our primary outcome.The stratification confounders were corrected by the Cochran-Mantel-Haenszel test.