Dexmedetomidine – Preventing Postpartum Depression

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Exploring Dexmedetomidine's Potential Role in Preventing Postpartum Depression

Postpartum depression (PPD) affects approximately 10% to 20% of women following childbirth, making it the most prevalent psychological disorder in this demographic, and thus, a clinically relevant public health priority.^3,6,7 PPD, a mental health condition occurring after childbirth, triggers emotions such as sadness, guilt, and diminished self-worth in affected women. Its ramifications extend beyond the individual, posing serious negative consequences for mothers, young children, and additional family members. This includes potential disruptions to the maternal-infant bond and adverse effects on child development.⁵ In light of this, there have been recent strides in PPD treatment, notably, the U.S. Food and Drug Administration (FDA) approval of Zurzuvae (zuranolone) on August 4th, 2023, the first oral PPD medication. Previously, Zulresso (brexanolone), approved in 2019, required hospital administration via a 60-hour IV infusion with strict monitoring. Zuranolone provides an oral alternative, potentially simplifying treatment for mothers with PPD.

Preventive measures for PPD are under investigation, as highlighted in a recent article published in the Journal of the American Medical Association (JAMA) focusing on dexmedetomidine's potential role. The study provides insights into dexmedetomidine's use as a possible preventative measure against PPD development.

Dexmedetomidine, a sedative drug used most commonly in the perioperative period, is a potent α2-adrenoreceptor (α2-AR) agonist. Research suggests that activating α2-ARs selectively can modulate norepinephrine release, restoring neurotransmitter balance and potentially mitigating depressive symptoms.⁸ Previous research in mouse models indicated dexmedetomidine's efficacy in improving depression-like behavior, particularly in situations not responsive to traditional antidepressants.⁴ Moreover, dexmedetomidine has been found to enhance levels of brain-derived neurotrophic factor (BDNF), a critical factor in neuronal growth, development, and synaptic plasticity.¹¹ A prior study involving 340 Chinese women revealed a correlation between reduced prenatal serum BDNF levels and PPD occurrence within three months, suggesting its potential as a predictive biomarker for PPD.²

Dexmedetomidine’s safety and efficacy was evaluated in a randomized, double-blinded, placebo-controlled clinical trial (ChiCTR2200057213) conducted at 2 hospitals in Hunan, China. The study, conducted from March 28, 2022, to April 16, 2023, aimed to assess dexmedetomidine's efficacy and safety in preventing PPD among women with prenatal depression undergoing cesarean delivery.

Patients 18 years or older with prenatal depression, defined as an Edinburgh Postnatal Depression Score (EPDS) of more than 9, choosing to undergo elective cesarean delivery under spinal anesthesia were randomized 1:1 to receive either dexmedetomidine (n=169) or placebo (n=169). Out of 355 individuals assessed for eligibility, 338 women were included. The mean age was 31.5 years for both the control group and dexmedetomidine group, and for the majority of patients enrolled in the study, this was not their first pregnancy. Most women carried to full term, and the pregnancy was planned.

After delivery of the infant via cesarean section, participants in the dexmedetomidine group were administered 0.5 mcg/kg of dexmedetomidine in 20 mL of 0.9% saline for a duration of 10 minutes. The placebo group received 20 mL of 0.9% saline for the same duration. All participants received Patient Controlled Intravenous Analgesia (PCIA) immediately after completion of the 10-minute infusion (dexmedetomidine group, dexmedetomidine, 2.0 mcg/kg, plus sufentanil, 2.2 mcg/kg, diluted in 100 mL; control group, sufentanil, 2.2 mcg/kg, diluted in 100 mL). The PCIA was set for continuous infusion at a rate of 2 mL/h for 48 hours.

The primary endpoint was the incidence of positive PPD screening results at 7 and 42 days postpartum, defined as a postpartum EPDS of more than 9. Notably, the findings revealed that the incidence of positive PPD screening results at 7 and 42 days postpartum was significantly decreased in the dexmedetomidine group vs. the control group (day 7: 12.6% vs. 32.1%; risk ratio [RR] 0.39; 95% confidence interval [CI] 0.25 to 0.62; p < 0.001; day 42: 11.4% vs. 30.3%; RR 0.38; 95% CI 0.23 to 0.61; p< 0.001).

Additionally, there was a notable decrease in suicidal ideation at 7 days postpartum in the dexmedetomidine group. The median EPDS score was significantly decreased in the dexmedetomidine group at 7 and 42 days postpartum compared with the control group (day 7: 3.0 vs. 6.0; Interquartile Range [IQR] 1.0-6.0 vs. IQR 2.0-10.0; p< 0.001; day 42: 3.0 vs. 6.0; IQR 1.0-5.0 vs. IQR 3.0-10.0; p< 0.001). Compared with the control group, the postpartum plasma BDNF level (mean difference [MD] 61.53 ng/L; 95% CI 14.56 to 108.50 ng/L) and their change value in the dexmedetomidine group were significantly increased (MD 71.57 ng/L; 95% CI 13.30 to 129.93 ng/L), while the change value of the pro-BDNF was significantly reduced (−20.36 ng/L; 95% CI −38.35 to −2.38 ng/L).

