By Nicole Cirino, MD, CST, IF
Reproductive Psychiatrist, Professor of Psychiatry and OB/GYN, Oregon Health & Science University, Portland
SYNOPSIS: A double-blinded, randomized clinical trial of 134 low-risk pregnant women in Iran undergoing scheduled cesarean deliveries was conducted to address if a single dose of ketamine during anesthesia induction has a role in the prevention of postpartum depression. The authors reported that depression scores using the Edinburgh Postnatal Depression Scale at two and four weeks after the cesarean delivery were significantly lower in the ketamine group vs. the control group.
SOURCE: Alipoor M, Loripoor M, Kazemi M, et al. The effect of ketamine on preventing postpartum depression. J Med Life 2021;14:87-92.
The study population for this double-blinded, randomized controlled trial included low-risk pregnant women who were candidates for scheduled cesarean delivery at Rafsanjan University of Medical Sciences in Iran. The inclusion criteria included low-risk pregnancy, ages 18 to 35 years, being a candidate for a cesarean delivery, being American Society of Anesthesiologists (ASA) class 1 or 2 (not having any underlying diseases, such as ischemic heart diseases, diabetes mellitus, or hypertension), not having any contraindication to receiving ketamine, and absence of a history of drug abuse. Subjects with post-delivery hemorrhage requiring a blood transfusion were not included in the analysis. Participants were allocated randomly to two groups to induce anesthesia. In the intervention group, 1 mg/kg to 2 mg/kg of body weight of thiopental (Nesdonal) and 0.5 mg/kg of body weight of ketamine were used, and in the control group, 3 mg/kg to 5 mg/kg of body weight of thiopental was administered.
Data were gathered over the phone using the Edinburgh Postnatal Depression Scale (EPDS) at three time points: before the cesarean delivery, at two weeks after cesarean delivery, and at four weeks after cesarean delivery. The two studied groups were similar regarding the number of past pregnancies, having a wanted or unwanted pregnancy, education, history of depression, and satisfaction with life.
In this study, the investigators measured depression using the EPDS, a validated screening tool. They used a score of 13 or higher as a cut-off to indicate the subject is “probably suffering from depression with various intensities, and they need further investigation to diagnose depression.” They used 13 as the cut-off (as opposed to a lower value used in many studies), since its reliability of 0.70 has been studied specifically among the Iranian population. Results showed that median depression scores in both arms before intervention were positive (> 13) and roughly equivalent (13.79 in the control group vs. 13.78 in the treatment group). After the infusion, the ketamine arm showed significantly lower and descending depression scores: intervention vs. control group mean (± standard deviation) score was 11.82 ± 3.41 and 14.34 ± 4.29 (P < 0.001), respectively, two weeks after cesarean delivery and 10.84 ± 3.48 and 13.09 ± 3.79 (P = 0.001), respectively, four weeks after cesarean delivery. The depression mean scores in the intervention group also were below the EPDS cut-off point at two and four weeks after the cesarean delivery (11.82 and 10.84, respectively). The depression scores remained positive for the control group at two and four weeks (14.34 and 13.09, respectively).
The authors also used Apgar scores to measure neonatal outcomes. The mean Apgar score in the first minute after delivery was 7.30 ± 0.63 in the thiopental group and 7.82 ± 0.68 in the ketamine-thiopental group. The difference between the two groups was statistically significant (P > 0.001), but the authors concluded this was not clinically significant. Both groups received a score of 7 and had similar categorization regarding their need for resuscitation. The Apgar score of all the neonates in the fifth minute was 10. The authors concluded that “considering the reported advantageous effects of ketamine in the conducted studies, such as analgesia, analgesia during labor after cesarean [delivery] and vaginal delivery, safety during labor and cesarean [delivery], and its relatively known effect for the treatment of major depression, if its effect on preventing postpartum depression would be confirmed through another clinical trial, it would become a multipurpose appropriate option in gynecology and midwifery departments.”
