In 2019, the US Preventive Services Task Force (USPSTF) issued recommendations that all pregnant and postpartum women should be evaluated to determine risk for depressive illness and recommended that women at increased risk be referred for counseling interventions. Ultimately, the goal is to identify women who are 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 choice of an effective intervention. The medical literature reports a wide range of interventions designed to prevent PPD. However, many of these interventions have not been tested in multiple settings. In a recent studyresearchers investigated the use of dexmedetomidine to reduce the risk of postpartum depression after childbirth in a group of women who underwent cesarean section.
What is dexmedetomidine? Why did they try it?
Dexmedetomidine or DEX is a highly selective α2-adrenergic receptor (α2-AR) agonist. It is commonly used in 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 can 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 the antidepressant effects of DEX. 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 cesarean section women who experienced depression during pregnancy, defined as an Edinburgh Postpartum Depression Scale (EPDS). 9 or greater.
Postpartum, 338 participants were randomized to receive either intravenous infusion of DEX (0.5 μg/kg) or saline. After this infusion, women in the DEX group received DEX (2.0 μg/kg) and opioid analgesic sufentanil (2.2 µg/kg); the control group received only sufentanil (2.2 μg/kg).
At 1 and 6 weeks postpartum, depressive symptoms were measured using the EPDS. Participants were also asked about sleep, pain and other side effects.
Prevalence of postpartum depression symptoms
At Week 1, 12.6% of women in the dexmedetomidine group were positive for PPD versus 32.1% of women in the control group. At 6 weeks, 11.4% of the dexmedetomidine group versus 30.3% of the control group were positive.
They also noticed some other differences between the DEX and control groups:
- Insomnia scores in the DEX group were significantly reduced from baseline to 1 and 2 days postpartum compared to the control group. However, there were no differences in insomnia symptoms between groups at 1 and 6 weeks postpartum.
- Women in the DEX group reported less pain at 6, 24, and 48 hours postpartum than women in the control group.
The two groups had 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 a2-adrenergic receptor agonist HeyExmedetomidine was associated with a 60% reduction in the prevalence of postpartum depressive symptoms at week 1 and week 6. This represents a significant risk reduction in a group of women who, because they already had depressive symptoms during pregnancy, were at increased risk for PPD. Additionally, DEX treatment was associated with improved sleep and better pain control.
The study authors question 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 received DEX treatment. This is based on the finding that women with PPD often experience the onset of depressive symptoms during pregnancy, usually in the last trimester. Thus, it is possible that DEX may prevent postpartum depression, but we must also entertain the possibility that DEX may also alleviate or prevent worsening of preexisting depressive symptoms. This publication did not include data on changes in depressive symptoms in individual participants, information that could help separate these possibilities.
Some other questions to consider:
- Would DEX treatment reduce the risk for PPD in women with other risk profiles, such as women with a history of PPD? Or in women with a history of depression before birth? Or women in the general population?
- Given that women with insomnia during late pregnancy and the 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 shown a lower risk of PPD in women with better pain control during labor. Could the benefits seen with DEX be related to better pain relief?
However, 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 a2-adrenergic receptor (a2-AR) agonists are currently on the market but are not used as antidepressants. Clonidine or catapres is used to treat ADHD, anxiety and high blood pressure. Tizanidine or Zanaflex is used as a muscle relaxant. As far as I know, we have not seen antidepressants that specifically target adrenergic receptors.
Ruta Nonacs, MD PhD
bibliographical references
Al-Mahrouqi T, Al Alawi M, Freire RC. Dexmedetomidine in the treatment of depression: An updated narrative review. Clin Pract Epidemiol Ment Health. 2023 30 Aug 19: e174501792307240.
Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. Spring 2015;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 antenatal depression: A randomized clinical trial. JAMA Network Open. 2024 January 2; 7(1):e2353252.
