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 given in subanesthetic doses have rapid antidepressant and anti-suicidal effects.
Several studies have investigated the use of ketamine and ketamine to treat PPD. Most of these studies have not tested ketamine or esketamine as an antidepressant specifically for the treatment of women with postpartum depression. In contrast, these studies have measured depressive symptoms in women receiving ketamine or esketamine as an anesthetic agent given during or after cesarean delivery.
In a highly publicized study was published in the BMJ Last month, researchers investigated the effectiveness of a single low dose of esketamine given postpartum to mothers with depressive symptoms during pregnancy. In this randomized controlled trial, 364 women with an Edinburgh Postnatal Depression Score (EPDS) score of 10 or greater at the time of delivery, but no history of depression before pregnancy, were randomized to receive either 0.2 mg/kg esketamine or placebo is injected intravenously over 40 minutes after delivery. Assessments were performed 18–30 hours postpartum, 1 week postpartum, and again at 6 weeks.
The results were quite remarkable. EPDS scores were lower in the esketamine group at 1 week (median difference 03) and at 6 weeks (median difference 03). At 6 weeks postpartum, PPD occurred in 6.7% of participants in the esketamine group compared with 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 adverse events 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 nightmare-like terror (3.3% vs. 0%). Approximately 10% of participants in the esketamine group required temporary interruption of the infusion due to dizziness. Adverse effects were transient and did not require medical intervention.
In summary, this study showed that a single dose of esketamine administered intravenously to women with mild postpartum depressive symptoms was associated with reduced depressive symptoms at week 1 postpartum. Additionally, those who received esketamine had a 75% lower risk of experiencing major depressive symptoms at 6 weeks postpartum.
Who is a good candidate for ketamine?
So far, most studies investigating the use of ketamine and esketamine for postpartum depression have not been traditional treatment studies, where a specific drug or placebo is given to women with postpartum depression. In contrast, ketamine or esketamine is administered to women undergoing caesarean section and depressive symptoms are assessed in 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 showed that women who received esketamine had lower levels of postpartum depressive symptoms and the overall incidence of PPD was reduced in those who received esketamine after caesarean section. Even at 42 days postpartum, the incidence of PPD was still significantly lower in the esketamine group. Similar results have been observed in subjects receiving ketamine after caesarean section (Li et al, 2024). So based on these findings, it seems that ketamine and esketamine may prevent or reduce the risk for PPD, but these studies don’t tell us whether esketamine and ketamine would be effective for treating PPD.
While the results of the BMJ study are impressive, they included a very well-defined subgroup of women, specifically women with no history of depression before 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 before pregnancy will be referred for psychotherapy and follow-up. Although there are benefits to esketamine in terms of postpartum pain relief, would women with mild symptoms choose 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
bibliographical references
Wang S, et al. Efficacy of a single low-dose postpartum esketamine for mothers with antenatal depressive symptoms: a randomized 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 esketamine in postpartum depression: A meta-analysis of randomized controlled trials. Psychiatry Res. March 2024? 333:115765.
Li S, Zhou W, Li P, Lin R. Effects of ketamine and esketamine in the prevention of postpartum depression after caesarean section: A meta-analysis. J Affect Disord. 2024 Apr 15;351:720-728.