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and has long been considered an inexpensive, accessible anesthetic medicine used in surgeries, including some cesarean deliveries. Over the past two decades, it has proven to be a novel and effective rapid treatment for treatment-refractory major depression and suicidality in adults.1 This study adds to the small body of literature looking specifically at the use of ketamine in postpartum depression. This is the fourth randomized controlled trial published studying ketamine infusions in women receiving scheduled cesarean deliveries. In 2019, Jia-Hui et al conducted a large randomized controlled trial on 654 Chinese women undergoing cesarean deliveries with spinal anesthesia.2 They administered ketamine (0.5 mg/kg of body weight) intravenously 10 minutes after delivery and through a patient-controlled intravenous analgesia device (PCIA). Jia-Hui et al reported positive findings with a reduction in depressive symptoms at four to six days and six to eight weeks postpartum.2 Gao et al also found similar results in 2015 and reported the positive effect of ketamine on preventing postpartum depression.3 In 2017, Xu et al used a lower dose of ketamine (0.25 mg/kg of body weight) and failed to find an effect on preventing postpartum depression.4
One of the barriers to using ketamine to treat major depression in non-perinatal patients is the requirement for intravenous infusion and monitoring outside the traditional outpatient mental health clinical setting. The scenario of a dual use of ketamine both for anesthesia/analgesia for cesarean deliveries and for postpartum depression prevention is promising. However, this study and the existing data have significant limitations. One of the limitations of this study is the generalizability of the data. In the United States, general anesthesia typically is not administered, particularly for low-risk pregnant women. All the studies on ketamine for postpartum depression, thus far, have looked at a specific demographic: the use of ketamine perioperatively during scheduled cesarean deliveries in hospital settings outside the United States. Another limitation of this study is that it does not address concerns about the effect of ketamine on infant neurobehavioral development. Although the Apgar scores were not reduced, other neurodevelopmental measures were not conducted. Animal models have shown apoptogenic action of ketamine at both the fetal and neonatal age, and an exposure duration of five hours is sufficient to induce a significant neuroapoptosis response at either age.5
The lack of both obstetric history and a validated clinical mental health interview in this study are of concern as well. We do not know the indication for cesarean delivery in the low-risk pregnant subjects nor important aspects of the mental health history obtained from a formal clinical interview (including diagnosis, active or recent treatment, and objective improvement). Although self-reported scores can be helpful, this is not the standard of care when evaluating a new pharmacologic intervention. Furthermore, the self-reported scores were elicited over the phone. Also, this study appears to capture a population with a high prevalence of self-reported active depression or other mental health conditions before treatment, since the average EPDS score at delivery before the infusion was > 13. However, without a proper assessment by a mental health professional, we do not know the current psychiatric condition of the subject, the current treatments being used, the other treatments offered in the postpartum period, or if clinical improvement has indeed occurred.
Clearly, more extensive clinical trials with a multidisciplinary team (pediatrics, obstetrician gynecologists, psychiatrists, anesthesiologists) still are needed in this area. Since ketamine is inexpensive and available in clinical settings in many countries where women are giving birth, this is an area that should be explored further. Remaining clinical questions regarding the use of ketamine for postpartum depression include the timing and dose of ketamine (prior to or following delivery), the effect ketamine has on the neonate (including in lactation), the length of treatment effect, and if, indeed, ketamine is effective for the treatment or prevention of postpartum depression (and, if so, in which population of women at risk). It may be feasible that one day women who are candidates for a cesarean delivery and are at risk for postpartum depression may benefit from the protective role of a single ketamine infusion, but for now, both safety and efficacy need to be established first.
- Aroni F, Iacovidou N, Dontas I, et al. Pharmacological aspects and potential new clinical applications of ketamine: Reevaluation of an old drug. J Clin Pharmacol 2009;49:957-964.
- Ma JH, Wang SY, Yu HY, et al. Prophylactic use of ketamine reduces postpartum depression in Chinese women undergoing cesarean section. Psychiatry Res 2019;279:252-258.
- Gao J, Xu J. Efficacy of ketamine in preventing postpartum depression in patients undergoing cesarean section. Chinese Journal of Anesthesiology 2015;35:674-676.
- Xu Y, Li Y, Huang X, et al. Single bolus low-dose of ketamine does not prevent postpartum depression: A randomized, double-blind, placebo-controlled, prospective clinical trial. Arch Gynecol Obstet 2017;295:1167-1174.
- Brambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012;116:372-384.