Original Investigation | Anesthesiology

Perioperative Adjunctive Esketamine for Postpartum Depression

Among Women Undergoing Elective Cesarean Delivery
A Randomized Clinical Trial
Yu Chen, MD; Yu Guo, MS; Han Wu, MS; Yi-Jie Tang, MD; Suren Rao Sooranna, PhD; Li Zhang, MS; Ting Chen, MS; Xi-Yuan Xie, MD; Liang-Cheng Qiu, MS; Xiao-Dan Wu, MD

Abstract Key Points

Question Does perioperative
IMPORTANCE Postpartum depression (PPD) is one of the most common mental health conditions
administration of adjunctive esketamine
during the perinatal and postpartum periods, which can have adverse effects on both mother
during cesarean delivery prevent
and infant.
postpartum depression?

OBJECTIVE To investigate the efficacy of perioperative adjunctive esketamine administration after Findings In this randomized clinical trial
cesarean deliveries in the prevention of PPD. of 298 pregnant women who
underwent elective cesarean delivery,
DESIGN, SETTING, AND PARTICIPANTS A single-center, double-blind, placebo-controlled, intravenous administration of
randomized clinical trial was conducted from January 1, 2022, to January 1, 2023, at Fujian Provincial esketamine significantly decreased the
Hospital among 298 women aged 18 to 40 years, with an American Society of Anesthesiologists incidence of screened positivity for
grade I to III classification and singleton full-term pregnancies who were scheduled for elective postpartum depression and improved
cesarean deliveries. Primary analyses were performed on a modified intention-to-treat basis. depressive symptoms during the early
postpartum period.
INTERVENTIONS Patients were randomly assigned to the esketamine (n = 148) and control
Meaning This study suggests that
(n = 150) groups. Those in the esketamine group received a single intravenous injection of 0.25
perioperative adjunctive esketamine
mg/kg of esketamine immediately after fetal delivery, followed by 50 mg of esketamine as an
during cesarean delivery mitigates
adjuvant in patient-controlled intravenous analgesia for 48 hours after surgery. Saline was given to
depressive symptoms, although the
the control group of patients.
effect is transient and preoperative
assessment of the mental status of
MAIN OUTCOMES AND MEASURES The primary outcome was assessments of PPD symptoms by
patients should be a concern.
using the Edinburgh Postnatal Depression Scale (EPDS) at postpartum day 7. Positive screening for
PPD was defined as a score of 10 or more points on the EPDS. In addition, the EPDS was analyzed as a
continuous variable to evaluate depressive symptoms. Secondary outcomes included the Numeric + Visual Abstract
Rating Scale (NRS) of postoperative pain, along with safety evaluations including adverse events and
clinical assessments at postpartum days 14, 28, and 42.
+ Supplemental content
Author affiliations and article information are
listed at the end of this article.
RESULTS A total of 298 pregnant women were included, with 150 in the control group (median age,
31.0 years [IQR, 29.0-34.0 years]) and 148 in the esketamine group (median age, 31.0 years [IQR,
28.0-34.0 years]). The prevalence of depression symptoms was significantly lower among patients
given esketamine compared with controls (23.0% [34 of 148] vs 35.3% [53 of 150]; odds ratio, 0.55;
95% CI, 0.33-0.91; P = .02) on postpartum day 7. In addition, the esketamine group also showed a
significantly lower change in EPDS scores (difference of least-squares means [SE], −1.17 [0.44]; 95%
CI, −2.04 to −0.31; effect size, 0.74; P = .008). However, there were no differences between the
groups in the incidence of positive screening results for PPD or in changes from the baseline EPDS
scores at postpartum days 14, 28, and 42. There were no differences in NRS scores at rest and on
movement except on movement at 72 hours postoperatively, when scores were significantly lower

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

in the esketamine group (median, 3.0 [IQR, 2.0-3.0] vs 3.0 [IQR, 3.0-3.5]; median difference, 0 [95%
CI, 0-0]; P = .03).

CONCLUSIONS AND RELEVANCE These results suggest that intravenous administration of

esketamine during the perioperative period of elective cesarean delivery can improve depression
symptoms during the early postpartum period. However, this antidepression effect may not be
universally applicable to patients with low EPDS scores.