While dexmedetomidine showed a favorable safety profile, an increase in hypotension incidence was noted hypotension increased (18.3% vs.  9.5%; RR 2.15; 95% CI 1.13 to 4.10; p= 0.02). However, no significant difference in adverse reactions such as dizziness or nausea was observed between the groups. Overall, these findings suggest a potential mechanism for the antidepressant effect of upregulating plasma BDNF.

Although the preventive administration of dexmedetomidine in the early postpartum period reduced the incidence of positive PPD screening (> 9 on EPDS score) and maintained a favorable safety profile in this trial, there are pregnancy and breastfeeding considerations with dexmedetomidine. Dexmedetomidine crosses the placenta, and fetal bradycardia is reported with dexmedetomidine use. Additionally, dexmedetomidine is present in breast milk. However, data from available meta-analyses of randomized controlled studies found no adverse effects on neonatal outcomes.¹

It is important to recognize the limitations of the study. The trial was solely conducted in China which may limit its generalizability. Additionally, not all included patients were assessed for plasma BDNF and pro-BDNF levels (dexmedetomidine n= 56; control n= 54). It is also important to note that the EPDS score is a self-reported questionnaire which could introduce potential bias.

Overall, this study highlights the benefits of dexmedetomidine for cesarean section patients who are at risk of PPD, despite potential risks and considerations associated with its use. As dexmedetomidine is frequently employed as a sedative during the perioperative period, this study’s findings carry significant implications, especially for mothers undergoing cesarean sections, providing them with a renewed sense of hope in managing PPD.

References:

1. Bao Z, Zhou C, Wang X, Zhu Y. Intravenous dexmedetomidine during spinal anaesthesia for caesarean section: a meta-analysis of randomized trials. J Int Med Res. 2017;45(3):924-932. doi:10.1177/0300060517708945
2. Gao X, Wang J, Yao  H, Cai  Y, Cheng  R.  Serum BDNF concentration after delivery is associated with development of postpartum depression: a 3-month follow up study.   J Affect Disord. 2016;200:25-30. doi:10.1016/j.jad.2016.04.002
3. Meltzer-Brody S, Colquhoun H, Riesenberg  R,  et al.  Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.   Lancet. 2018;392(10152):1058-1070. doi:10.1016/S0140-6736(18)31551-4
4. Moon EJ, Ko IG, Kim  SE,  et al.  Dexmedetomidine ameliorates sleep deprivation-induced depressive behaviors in mice.   Int Neurourol J. 2018;22(suppl 3):S139-S146. doi:10.5213/inj.1836228.114
5. Mughal S, Azhar Y, Siddiqui W. Postpartum Depression. In: StatPearls. Treasure Island (FL): StatPearls Publishing; October 7, 2022.
6. Kanes S, Colquhoun H, Gunduz-Bruce  H,  et al.  Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.   Lancet. 2017;390(10093):480-489. doi:10.1016/S0140-6736(17)31264-3
7. Ko JY, Rockhill KM, Tong  VT, Morrow  B, Farr  SL.  Trends in postpartum depressive symptoms—27 states, 2004, 2008, and 2012.   MMWR Morb Mortal Wkly Rep. 2017;66(6):153-158. doi:10.15585/mmwr.mm6606a1
8. Schramm NL, McDonald MP, Limbird LE. The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J Neurosci. 2001 Jul 1;21(13):4875-82. doi: 10.1523/JNEUROSCI.21-13-04875.2001. PMID: 11425914; PMCID: PMC6762349.
9. U.S. Food and Drug Administration (FDA). FDA Approves first oral treatment for postpartum depression. August 4, 2023. Accessed August 26, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression.
10. U.S. Food and Drug Administration (FDA). FDA Approves first oral treatment for postpartum depression. August 4, 2023. Accessed August 26, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression.
11. Wang DS, Kaneshwaran K, Lei  G,  et al.  Dexmedetomidine prevents excessive γ-aminobutyric acid type A receptor function after anesthesia.   Anesthesiology. 2018;129(3):477-489. doi:10.1097/ALN.0000000000002311
12. Weiner MM, Chow R, Salter BS. Case report: a case of fetal bradycardia following dexmedetomidine bolus. Journal of Obstetric Anaesthesia and Critical Care. 2014;4(2):75-77. doi:10.4103/2249-4472.143876
13. Zhou Y, Bai Z, Zhang W, et al. Effect of Dexmedetomidine on Postpartum Depression in Women With Prenatal Depression: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(1):e2353252. doi:10.1001/jamanetworkopen.2023.53252

 

Photo: FRESENIUS KABI

 

 

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