Esketamine and the Prevention of Postpartum Depression: A Promising Step Forward in Maternal Mental Health

Esketamine and the Prevention of Postpartum Depression: A Promising Step Forward in Maternal Mental Health

Postpartum depression (PPD) remains one of the most underrecognized and undertreated complications following childbirth. Affecting up to 1 in 5 women globally, its impact extends far beyond the individual—disrupting maternal-infant bonding, family dynamics, and long-term emotional development in children. At South Chesapeake Psychiatry, we believe in pursuing not only the most effective treatments for our clients but also advocating for the best possible care for all people—because we all have someone we love, and we all want the best for them.

A growing body of research suggests that esketamine, the S-enantiomer of ketamine, may offer a significant protective effect against the development of postpartum depression—especially in women undergoing cesarean section. While ketamine has been studied for decades for its antidepressant and anesthetic properties, esketamine is proving to be a more targeted, safer, and more potent option.

Clinical Evidence Supporting Esketamine

In a pragmatic randomized controlled trial published in JAMA Network Open (Ren et al., 2025), 308 women undergoing cesarean delivery were randomized to receive either esketamine or placebo intraoperatively. The results were compelling: only 10.4% of those who received esketamine screened positive for postpartum depression at 6 weeks, compared to 19.5% in the control group. This nearly 50% reduction in PPD risk (Relative Risk: 0.53; 95% CI, 0.30–0.93; p = .02) occurred after just a single 0.25 mg/kg infusion given during surgery.

This study is especially notable because it was conducted in a real-world clinical setting, enhancing its relevance for everyday practice (Ren et al., 2025).

Meta-Analytic Evidence: Esketamine vs. Ketamine

While both ketamine and esketamine have shown antidepressant potential, esketamine appears to outperform ketamine in the prevention of postpartum depression. A 2024 meta-analysis of 22 randomized controlled trials (n = 3,463) published in PLOS ONE found that esketamine provided a significantly greater reduction in PPD symptoms at both 1-week and 4–6-week postpartum intervals, particularly when administered postoperatively via patient-controlled analgesia (Hung et al., 2024).

Subgroup analyses showed esketamine was more effective than ketamine at reducing depressive symptoms at 4–6 weeks (Risk Ratio: 0.39 vs. 0.73; p = .004), with fewer side effects such as hallucinations and postoperative nausea (Hung et al., 2024).

Mechanism and Safety

Esketamine acts primarily as an NMDA receptor antagonist, but its efficacy may also involve upregulation of AMPA receptors and increased brain-derived neurotrophic factor (BDNF), contributing to synaptic repair and mood stabilization. Its higher receptor affinity (compared to racemic ketamine) likely accounts for its greater potency and faster onset.

Concerns about side effects are valid, but data consistently show that adverse events are mild, transient, and resolve quickly. The most commonly reported effects include temporary dizziness or dreamlike sensations—none of which impacted neonatal outcomes or required clinical intervention (Li et al., 2024).

Looking Ahead

At South Chesapeake Psychiatry, we remain committed to staying ahead of the curve when it comes to innovative treatments. Whether it’s the flexible use of intranasal esketamine (Spravato) for treatment-resistant depression or exploring the evolving role of psychedelics in mental health, we continuously evaluate emerging research—not only for our own clients, but for the betterment of care across the mental health field.

Because when it comes to protecting new mothers, we’re not just talking about patients—we’re talking about sisters, daughters, partners, and friends. This is personal. And if one safe, low dose esketamine infusion can cut the risk of postpartum depression in half, then it’s time we start talking about making this standard care, not just innovative care.

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References

Hung, K.-C., Kao, C.-L., Lai, Y.-C., Chen, J.-Y., Lin, C.-H., Ko, C.-C., Lin, C.-M., & Chen, I.-W. (2024). Perioperative administration of sub-anesthetic ketamine/esketamine for preventing postpartum depression symptoms: A trial sequential meta-analysis. PLOS ONE, 19(11), e0310751. https://doi.org/10.1371/journal.pone.0310751

Li, S., Zhou, W., Li, P., & Lin, R. (2024). Effects of ketamine and esketamine on preventing postpartum depression after cesarean delivery: A meta-analysis. Journal of Affective Disorders, 351, 720–728. https://doi.org/10.1016/j.jad.2024.01.202

Ren, L., Zhang, T., Zou, B., Su, X., Tao, Y., Yang, J., Lv, F., Li, P., Peng, F., & Wu, G. (2025). Intraoperative esketamine and postpartum depression among women with cesarean delivery: A randomized clinical trial. JAMA Network Open, 8(2), e2459331. https://doi.org/10.1001/jamanetworkopen.2024.59331

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