TRIAL REGISTRATION Chinese Clinical Trial Registry Identifier: ChiCTR2100054199

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Introduction
Postpartum depression (PPD) is a prevalent major depressive disorder that occurs in women during
the puerperal period; it represents the most common mental health condition during both the
perinatal and postpartum periods. The global incidence of PPD ranges from 15% to 30%,1,2 and in
China approximately 25% of new mothers may be prone to PPD.3,4 Postpartum depression is
characterized by a range of symptoms, including low mood, reduced interest in activities, sadness,
irritability, insomnia, burnout, decreased attention, and even recurrent suicidal tendencies.5 These
manifestations can influence the physical and psychological well-being of new mothers. Fourteen US
Maternal Mortality Review Committees recently identified maternal mental health conditions as
being responsible for 68% of pregnancy-related deaths, with PPD being the primary contributing
factor.6 Furthermore, PPD may also adversely affect infants’ behavior, emotions, and cognition
development.7-10 Such disorders can impose an additional burden to the mother and newborn as well
as the entire family unit. These findings have encouraged researchers to search for possible remedies
for PPD.
There is compelling evidence to link the glutamatergic system to depressive disorders, and
excessive glutamate release can aggravate neural circuit injuries and functional impairment in mood
regulation. There is a positive correlation between glutamate concentrations in crucial brain regions
and PPD in new mothers when compared with controls.11,12 N-methyl-D-aspartate (NMDA) receptors
have been implicated in glutamatergic neurotransmitter dysregulation13,14; these receptors may be
a critical causative feature of mood disorders.15,16 Not only can ketamine, a classic uncompetitive
glutamatergic NMDA receptor antagonist, block NMDA receptors directly, but it also inhibits the
γ-aminobutyric acid–ergic interneuron activity and stimulates synaptogenesis,17,18 enabling it to
provide antidepressant effects as well as acting as an anesthetic and analgesic.19 Several clinical trials
have demonstrated that ketamine delivers rapid and effective antidepressant actions in patients with
depression.20-22 It has also been shown to have a potential role in the treatment of PPD.23
Recently, esketamine, a novel antagonist of the NMDA receptor with a higher affinity than
ketamine, has been used in several countries, including China. As a dextral resolution of ketamine,
esketamine has been shown to improve the effectiveness of anesthetics and analgesics, with a
similar antidepressant effect to its predecessor.24,25 Numerous studies have found that an
esketamine nasal spray could rapidly induce and sustain beneficial effects for patients with a
diagnosis of treatment-resistant depression and risk of suicides.26-29 Previous studies have also
found that, for women who have undergone cesarean deliveries, a preventive administration of
esketamine, either by the intrathecal or intravenous route, could yield both safe and efficacious
analgesic effects.30,31 Given its bidirectional efficacy as an analgesic and antidepressant, we
performed a double-blind, randomized clinical trial to investigate the effects of perioperative
adjunctive esketamine administration during cesarean delivery on patients with PPD.

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Methods
Study Design
This prospective, double-blind, placebo-controlled randomized clinical trial was approved by the
Institutional Ethics Committee of Fujian Provincial Hospital and registered in the Chinese Clinical
Trials Registry (ChiCTR2100054199). The trial protocol and statistical analysis plan are provided in
Supplement 1. Patients were enrolled between January 1, 2022, and January 1, 2023. All participants
provided written informed consent to participate in this study, which followed the Consolidated
Standards of Reporting Trials (CONSORT) reporting guideline.
We enrolled 18- to 40-year-old pregnant women with an American Society of Anesthesiologists
(ASA) grade I to III classification and a singleton pregnancy at full term (>37 weeks). They were
scheduled for elective cesarean deliveries in either the Fujian Provincial Hospital or its southern
branch. Patients excluded were those with prenatal mental disorders, either hypertension or risk of
intracranial hypertension, preeclampsia, eclampsia, hyperthyroidism, placenta previa, placental
abruption, and placenta accreta. Others with an allergy to NMDA receptor antagonists and an
inability or unwillingness to cooperate with questionnaires and clinical examinations were also
excluded.

Randomization and Blinding

Patients were randomly assigned in a 1:1 ratio into 2 groups, the esketamine and control groups, using
a computerized randomization table. Before anesthesia, the study coordinator opened the
envelopes consecutively according to the recruitment sequence and the drugs to be used for each
patient were prepared. All patients, anesthesiologists, surgeons, follow-up interviewers, and
investigators who were involved in data collection and analysis were blinded to the allocation quota
of each group throughout the study period (eFigure in Supplement 2).

