In This article

• Esketamine, an NMDA receptor antagonist, has rapid antidepressant effects at sub-anesthetic doses.
• Meta-analysis shows lower rates of PPD one week after delivery with administration of esketamine at childbirth.
• Benefits may include improved mood, anxiety reduction, pain relief, and improved sleep.
• Data regarding the long-term antidepressant effects of esketamine are mixed, with some studies showing no benefit after 4-6 weeks.
• More research is needed to better understand the role of esketamine in treating, not just preventing, PPD.

Approved by the FDA as an anesthetic in 1970, ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been used for decades in anesthesia and pain management. More recently, research has demonstrated that ketamine and esketamine, the more potent S-enantiomer of ketamine, can produce rapid antidepressant and anti-suicidal effects at sub-anesthetic doses.

Several studies have examined ketamine and esketamine use in postpartum women. While these studies were not specifically designed to test these agents as antidepressants, they assessed depressive symptoms in women receiving ketamine or esketamine as anesthetic agents during or after Cesarean section.

Meta-Analysis: Prevention of Postpartum Depression

In the most recent meta-analysis (Li et al, 2025), researchers pooled data from ten studies (one retrospective and nine randomized controlled trials), including 1,975 participants. In all studies, esketamine was administered either during Cesarean section as an injection or as a continuous infusion for up to 48 hours afterward, with doses ranging from 0.1 mg/kg to 2 mg/kg.

At one week postpartum, the incidence of postpartum depression (PPD) was significantly lower in the esketamine group compared to the control group (RR = 0.49, 95% CI: 0.30–0.79, P = 0.004). Edinburgh Postnatal Depression Scale (EPDS) scores were also lower in the esketamine group (95% CI: -1.67 to -0.52, P < 0.0005). Subgroup analyses indicated that women receiving intravenous esketamine during C-section followed by an esketamine-infused analgesic pump experienced the greatest reduction in depressive symptoms.

By 4–6 weeks postpartum, there were no significant differences in PPD risk or depression severity between groups; however, several individual studies reported that the antidepressant benefits of esketamine persisted beyond 6 weeks.

Randomized Controlled Trial in Women with Late-Pregnancy Depressive Symptoms

While most studies have focused on women without depressive symptoms at delivery, a recent double-blind, randomized, placebo-controlled trial investigated esketamine use in women who scored >10 on the EPDS in late pregnancy and underwent C-section. Women with prior psychiatric disorders were excluded.

A total of 174 participants were randomized to receive either esketamine (0.25 mg/kg) or placebo (normal saline infusion). Postoperative patient-controlled intravenous analgesia (PCIA) included 100 ug sufentanil for both groups, with an additional 1.25 mg/kg esketamine for women in the esketamine arm.

At 3 days postpartum:

• Depressive symptoms (EPDS scores) were lower in the esketamine group.
• Anxiety symptoms (EPDS-3A scores) were lower in the esketamine group.
• Rates of PPD (EPDS >13) were lower in the esketamine group (12.9%) compared to controls (26.2%).

At 6 weeks postpartum:

• PPD (EPDS >13) occurred less frequently in the esketamine group (5.9%) than in controls (17.9%).
• Sleep duration was longer in the esketamine group.

This trial showed that perioperative esketamine treatment significantly reduced the prevalence of PPD among women with antenatal depressive symptoms. Esketamine also improved early postpartum outcomes, including reduced depression and anxiety, better pain control, and improved sleep—likely reflecting its combined antidepressant and analgesic properties.

Next Steps

While multiple studies suggest that ketamine and esketamine administered around delivery may lower the risk of PPD, several questions remain.

First, how long do the antidepressant effects last? Most studies have been short-term, typically lasting less than 6 weeks. In the meta-analysis by Li and colleagues, rates of PPD in esketamine and placebo groups were similar at 4–6 weeks postpartum, although individual studies did note effects persisting beyond 6 weeks. Further research is needed to track depressive symptom trajectories over time.

Another key question is whether esketamine can treat postpartum depression, not just prevent it. Most studies have included women without depressive symptoms at delivery. The trial by Xue-Song et al evaluated women with mild depressive symptoms late in pregnancy and found significantly lower PPD rates at 6 weeks. However, in a study with this design, it remains unclear whether esketamine prevented the worsening of depressive symptoms or actively treated depression.

In addition, many of the studies have excluded women with previous histories of psychiatric illness.  We therefore do not know whether ketamine would be effective for those patients with recurrent depressive disorders.

The current literature suggests that ketamine and esketamine may be a promising intervention; however, we need more information on how these agents can be utilized in this setting.  Ideally, we would like to see future studies that administer ketamine or esketamine to patients with clinically significant depressive symptoms (with and without histories of depression prior to pregnancy) and to assess depressive symptoms over a longer period of time.

—Ruta Nonacs, MD PhD