Table 1.

Representative Randomized Trials of Esketamine for Postpartum Depressive Outcomes

Study	Design and Population	Sample Size	Esketamine Regimen	Outcome Definition and Follow-Up	Main Findings	Main Limitations	Reference
Han et al, 2022	Single-center RCT; women undergoing cesarean delivery with postoperative PCIA	375 randomized; 275 analyzed	S-ketamine 0.5 mg/kg added to sufentanil-based PCIA for 48 h, corresponding to approximately 0.01 mg/kg/h	EPDS-defined screen-positive postpartum depressive symptoms on postpartum days 3, 14, and 28	Screen-positive depressive symptoms were less frequent on day 3 (8.2% vs 17.6%) and day 14 (9.8% vs 24.2%), but not on day 28 (17.2% vs 19.0%); early postoperative pain was also reduced.	Single center; substantial post-randomization exclusion; screening rather than diagnostic outcome; effect was not sustained to day 28.	[44]
Liu et al, 2023	Randomized trial; elective cesarean delivery	150 randomized; 123 analyzed	Intravenous esketamine 0.25 mg/kg during surgery followed by esketamine 1.25 mg/kg in PCIA for 48 h	EPDS-defined screen-positive postpartum depressive symptoms at 3 days, 42 days, 3 months, and 6 months postpartum	No significant reduction in screen-positive depressive symptoms or postpartum anxiety was observed at the assessed time points; cumulative sufentanil consumption was reduced.	Small analyzed sample; loss to follow-up; screening rather than psychiatric diagnosis.	[60]
Ling et al, 2023	Single-center, randomized, double-blind trial; women receiving epidural labor analgesia	120 enrolled	Single intravenous dose of 0.2 mg/kg after delivery	EPDS-defined screen-positive postpartum depressive symptoms at 1 and 6 weeks postpartum	Screen-positive depressive symptoms were less frequent at 1 week (3.4% vs 15.3%) and 6 weeks (5.2% vs 18.6%); exploratory stress- and inflammation-related biomarkers also changed.	Single center; screening outcome; biomarker analyses were exploratory; limited generalizability.	[62]
Chen et al, 2024	Single-center, double-blind, placebo-controlled RCT; elective cesarean delivery	298	Intravenous 0.25 mg/kg immediately after fetal delivery plus 50 mg in PCIA for 48 h	EPDS-defined screen-positive postpartum depressive symptoms on day 7, with additional assessments on days 14, 28, and 42	Screen-positive symptoms were less frequent on day 7 (23.0% vs 35.3%; OR 0.55, 95% CI 0.33–0.91), but not on days 14, 28, or 42.	Predominantly low baseline EPDS scores; composite intraoperative-plus-PCIA regimen; benefit was transient.	[7]
Wang et al, 2024	Five-center, double-blind RCT; women with antenatal EPDS ≥10 undergoing childbirth	364 randomized; 361 included in primary analysis	Single intravenous infusion of 0.2 mg/kg over 40 min after childbirth	Major depressive episode diagnosed by structured interview at 42 days postpartum	Major depressive episodes occurred in 6.7% versus 25.4% of participants (RR 0.26, 95% CI 0.14–0.48); EPDS scores were also lower at 7 and 42 days.	Follow-up limited to 42 days; most participants had mild antenatal symptoms; women with prepregnancy mood disorders were excluded.	[9]
Ren et al, 2025	Single-center randomized pragmatic trial; cesarean delivery	308	Intravenous infusion of 0.25 mg/kg over 20 min during surgery	EPDS-defined screen-positive postpartum depressive symptoms at 6 weeks postpartum	Screen-positive symptoms were less frequent at 6 weeks (10.4% vs 19.5%; RR 0.53, 95% CI 0.30–0.93), but not at 1 week; analgesic-pump activations were reduced.	Screening rather than diagnostic outcome; single center; transient neuropsychiatric events were more frequent immediately after treatment; same institution and overlapping investigator group as Yang et al,63 limiting independence of replication.	[8]
Chu et al, 2026	Three-center, double-blind RCT; primiparae undergoing elective cesarean delivery with antenatal EPDS <10	322 in modified intention-to-treat analysis	Intravenous 0.25 mg/kg followed by 80 mg in PCIA for 24 h	EPDS-defined cumulative screen-positive postpartum depressive symptoms within 3 months postpartum	Cumulative incidence was lower (11.59% vs 20.89%; adjusted RR 0.57, 95% CI 0.35–0.94), driven mainly by the day-7 difference; no significant differences were observed at 1, 2, or 3 months individually.	Composite regimen and cumulative endpoint; benefit was not sustained at individual later assessments; limited to low-risk primiparae.	[64]
Gao et al, 2026	Single-center, three-arm, open-label randomized study; low-risk women undergoing spontaneous vaginal delivery	299 analyzed	Esketamine 0.5 mg/kg plus labor analgesia versus labor analgesia alone or no labor analgesia	EPDS score at 42 days; longitudinal EPDS and VAS assessments	No significant between-group differences in EPDS or VAS outcomes; screen-positive depressive symptoms occurred in 4.0%, 2.0%, and 6.1% of the three groups, respectively.	Open-label and per-protocol design; retrospective registration; very low baseline event rate and probable floor effect.	[52]
Yang et al, 2026	Randomized, double-blind, three-arm superiority trial; cesarean delivery without antenatal depression	503 randomized; 459 analyzed	Intravenous bolus 0.25 mg/kg versus infusion of the same total dose versus saline	EPDS-defined screen-positive postpartum depressive symptoms at 6 weeks postpartum	The bolus arm had fewer screen-positive cases than control (9.15% vs 19.33%; RR 0.47, 95% CI 0.25–0.91). The equivalent-dose infusion arm did not show a significant reduction versus control, and bolus did not differ significantly from infusion (9.15% vs 11.54%). No group differences were observed at 1 or 4 weeks.	Screening endpoint; loss to follow-up; bolus-versus-infusion comparison was not significant; same institution and overlapping investigator group as Ren et al,8 so the two trials should not be regarded as fully independent replication.	[63]

Abbreviations: CI, confidence interval; EPDS, Edinburgh Postnatal Depression Scale; OR, odds ratio; PCIA, patient-controlled intravenous analgesia; RCT, randomized controlled trial; RR, relative risk; VAS, visual analogue scale.