Perioperative Anesthesia and Management of Analgesia

After the patient entered the operating room, an intravenous channel was established, and the
patient’s pulse oximetry, electrocardiograph, and noninvasive blood pressure were monitored.
Oxygen was provided at 2 L/min through a nasal catheter. The patient was laid in a left lateral position
and a spinal needle was punctured into the subarachnoid space through the L2-L3 or L3-L4
interspace. Then 12 mg of 0.6% ropivacaine was administered. After withdrawing the needle, a
reinforced epidural catheter was placed 3 to 4 cm into the epidural space; 5 mL of 2% lidocaine was
then administered through the catheter, which was used to assess the effect of the anesthetic. The
upper sensory block level was adjusted to between the T6 and T7 levels. While monitoring any
changes in blood pressure, if necessary, the patient was repositioned onto a left lateral tilt of 30° and
6 to 12 mg of ephedrine and colloidal solutions for hemodynamic stabilization were intravenously
administered. Immediately after delivery of the fetus, the patients in the esketamine group received
0.25 mg/kg of esketamine and 2 mg of midazolam intravenously, which were diluted to a volume of
10 mL with 0.9% saline. An equal volume of normal saline and 2 mg of midazolam were injected for
patients in the control group. Then, a patient-controlled intravenous analgesia device was used to
administer a mixture of 100 μg of sufentanil, 50 mg of esketamine, and 0.25 mg of palonosetron
hydrochloride in 100 mL of saline. For the patients in the control group, only 100 μg of sufentanil and
0.25 mg of palonosetron hydrochloride in 100 mL of saline were given via a patient-controlled
intravenous analgesia pump. The pumps were set to a background infusion rate of 2 mL/h for 48
hours. A bolus dose of 2 mL was given and a lockout time of 10 minutes was used in both groups.

Outcome Measurements
The baseline data encompassed demographic characteristics, ASA classification, number of
deliveries, gestational duration, and pregestational comorbidities. Intraoperative data consisted of
duration of surgery, intraoperative bleeding, and vasopressor use. Neonatal data included newborn

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weight, Apgar scores assessed at 1 and 5 minutes after birth, umbilical arterial blood gas values, and
the neonatal intensive care unit admission rate.
Our primary outcome was the self-report of postpartum depressive symptoms, which were
assessed using the Edinburgh Postnatal Depression Scale (EPDS).32 This scale is a widely used
postpartum depression screening test.33 It consists of 10 items, each of which is scored on a 4-point
scale (range, 0-3). Total EPDS scores, which ranged from 0 to 30 points, were the sum of the scores
from each item. To determine the incidence of PPD, a cutoff of 10 or more points was defined as
positive for PPD according to the published recommendations.34-36 Furthermore, to evaluate
depressive symptoms among the 2 cohorts, we also analyzed the EPDS score as a continuous
variable. This involved comparing the change in this parameter between the 2 groups from baseline
(the day before surgery) to the end points. Our primary efficacy end point was set at postpartum day
7, and secondary efficacy end points were assessed at days 14, 28, and 42 after delivery. The scale
evaluation was performed by a trained interviewer (T.C.) who was blinded to the protocol details and
group allocation.
Our secondary outcomes included maternal pain intensity at rest as well as during movements
and were evaluated at 12, 24, 48, and 72 hours after surgery, in addition to postpartum pain
sensitivity on postpartum day 7. The assessment of pain intensity was conducted using the Numeric
Rating Scale (NRS), an 11-point scale ranging from 0 to 10, where 0 represents no pain and 10
represents the most severe pain. Furthermore, the recovery of postoperative gastrointestinal
function was estimated by recording the times to first flatus and defecation. We also monitored all
postoperative complications within 3 days of surgery, including nausea and vomiting, as well as
neuropsychiatric symptoms (such as nystagmus, dizziness, headaches, nightmares, and
hallucinations).

