Is Ketamine or Esketamine an Option for the Treatment of Postpartum Depression?

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. More recently, we have learned that ketamine and esketamine administered at sub-anestetic doses have rapid antidepressant and anti-suicidal effects. 

Several studies have explored the use of ketamine and ketamine for the treatment of PPD. Most of these studies have not tested ketamine or esketamine as an antidepressant specifically for the treatment of women with postpartum depression; instead these studies have measured depressive symptoms in women receiving ketamine or esketamine as an anesthetic agent administered during or after a Cesarean section.

In a highly publicized study published in the BMJ last month, researchers investigated the efficacy of a single low dose of esketamine administered after childbirth to mothers with depressive symptoms during pregnancy. In this randomized controlled trial, 364 women with an Edinburgh Postnatal Depression Scale (EPDS) score of 10 or greater at the time of delivery, but no history of depression prior to pregnancy, were randomly assigned to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth. Assessments were conducted 18-30 hours after childbirth, at 1 week postpartum, and again at 6 weeks.

The results were fairly remarkable. EPDS scores were lower in the esketamine group at 1 week (median difference ?3) and at 6 weeks (median difference ?3). At 6 weeks postpartum, PPD was observed in 6.7% of participants in the esketamine group compared to 25.4% of those in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P < 0.001). 

Not surprisingly, women in the esketamine group reported more side effects than those receiving placebo (45.1% vs. 22.0%), including sedation (5.5% vs. 0.5%), dizziness (26.4% vs. 9.3%), double vision (4.9% vs. 0%), and hallucinations or acute anxiety, distress, or terror similar to nightmares (3.3% vs. 0%). About 10% of participants in the esketamine group required temporary interruption of the infusion due to dizziness. Side effects were transient and did not require any medical intervention.

In summary, this study demonstrated that a single dose of esketamine administered intravenously to women with mild depressive symptoms at delivery was associated with reduced depressive symptoms at week 1 postpartum. In addition, those who received esketamine had a 75% lower risk of experiencing significant depressive symptoms at 6 weeks postpartum. 

Who is a Good Candidate for Ketamine?

Thus far, most studies exploring the use of ketamine and esketamine for postpartum depression have not been traditional treatment studies, where a particular medication or placebo is administered to women with postpartum depression. Instead, ketamine or esketamine is administered to women undergoing cesarean section, and depressive symptoms are assessed during the postpartum period. 

A recent meta-analysis (Wen et al, 2024) analyzed seven studies and a total of 669 patients treated with esketamine and 619 comparisons. While esketamine was not used to treat depressive symptoms, the meta-analysis demonstrated that women receiving esketamine had lower levels of postpartum depressive symptoms, and the overall incidence of PPD was reduced in those receiving esketamine after a cesarean section. Even at 42 days postpartum, the incidence of PPD was still significantly lower in the esketamine group. Similar results have been observed in individuals receiving ketamine after Cesarean section (Li et al, 2024). So based on these findings, it appears that ketamine and esketamine may prevent or reduce risk for PPD, but these studies do not tell us whether esketamine and ketamine would be effective for the treatment of PPD. 

While the results of the BMJ study are impressive, it included a very well-defined subgroup of women, specifically women with no history of depression prior to pregnancy who developed mild depressive symptoms during pregnancy (with a median EPDS score of 10). In clinical practice, women with mild depressive symptoms and no history of depression prior to pregnancy would be referred for psychotherapy and monitoring. Although there are benefits to esketamine in terms of postpartum pain relief, would women with mild symptoms elect to receive an intravenous infusion of esketamine at the time of delivery? 

Further studies are needed to determine whether ketamine and esketamine are effective for the treatment of postpartum depression and, if useful in this setting, which women are most likely to benefit from this treatment. 

Ruta Nonacs, MD PhD

References

Wang S, et al. Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ 2024; 385:e078218.

Wen Y, Mao M, Wang X, Xu C, Shi X, Li P, Tian Z, Jiang M, Yuan H, Feng S. Efficacy and safety of perioperative application of esketamine on postpartum depression: A meta-analysis of randomized controlled studies. Psychiatry Res. 2024 Mar; 333:115765. 

Li S, Zhou W, Li P, Lin R. Effects of ketamine and esketamine on preventing postpartum depression after cesarean delivery: A meta-analysis. J Affect Disord. 2024 Apr 15;351:720-728.