Ketamine and Perinatal Mental Health: Problems and Potentials

The recent “Canadian Network for Mood and Anxiety Treatments (CANMAT) 2024 Clinical Practice Guideline for the Management of Perinatal Mood, Anxiety, and Related Disorders” provides pharmacotherapy recommendations for perinatal and postpartum depression (PPD), considering both drug efficacy and its safety profile in pregnancy and lactation. ¹ Ketamine, currently considered by other CANMAT guidelines to be a second-line adjunctive treatment for depression ² and third line for bipolar depression ³ is noted to have insufficient data for perinatal/postpartum use, and guidelines caution that “likely patients should not use it during pregnancy until further safety data are available.”

Though widespread use of a medication with insufficient data would be problematic, for pregnant or post-partum women with severe or difficult-to-treat depression (DTD), who have exhausted other treatment options, ketamine may offer potential, particularly if it is already being used with benefit prior to pregnancy. A recent case report ⁴ describes a woman with DTD who received ketamine and esketamine with good response, but was then required to discontinue treatment when she became aware she was pregnant. Despite other medication adjustments, the woman experienced a depressive relapse with intermittent suicidal ideation and remained moderately to severely depressed throughout the pregnancy.

This report highlights the patient's frustration with the lack of opportunity to make her own informed choice and states that her preference would have been to accept unknown potential harms and continue treatment to maintain mood stability and reduce suicidality during pregnancy. While the Perinatal guideline highlights that ketamine use in pregnancy may be problematic due to insufficient data, it also notes that if symptoms are well controlled, switching medications is not usually advisable. ¹ Furthermore, if the medication in question carries risks to the fetus but changing it to a safer alternative brings substantial risk of psychiatric instability, risks and benefits of continuing it should be fully discussed between patient and clinician. Guidelines note this to be the case even for valproate, with its known neurobehavioral and teratogenic risks. ¹ Similarly, it could be argued that in the case above, where other medications had not been effective, the patient may have been given option to continue treatment with informed consent, particularly if the maintenance treatments were infrequent.

In this case, continued ketamine treatment would have likely benefitted the patient. But what risks to the fetus must be considered? Human data are limited. This woman's pregnancy was complicated by pre-eclampsia and a brief neonatal intensive care admission for hypoglycemia, but there were no congenital defects, and developmental milestones were met in the first year. Motor and language delays were noted in the second year of life, and authors indicate that role of first-trimester ketamine/esketamine exposure was unclear, as PPD itself has been associated with developmental delays in the first 24 months. This child was also exposed to several other medications during pregnancy. ⁴

Safety data from animal studies is both concerning and inconsistent. Authors of the above case study make note of concerning animal studies that typically employ high-dose ketamine (20–200 mg/kg, compared to 0.5–1 mg/kg for antidepressant use), ⁴ but other authors have reviewed lower, subanesthetic dose animal studies that remain concerning. ⁵ Though no teratogenicity was reported, one review describes adverse neurobehavioral outcomes if ketamine is given during critical periods of brain development, even without repeated dosing. Heterogenous studies in terms of frequency/timing of exposure in the perinatal period are difficult to interpret. Clear characterization of potential deficits has not been fully clarified, nor has level of risk in different phases of development.

What about neonatal ketamine exposure and post-partum use? In consideration of breastfeeding, a relative infant dose (RID) of less than 10% of a drug is generally considered of minimal risk. ¹ The RID of both ketamine and norketamine, one of its metabolites, is reported in several small studies to be less than 1%. ⁶ In one report, breast milk levels of ketamine peaked at 1 h after initiation of intravenous infusion, then declined over 24 h. ⁶ Considering both ketamine's poor oral bioavailability and the noted low RID, ketamine exposure for breastfed infants is likely to be extremely low. ⁶ Though data is limited, one drug and lactation database ⁷ suggests that ketamine use in breastfeeding mothers may not affect neonates. It advises that breastfed infants be monitored closely for sedation, poor feeding, and poor weight gain ⁷ This positions the decision to breastfeed on ketamine as a case-by-case, risk/benefit consideration, rather than an absolute contraindication.

Though this approach is not typically recommended with other medications, ¹ the infrequent dosing schedule of ketamine may support a “pump and dump” approach on ketamine days. In an acute phase, ketamine treatment is typically administered twice weekly, then maintenance treatment typically decreases in frequency to weekly, every 2 weeks, or sometimes less. Though breastfeeding risks on ketamine appear low, with infrequent administration, a “pump and dump” approach, though not absolutely necessary, may be both feasible and preferred by some women until further safety data accumulates.

Identifying women at high risk for PPD is important, and the guideline reports that sertraline was effective in decreasing PPD in a small study of euthymic women with a history of depression. ¹ Interestingly, data looking at ketamine or esketamine for PPD prevention is accumulating. Since October 2023 (the end date for the perinatal guideline literature search), six meta-analyses (e.g. Li et al. ⁸ ) have reported that administration of esketamine or ketamine during or post-caesarian section had preventative effects against PPD. Used in this way, ketamine or esketamine may be delivered with minimal or no exposure to the baby to the drug.

Most of the studies in these meta-analyses were done in women with no history of depression, and sample sizes tended to be small. Dosing was heterogenous and did not always reflect evidence-based antidepressant doses. Perhaps more promising is a recent randomnized controlled trial that specifically included women with mild perinatal depression (n = 352) and found that a single administration of esketamine following delivery significantly reduced the occurrence of PPD at day 42 post-delivery (6.7% in esketamine group vs. 25% control group). ⁹

Similar potential in vaginal deliveries could also be considered, particularly for women who have had a previous positive ketamine response and are familiar with the common transient side effects. Dissociation, nausea, headache, and blood pressure elevation generally abate within a few hours, so would have minimal impact on mother-baby interactions or care of the neonate. Ketamine treatment could be timed after the mother has some initial bonding time with her new baby, but prior to milk production. While data currently do not support this practice, a preventative approach in women with a history of debilitating PPD or DTD presents potential.

Further research is needed, including animal models reflective of antidepressant dosing to better determine potential harms if used during pregnancy or during lactation. High-quality clinical research for use of ketamine during pregnancy seems ethically prohibitive due to existing concerns in animal data, but administration following delivery is amenable to future clinical trials. Notably, case reports and case series have informed and shaped the use of electroconvulsive therapy in pregnancy, ¹ and could do so similarly for ketamine. Intentional or unintentional exposures to ketamine or esketamine during pregnancy should be collected in pregnancy databases and/or reported in the literature along with neonatal outcomes. Clinical decision making for pregnant patients with DTD should present risks and unknowns in a balanced fashion, with consideration for risks/benefits of other treatment options, and place treatment decisions in the individual context of illness severity and risks.