Statistical Analysis
The estimated sample size was calculated using PASS software, version 15.0 (NCSS), and 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 delivery. The expected effect size was
subsequently calculated to detect a 50% prevalence reduction in PPD after surgery, with a 2-sided
α = .05 and 90% power. The sample size was determined to be 128 patients. After loss to follow-up
and consent withdrawals, 150 patients were selected for inclusion in each arm of this trial.
Statistical analysis was performed using SPSS, version 26.0 (IBM SPSS) and R statistical
software, version 4.2.0 (R Project for Statistical Computing). The normality of variables was
determined using the Kolmogorov-Smirnov test. Normally distributed continuous data were
presented as mean (SD) values, and intergroup comparisons used either the unpaired 2-tailed t test
or 1-way analysis of variance. Nonnormally distributed variables were presented as median (IQR)
values, and intergroup comparisons were determined using the Mann-Whitney test. Percentages
were used to present the categorical variables; these were compared using either the χ2 test or the
Fisher exact test. The changes in EPDS scores at different time points between the groups were
analyzed with a mixed-effect model using repeated measures. This model included the baseline
EPDS score as the covariate, and treatment day, as well as day-by-treatment interactions, as fixed
effects. Random intercepts and unstructured covariance structures were used to model the within-
patient errors. An exploratory analysis was conducted to evaluate the disparities in our primary
outcomes within the predetermined subgroups. The stratification confounders were corrected by
using the Cochran-Mantel-Haenszel test. Primary analyses were performed by a modified intention-
to-treat analysis set, which included all randomly assigned participants who received treatment and
had at least 1 PPD screening assessment.37 A P < .05 was considered to be statistically significant. The
findings for secondary outcomes and subgroup analyses should be considered exploratory due to
the potential for type I errors resulting from multiple comparisons.

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Results
A total of 1225 pregnant women were assessed for eligibility between January 1, 2022 and January 1,
2023. Of these, 357 were eligible, and 150 each were enrolled and randomly assigned to the
esketamine and control groups. Among the enrolled patients, 2 women refused follow-up at
postpartum day 5, and 298 women were included in the modified intention-to-treat analysis (148 in
the esketamine group [median age, 31.0 years (IQR, 28.0-34.0 years)] and 150 in the control group
[median age, 31.0 years (IQR, 29.0-34.0 years)]; Figure 1). Baseline characteristics, intraoperative
data, and neonatal outcomes were well balanced between the 2 groups (Table). Most patients were
classified as ASA class II (esketamine group, 97.3% [144 of 148]; control group, 96.0% [144 of 150])
and multipara (esketamine group, 66.9% [99 of 148]; control group, 63.3% [95 of 150]). The mean
(SD) baseline EPDS scores were 4.2 (2.3) and 4.0 (2.2) in the esketamine and control groups,
respectively.

Efficacy Outcomes
At the primary end point, the prevalence of PPD was significantly lower for patients assigned to the
esketamine group (34 of 148 [23.0%]) compared with the control group (53 of 150 [35.3%]; odds
ratio, 0.55; 95% CI, 0.33-0.91; P = .02) (eTable 1 in Supplement 2). In addition, a significant decrease
was observed in the extent of EPDS score elevation from baseline at postpartum day 7 in the
esketamine group compared with the control group (least-squares means difference [LSMD] [SE],
−1.17 [0.44]; 95% CI, −2.04 to −0.31; effect size, 0.74; P = .008). However, there were no meaningful
differences between the groups in PPD incidence in the other efficacy end points (day 14: 46 of 148
[31.1%] vs 57 of 150 [38.0%]; P = .23; day 28: 53 of 148 [35.8%] vs 55 of 150 [36.7%]; P = .90; day 42:
50 of 148 [33.8%] vs 56 of 150 [37.3%]; P = .55) (eTable 1 in Supplement 2; Figure 2A). With respect
to the antidepression effects of esketamine subsiding over time, no significant differences were
noted in least-squares mean between-group differences at day 14 (LSMD [SE], 0.32 [0.49]; 95% CI,
−0.63 to 1.28; P = .51), day 28 (LSMD [SE], 0.24 [0.52]; 95% CI, −0.78 to 1.26; P = .64), and day 42
(LSMD [SE], –0.06 [0.49]; 95% CI, −1.03 to 0.91; P = .90) (eTable 2 in Supplement 2; Figure 2B).
For subgroups of more than 15 patients, all the primary end points analyzed demonstrated a
favorable advantage toward esketamine, except for patients with baseline EPDS scores lower than
the median (relative risk, 1.09; 95% CI, 1.01-1.18; P = .05; Figure 3). However, the NRS pain scores for

Figure 1. CONSORT Diagram Representing the Protocol for Patients in This Study

1225 Patients assessed for eligibility

868 Excluded
721 Emergency cesarean delivery
20 Twin or multiple pregnancies
10 Pregnancy-induced hypertension,
preeclampsia, or eclampsia
35 Severe obstetric complications (placenta previa,
placental abruption, and placenta accreta)
3 History of psychiatric illness
79 Preterm births

