In 2019, the US Preventive Services Task Force (USPSTF) issued recommendations that all pregnant and postpartum women should be evaluated in order to determine risk for depressive illness and recommended that women at increased risk should be referred for counseling interventions. Ultimately the goal is to identify women at highest risk for depressive illness during pregnancy and the postpartum period, so that we can introduce interventions designed to prevent depression in this setting.
Of utmost importance is the selection of an effective intervention. The medical literature reports on a wide array of interventions designed to prevent PPD; however, many of these interventions have not been tested in multiple settings. In a recent study, researchers explored the use of dexmedetomidine to reduce the risk of postpartum depression after delivery in a group of women undergoing Cesarean section.
What is Dexmedetomidine? Why Did They Test It?
Dexmedetomidine or DEX is a highly selective α2 -adrenergic receptor ( α2 -AR) agonist. It is used commonly during the perioperative period and has sedative, anxiolytic, and analgesic properties. It produces these effects by inhibiting central sympathetic outflow by blocking alpha receptors in the brainstem and inhibiting the release of norepinephrine.
It seems that the idea that DEX may be used as an antidepressant came from a 2014 study from India where DEX was used for anesthesia in patients receiving ECT; this study noted that patients receiving DEX experienced less agitation and a greater reduction in depressive symptoms. Animal studies later demonstrated DEX’s antidepressant effects. Exactly how DEX works as an antidepressant is not fully understood; however, DEX appears to have anti-inflammatory effects and upregulates the production of brain-derived neurotrophic factor (BDNF).
Dexmedetomidine in Postpartum Women
In this randomized, double-blind, placebo-controlled clinical trial, Zhou and colleagues recruited women who were undergoing a Cesarean section and who experienced depression during pregnancy, defined as an Edinburgh Postnatal Depression Scale (EPDS) score of 9 or greater.
After delivery, 338 participants were randomized and received either an intravenous infusion of DEX (0.5 μg/kg) or saline. Following this infusion, women in the DEX group received DEX (2.0 μg/kg) and the opioid analgesic sufentanil (2.2 μg/kg); the control group received only sufentanil (2.2 μg/kg).
At 1 and 6 weeks after delivery, depressive symptoms were measured using the EPDS. The participants were also asked about sleep, pain, and other adverse events.
Prevalence of Postpartum Depressive Symptoms
At Week 1, 12.6% of the women in the dexmedetomidine group screened positive for PPD versus 32.1% of the women in the control group. At 6 weeks, 11.4% of the dexmedetomidine group versus 30.3% of the control group screened positive.
They also observed some other differences between the DEX and control groups:
- Insomnia scores in the DEX group were significantly decreased from baseline to 1 and 2 days postpartum compared to the control group. However, there were no differences in insomnia symptoms between the groups at 1 and 6 weeks postpartum.
- Women in the DEX group reported less pain at 6, 24, and 48 hours after delivery than women in the control group.
The two groups experienced similar rates of adverse events; however, those in the DEX group had higher rates of hypotension (systolic blood pressure less than 90 mm Hg or 20% lower than baseline).
Interesting Study, But Still More questions
This is a very interesting study. In a group of women who had elevated EPDS scores during pregnancy, postpartum treatment with the α2-adrenergic receptor agonist dexmedetomidine was associated with a 60% reduction in the prevalence of postpartum dpepressive symptoms at weeks 1 and at week 6. This represents a significant reduction of risk in a group of women who, because they already had experienced depressive symptoms during regnancy, were at increased risk for PPD. In addition, treatment with DEX was associated with improved sleep and better pain control.
The authors of the study ask whether DEX can be used to “prevent” postpartum depression. The fact that these women already had depressive symptoms during pregnancy raises the possibility that some (or many?) women were already depressed at the time they were treated with DEX. This is based on the finding that women with PPD often experience the onset of depressive symptoms during pregnancy, typically during the last trimester. So it is possible that DEX may prevent postpartum depression, but we must also entertain the possibility that DEX may also alleviate or prevent the worsening of already present depressive symptoms. This publication did not include data on changes in depressive symptoms in individual participants, information that might help to separate these possibilities.
Some other questions to consider:
- Would treatment with DEX reduce risk for PPD in women with other risk profiles, such as women with a history of PPD? Or in women with a pregravid history of depression? Or women in the general population?
- Given that women with insomnia during late pregnancy and early postpartum period are at increased risk for PPD, could the beneficial effects of DEX be related to improvements in sleep during the early postpartum period?
- Previous studies have indicated lower risk of PPD in women with better peripartum pain control; could the benefits seen with DEX be related to better pain relief?
Nonetheless, this study provides another avenue of exploration for the treatment of postpartum depression, an option that could be administered once at the time of delivery. Further studies are needed to better understand which women are most likely to benefit from this intervention.
Several other α2-adrenergic receptor ( α2-AR) agonists are currently on the market but are not used as antidepressants. Clonidine or Catapres is used to treat ADHD, anxiety and hypertension. Tizanidine or Zanaflex is used as a muscle relaxant. To the best of my knowledge, we have not seen any antidepressants that specifically target adrenergic receptors.
Ruta Nonacs, MD PhD
References
Al-Mahrouqi T, Al Alawi M, Freire RC. Dexmedetomidine in the Treatment of Depression: An Up-to-date Narrative Review. Clin Pract Epidemiol Ment Health. 2023 Aug 30;19:e174501792307240.
Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015 Spring;62(1):31-9.
Zhou Y, Bai Z, Zhang W, Xu S, Feng Y, Li Q, Li L, Ping A, Chen L, Wang S, Duan K. Effect of Dexmedetomidine on Postpartum Depression in Women With Prenatal Depression: A Randomized Clinical Trial. JAMA Netw Open. 2024 Jan 2;7(1):e2353252.
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