Brexanolone: A Possible Novel Treatment in Severe Postpartum Depression

Depressed woman with baby
Depressed woman with baby
The rapidity of symptom remission (within 24 hours) and its efficacy are exciting developments in finding a novel treatment for PPD.

In women with severe postpartum depression, infusion of brexanolone significantly reduced total Hamilton Rating Scale for Depression (HAM-D) scores vs placebo according to study findings published in Human Psychopharmacology: Clinical and Experimental.

While standard treatments for postpartum depression (PPD) are similar to those used for any major depressive episode, it is thought that there are different characteristics for a general major depressive episode compared with an episode that occurs postpartum. There have therefore been efforts to provide a more targeted approach for the treatment of PPD, which affects between 15% and 20% of women.

Allopregnanolone is a major metabolite of progesterone and an allosteric modulator of GABA-A receptors. Allopregnanolone levels rise proportionately to progesterone throughout pregnancy, with the highest levels occurring in the third trimester. However, after childbirth, the levels of both allopregnanolone and progesterone quickly drop. Data suggests that allopregnanolone plays a role in affective regulation of reproductive hormonal changes.

Therefore, Stephen Kanes, MD, from Sage Therapeutics, Inc., in Cambridge, Massachusetts, and colleagues hypothesized that “the abrupt postpartum decline in allopregnanolone may be associated with symptoms of PPD. This supports the rationale for examining the effects of treatment of PPD patients with therapeutic doses of allopregnanolone equivalent to third trimester levels.” 

Dr Kanes and colleagues enrolled 4 patients in an open-label, proof-of-concept study. Inclusion criteria included age 18 to 45, admission to the Perinatal Psychiatry Inpatient Unit for a major depressive episode between the third trimester and 12 weeks postpartum, and a HAM-D score of ≥20. Breastfeeding weaning was a requirement, and antidepressants could only be continued if they were given at a stable dose over the 2 weeks prior to the study. The 4 women were given a 12-hour titrated infusion, followed by a 36-hour maintenance infusion and a 12-hour taper infusion of brexanolone, a formulation of allopregnanolone.

The primary outcomes of this study were safety and tolerability, while the secondary outcome was efficacy. The HAM-D score for all patients was ≤7 (remission) at ≥24 hours.

The main adverse events reported were sedation, infusion site issues, dizziness, and flushing. They were all tolerable and self-limited. No patients withdrew from the study due to these adverse events.

“Infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABA-A receptors in the development of therapies for patients with post-partum depression,” the researchers wrote.

This study has given hope for alternative options in the treatment of PPD. Due to its success, the trial was stopped prematurely in order to proceed with a larger placebo-controlled double-blind trial. The rapidity of symptom remission (within 24 hours) and efficacy with brexanolone use are exciting developments in the effort to find a novel treatment for PPD.

Limitations and Disclosures

  • This was a small study for proof-of-concept
  • The majority of patients were also on other medications, so the efficacy of brexanolone alone is unclear 
  • At this stage, brexanolone must be delivered via infusion

Funding provided by Sage Therapeutics, Inc.

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Kanes SJ, Colquhoun H, Doherty J, et al. Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Hum Psychopharmacol Clin Exp. 2017;32:e2576. doi:10.1016/S0140-6736(17)31264-3