357 Eligible

57 Refused to participate

300 Randomized

150 Randomized to esketamine group 150 Randomized to control group

2 Lost to follow-up

148 Included in modified intention-to-treat analysis 150 Included in modified intention-to-treat analysis

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movements at 72 hours postoperatively were significantly lower in the esketamine group compared
with the control group (median, 3.0 [IQR, 2.0-3.0] vs 3.0 [IQR, 3.0-3.5]; median difference, 0 [95%
CI, 0-0]; P = .03), although there were no differences on movements observed at the other time
points (eTable 3 in Supplement 2). In addition, the NRS scores at rest were similar at all measured
time points (eTable 3 in Supplement 2; Figure 4). The mean times to first flatus and first defecation
were 1 day and 2 days, respectively, for both groups (eTable 4 in Supplement 2). The mean length of
hospital stay, which was 4 days, was also not different between the groups.

Safety Outcomes
During the 3 days after surgery, esketamine was generally well tolerated. There was no difference in
the incidence of nausea and vomiting between the 2 groups. In addition, mothers in the esketamine
group did not demonstrate any significant differences in mental symptoms, including dizziness,

Table. Baseline Characteristics and Intraoperative Variables of the Patients and Neonatal Outcomesa

Variable Esketamine group (n = 148) Control group (n = 150)

Baseline data
Age, median (IQR), y 31.0 (28.0-34.0) 31.0 (29.0-34.0)
ASA classification, No. (%)
I 4 (2.7) 6 (4.0)
II 144 (97.3) 144 (96.0)
III 0 0
Primipara, No. (%) 49 (33.1) 55 (36.7)
Cause of elective cesarean delivery, No. (%)
Malpresentation 46 (31.1) 49 (32.7)
Scarred uterus 93 (62.8) 91 (60.7)
Suspected fetal macrosomia 5 (3.4) 5 (3.3)
CDMR 4 (2.7) 5 (3.3)
Weight, mean (SD), kg 70.1 (8.8) 68.6 (9.4)
Height, mean (SD), cm 159.5 (5.3) 159.5 (5.9)
Prenatal BMI, mean (SD) 27.5 (3.1) 26.9 (3.3)
Duration of gestation, median (IQR), d 275.0 (270.0-279.0) 275.5 (271.0-279.0)
Comorbidities, No. (%)
GDM 28 (18.9) 28 (18.7)
Anemia 8 (5.4) 5 (3.3)
Hyperlipidemia 59 (39.9) 52 (34.7) Abbreviations: ASA, American Society of
Hypothyroidism 3 (2.0) 0 Anesthesiologists; BMI, body mass index (calculated as
Baseline EPDS score, mean (SD) 4.2 (2.3) 4.0 (2.2) weight in kilograms divided by height in meters
Intraoperative variables squared); CDMR, cesarean delivery on maternal
request; EPDS, Edinburgh Postnatal Depression Scale
Duration of surgery, mean (SD), min 113.8 (9.2) 111.2 (8.7)
(range, 0-30; a cutoff of ⱖ10 points was defined as a
Estimated blood loss, mean (SD), mL 366.8 (137.1) 371.5 (137.6) positive screening result for postpartum depression);
Dose of oxytocin, mean (SD), μg 95.0 (19.9) 96.0 (26.9) GDM, gestational diabetes mellitus; NICU, neonatal
Use of vasopressors, No. (%) 73 (49.3) 68 (45.3) intensive care unit.
Neonatal outcomes SI conversion factors: To convert glucose to millimoles
Birth weight, mean (SD), g 3359.5 (440.5) 3364.5 (416.3) per liter, multiply by 0.0555.
a
Apgar scores, median (IQR) Data presented as mean (SD) values were compared
using the unpaired, 2-tailed t test. Data presented
1 min 10.0 (10.0-10.0) 10.0 (10.0-10.0)
as median (IQR) values were compared using the
5 min 10.0 (10.0-10.0) 10.0 (10.0-10.0)
Mann-Whitney test. Data reported as the number
10 min 10.0 (10.0-10.0) 10.0 (10.0-10.0) (percentage) of patients were compared using either
Umbilical arterial blood gas values the χ2 test or the Fisher exact test.
pH, mean (SD) 7.1 (0.2) 7.1 (0.3) b
Needed by the pediatricians for further monitoring
Glucose, mean (SD), mg/dL 95.4 (25.2) 97.2 (30.6) and/or treatment of patients. Indications included
Lactate, mean (SD), mmol/L 6.2 (2.2) 6.5 (2.3) low Apgar scores (<7), neonatal acidosis, neonatal
hypoglycemia, neonatal malformation, and
Transferred to NICU, No. (%)b 13 (8.8) 15 (10.0)
premature delivery.

