Using Predictive Modeling to Examine IV Ketamine and Esketamine for the Prevention of Postpartum Depression

There has been considerable interest over the last decade in the use of ketamine as an antidepressant. While ketamine is certainly not a first line treatment for depression, researchers have questioned whether ketamine administered at the time of delivery could be used to either treat or prevent postpartum depressive symptoms. Most of these studies come from China, where ketamine is often used for perioperative pain management after Cesarean section. The studies have yielded mixed results; however, a recent study from Yang and colleagues (2022) suggests that ketamine may have much greater effects in women at high risk for PPD, as compared to women at lower risk. This study used mathematical modeling to identify five variables that predicted PPD in this population: stress during pregnancy, mood during pregnancy, domestic violence, prenatal self-harm ideation and elevated prenatal EPDS score.

In another study, Li and colleagues use logistic regression and machine learning algorithms to predict the effectiveness of IV ketamine or esketamine administered during cesarean section for the prevention of PPD. The researchers analyzed data from two randomized controlled trials, and focused on 12 prenatal features in 507 women who received intravenous ketamine or esketamine at the time of cesarean section.

Several different prediction models were tested using prenatal features and ketamine dosage regimen as predictors. They observed the following:

  • Women with prenatal EPDS scores of 10 or greater or thoughts of self-injury were less likely to benefit from ketamine
  • A higher dose of esketamine (0.25 mg/kg loading dose + 2 mg/kg PCIA) was the most effective dosage regimen
  • In general, esketamine was more effective and had fewer side effects than ketamine 

What we can glean from these studies is that while IV ketamine or esketamine may not be a suitable intervention for all women, some women may benefit. The studies from Yang and colleagues indicate that women at high risk for PPD based on certain risk factors (higher prenatal EPDS scores, prenatal thoughts of self-injury, domestic violence, and stress during pregnancy) are more likely to experience a reduction in risk for PPD than women at low risk.

The research of Li and colleagues builds on these earlier findings, noting that women with higher prenatal EPDS scores and self-harm ideation are less likely to benefit from ketamine.  They recommend that women with these risk factors may respond better to a higher dose of esketamine. In general, they note that esketamine is more effective and better tolerated than ketamine.

While there may be understandable resistance to using ketamine, one could imagine that this might be an attractive intervention for women at high risk for PPD, for example women with a history of severe PPD after a previous pregnancy. Intravenous ketamine could easily be administered at the time of delivery; however, further studies are necessary to better understand who is most likely to benefit from this intervention.  

Ruta Nonacs, MD PhD


Li Q, Gao K, Yang S, Yang S, Xu S, Feng Y, Bai Z, Ping A, Luo S, Li L, Wang L, Shi G, Duan K, Wang S. Predicting efficacy of sub-anesthetic ketamine/esketamine i.v. dose during course of cesarean section for PPD prevention, utilizing traditional logistic regression and machine learning models. J Affect Disord. 2023 Jul 13; 339:264-270.

Yang ST, Yang SQ, Duan KM, Tang YZ, Ping AQ, Bai ZH, Gao K, Shen Y, Chen MH, Yu RL, Wang SY. The development and application of a prediction model for postpartum depression: optimizing risk assessment and prevention in the clinic. J Affect Disord. 2022 Jan 1;  296:434-442.

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