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headaches, somnolence, hallucinations, nightmares, and nystagmus, compared with the control
group (eTable 5 in Supplement 2).

Discussion
In this randomized clinical trial, we observed that intravenous administration of esketamine during
the perioperative period of elective cesarean delivery can provide significant and short-term
reduction in depressive symptoms during the initial postpartum period. However, the
aforementioned effects tended to diminish quickly with time.
Both preclinical and clinical studies have found that NMDA receptor abnormalities play a role in
several psychiatric diseases, especially during depression disorders, by altering glutamatergic
neurotransmission.16,38,39 Therefore, the roles of NMDA receptor antagonists in the prevention of
PPD have attracted increasing attention. A recent meta-analysis of clinically controlled trials of
intravenous administration of a subanesthetic dose of ketamine during the cesarean delivery period
in PPD reported that a dose of 0.5 mg/kg or more might help in reducing the prevalence of PPD
within 1 week after delivery, but had no beneficial effect after 4 weeks post partum.40 Esketamine, a
novel NMDA receptor antagonist, is generally considered to have more potent efficacy among
antidepressants.41 In the present study, we found that a single dose of 0.5 mg/kg of esketamine
during cesarean delivery, followed by continuous intravenous administration of low-dose
esketamine, 1.0 mg/h, for 48 hours can significantly reduce depressive symptoms associated with

Figure 2. Incidence of Positive Screening Results for Postpartum Depression (PPD) and Least-Square Mean (LSM)
Changes From the Baseline Edinburgh Postnatal Depression Scale (EPDS) Scores

A Incidence of positive screening results for PPD

100 No PPD PPD

P =.02

80
Incidence of PPD, %

60

40

20

0
Control Esketamine Control Esketamine Control Esketamine Control Esketamine

Postpartum week 1 Postpartum week 2 Postpartum week 4 Postpartum week 6

B LSM changes from the baseline EPDS scores

6 Control Esketamine
P =.008
LSM change from baseline EPDS score

4 A, Compared with the control group, the esketamine

group showed a significant decrease in the incidence
3 of positivity screening results for PPD at 7 days post
partum, with no significant differences observed at the
2 rest of the time points. B, Significant enhancements in
depressive symptoms, as evaluated by the EPDS
1 scores, were observed at 7 days post partum in the
esketamine group compared with the control group.
0 However, no statistically significant differences were
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 found between the 2 groups at any subsequent
Time, d time points.

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 JAMA Network Open | Anesthesiology Esketamine for Postpartum Depression Among Women Undergoing Cesarean Delivery

PPD within 7 days after delivery. However, this effect rapidly disappeared after withdrawal of the
esketamine treatment.
Our findings were similar to previous studies that reported that combined intravenous
administration of esketamine during the perioperative period could achieve a rapid and short-term
antidepressive effect in women undergoing cesarean delivery.42,43 However, some studies have
shown inconsistent results of the antidepressant effect of esketamine on patients undergoing

Figure 3. Forest Plot Assessing the Effects of Esketamine vs Control in the Predefined Subgroups

Patients, No./total No. Favors Favors

Subgroup Esketamine Control RR (95% CI) esketamine placebo
All patients 34/148 53/150 0.84 (0.72-0.97)
ASA grade
I 3/6 0/4 2.00 (0.90-4.45)
II 31/142 53/146 0.81 (0.70-0.95)
Age, y
<35 30/115 44/116 0.84 (0.70-1.00)
≥35 4/33 9/34 0.84 (0.66-1.06)
BMI
18.5-24.9 6/32 20/46 0.69 (0.51-0.94)
25.0-29.9 21/84 25/76 0.90 (0.73-1.09)
≥30.0 7/32 8/28 0.91 (0.68-1.23)
Baseline EPDS score
<Median 5/58 0/48 1.09 (1.01-1.18)
≥Median 29/90 53/102 0.71 (0.55-0.91)
Primigravida
Yes 14/47 24/55 0.80 (0.60-1.08)
No 20/101 29/95 0.85 (0.73-1.02)
GDM
Yes 7/28 13/28 0.71 (0.48-1.07)
No 27/120 40/122 0.87 (0.74-1.01)
Hyperlipidemia
Yes 14/52 23/59 0.84 (0.64-1.09)
No 20/96 30/91 0.85 (0.71-1.01) ASA indicates American Society of Anesthesiologists;
NICU admission BMI, body mass index (calculated as weight in
Yes 2/9 6/10 0.51 (0.22-1.19) kilograms divided by height in meters squared); EPDS,
No 32/139 47/140 0.86 (0.74-1.00) Edinburgh Postnatal Depression Scale; GDM,
0 0.5 1.0 1.5 2.0 2.5 gestational diabetes mellitus; NICU, neonatal intensive
RR (95% CI) care unit; and RR, relative risk.

Figure 4. Numeric Rating Scale (NRS) Pain Scores Between the 2 Study Groups

A NRS scores at rest B NRS scores on movement

8 8

Control Esketamine

6 6
P =.03
NRS score

NRS score

4 4

2 2

0 0

12 24 48 72 12 24 48 72
Time points of evaluation, h Time points of evaluation, h

The NRS is an 11-point scale, with 0 and 10 indicating no pain and the worst pain, plots show the median values, IQRs, and outlier values, with the circles and triangles
respectively. A, Comparison of the NRS value at rest between the 2 groups. B, indicating outliers for the control and esketamine groups, respectively.
Comparison of the NRS value on movement between the 2 groups. The box and whisker

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 JAMA Network Open | Anesthesiology Esketamine for Postpartum Depression Among Women Undergoing Cesarean Delivery

cesarean delivery. A recent randomized clinical trial involving 150 patients undergoing elective
cesarean delivery showed that perioperative use of esketamine might not help in reducing the
incidence of PPD among new mothers.44 Moreover, another study also found that a single
intravenous injection of low-dose esketamine was unable to reduce the prevalence of depression
after birth.45 These discrepancies may be due to differences in the dose, mode, and timing of
therapeutic administration.
Unexpectedly, our subgroup analysis discovered that patients with low baseline EPDS scores in
the control group had greater reduction in depressive symptoms than those in the esketamine group.
These results emphasize that esketamine may not be administered to all women in childbirth. A
preclinical study performed on male rhesus monkeys showed that a single administration of
intravenous esketamine could induce the release of dopamine in the striatum.46 In addition,
esketamine-mediated presynaptic dopamine release can induce some psychotomimetic and
dissociative effects in healthy individuals.47 A randomized crossover trial in healthy control
individuals also showed that ketamine could elicit depressive symptoms, specifically anhedonia.48
Collectively, these data suggest that caution is warranted with using esketamine in women during
cesarean delivery without prior evidence of prenatal depression, and the importance of a prenatal
mental status assessment for patients undergoing elective cesarean delivery is emphasized.
The pathophysiology of PPD is still unclear,49 and its onset and progression may be associated
with perinatal pain.50 Lim et al51 linked labor analgesia to PPD, and found that adequate perinatal
analgesia was an effective strategy for reducing its incidence. Moreover, a previous prospective
cohort study stratified parturient women who received labor analgesia based on their individual
preferences and found that the incidence of PPD increased significantly among women who received
unplanned emergency labor analgesia due to their inability to tolerate pain.52 This finding indicated
that perinatal pain may affect the postpartum mental state, thereby contributing to the development
of PPD. Whereas, we found, as in previous studies, that adjunctive esketamine administration during
the perioperative period could not effectively improve pain symptoms for up to 72 hours
postoperatively.23,44,53 Accordingly, it was presumed that the antidepressant effect of esketamine on
postpartum women might not be related to its analgesic property. However, further studies are
required to confirm the role of antihyperalgesics in the preventive effect of esketamine on PPD. In
addition, there were no notable neurologic symptoms observed during the postoperative period in
the esketamine group, in line with previous reports.31,44

Limitations
This study has some limitations. We evaluated the influence of esketamine only on PPD, and some
other potential confounding factors of PPD were not collected, including socioeconomic status,
emotional support from the spouse and extended family, stressful life events, and other negative
stressful events. These factors may have affected our results. Second, considering that the peak time
for PPD to manifest is approximately 42 days post partum,54 we set our follow-up end at this time
point. However, the long-term sustainability of any treatment response beyond this specified period
remains uncertain, and needs to be clarified. Third, this trial was conducted at 2 sites within a single
center, and our participants were limited to Chinese new mothers. Therefore, the findings may lack
generalizability to wider global populations and multicenter studies, involving different regions,
countries, and races and ethnicities, are needed.

Conclusions
This randomized clinical trial showed that an intravenous injection of esketamine during the
perioperative period of elective cesarean delivery was effective in improving depressive symptoms
in the early postpartum period, although the effect faded rapidly over time. We also found that this
antidepression effect may not be generalized to all patients because those with low baseline EPDS
scores performed better in the absence of esketamine. Moreover, the administration of esketamine

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 JAMA Network Open | Anesthesiology Esketamine for Postpartum Depression Among Women Undergoing Cesarean Delivery

to the patients demonstrated a satisfactory level of safety and tolerability. Overall, our study
demonstrated a potential beneficial effect of perioperative adjunctive esketamine administration on
the treatment of PPD in women undergoing elective cesarean deliveries.

ARTICLE INFORMATION
Accepted for Publication: January 12, 2024.
Published: March 6, 2024. doi:10.1001/jamanetworkopen.2024.0953
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 Chen Y
et al. JAMA Network Open.
Corresponding Author: Xiao-Dan Wu, MD, Department of Anesthesiology, Shengli Clinical Medical College of
Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian, China ([email protected]).
Author Affiliations: Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University,
Fuzhou, Fujian, China (Y. Chen, Guo, H. Wu, Tang, T. Chen, Xie, Qiu, X.-D. Wu); Department of Anesthesiology,
Fujian Provincial Hospital, Fuzhou, Fujian, China (Y. Chen, Guo, H. Wu, Tang, T. Chen, Xie, Qiu, X.-D. Wu);
Department of Metabolism, Digestion and Reproduction, Imperial College London, Chelsea and Westminster
Hospital, London, United Kingdom (Sooranna); Life Science and Clinical Research Center, Youjiang Medical
University for Nationalities, Baise, China (Sooranna); Department of Anesthesiology, Fujian Maternity and Child
Health Hospital, Fuzhou, Fujian, China (Zhang).
Author Contributions: Dr. X.-D. Wu had full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis. Dr Y. Chen, Mrs Guo, and Mr H. Wu are co–first authors
and contributed equally to the article.
Concept and design: Y. Chen, H. Wu, Tang, Xie, X.-D. Wu.
Acquisition, analysis, or interpretation of data: Y. Chen, Guo, Sooranna, Zhang, T. Chen, Xie, Qiu, X.-D. Wu.
Drafting of the manuscript: Y. Chen, Xie, Qiu.
Critical review of the manuscript for important intellectual content: Y. Chen, Guo, H. Wu, Tang, Sooranna, Zhang, T.
Chen, Xie, X.-D Wu.
Statistical analysis: Y. Chen, H. Wu, Tang, Sooranna, Zhang, Xie.
Obtained funding: Xie.
Administrative, technical, or material support: T. Chen, Xie.
Supervision: Guo, Xie, Qiu, X.-D. Wu.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by grant 82271238 from the National Natural Science Foundation of
China (Dr X.-D. Wu); grant 2020CXA009 from the Fujian Provincial Health Technology Project (Dr X.-D. Wu); grant
2023J011167 from the Natural Science Foundation of Fujian Province (Dr Y. Chen); and grant 2020QH1155 from
the Startup Fund for Scientific Research, Fujian Medical University (Dr Y. Chen).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.

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SUPPLEMENT 1.
Trial Protocol and Statistical Analysis Plan

SUPPLEMENT 2.
eTable 1. The Prevalence of Women With a Positive PPD Screening (EPDS Score ⱖ10) Between the Two Groups
eTable 2. The Changes in EPDS Scores From Baseline Values to the End-Points of the Trial Period Between the Two
Groups
eTable 3. The Numeric Rating Scale Pain Scores Between the Two Groups at Different Time Points
eTable 4. Postoperative Recovery Outcomes Between the Two Groups
eTable 5. Adverse Events in the Study Participants
eFigure. Trial Intervention Diagram

SUPPLEMENT 3.
Data Sharing Statement

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