Neurosteroid Therapeutics “Offer Great Promise” in Postpartum Depression

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CONFERENCE REPORTER

“I am a passionate advocate for women’s mental health, and I am always extremely honored to work with women and mothers. Wherever you go around the world, childbirth, is such a profound time really represents our common humanity in a powerful way,” said Samantha Meltzer-Brody, MD, MPH, during her President’s Plenary session, “The Development of Neurosteroid Therapeutics in Postpartum Depression: Where Are We Now?” at the American College of Neuropsychopharmacology 2023 Annual Meeting. Dr Meltzer-Brody is the Assad Meymandi Distinguished Professor and Chair of the Department of Psychiatry at the University of North Carolina at Chapel Hill, as well as the director of the UNC Center for Women’s Mood Disorders.

Approximately 10% to 15% of the general population, or about 1 in 8 women, has postpartum depression (PPD), shared Melter Brody, which can be incredibly debilitating and can increase maternal mortality. There is a great need for new, effective, rapid-acting therapies for PPD, which is where neurosteroid therapeutics come in.

The standard pharmacological treatment for PPD are antidepressants, commonly SSRIs. Meltzer-Brody argued that antidepressants are not rapid-acting enough to serve as a treatment for PPD, as untreated PPD can lead to poor bonding, poor development of the infant, and higher rates of substance use, suicide, and more.^1-5

“The period postpartum is extremely vulnerable for the mother, the baby, and the entire family,” said Meltzer-Brody. “It is a critical window for mother-child connection.”

Additionally, antidepressants are not specifically meant to treat the disorder PPD, but rather major depressive disorder (MDD) symptomology. Adequate treatments, according to Meltzer-Brody, would target the underlying pathophysiology of PPD itself, and do so quickly.

“Neurosteroid treatments offer great promise in the treatment of PPD,” shared Meltzer-Brody. She hopes these novel therapeutics will provide fast-acting treatment for mothers with PPD and improve of our understanding of depressive disorders as a whole.

The best studied neuroactive steroids for PPD are brexanolone and zuranolone.

Brexanolone, the first US Food and Drug Administration (FDA) approved treatment for PPD, is intravenously administered over 60 hours. This timing was chosen to potentially replicate a mother’s third trimester levels of allopregnanolone. The injection is hypothesized to work in PPD by increasing GABA fuction. Onset of effect happens within 12 hours and can be followed out 30 days. Its main adverse effect is sedation.

Since 2019, Meltzer-Brody and colleagues have infused over 60 mothers with brexanolone in the clinical program at UNC. Their post-infusion data show a drop in HAM-D score from 23.9 to 7.6 after the 60 hour infusion, and 94% of cases reached a meaningful reduction in score and 56% reached remission.

Zuranolone—which is not just an oral brexanolone, Meltzer-Brody stressed—is the first oral treatment for PPD. It is also a GABAA receptor positive allosteric modulator.⁶ Zuranolone does come with a box warning for sedation while driving for up to 12 hours, and is recommended for nighttime use to minimize this effect. Notably, zuranolone did fail to receive FDA approval for MDD in August 2023.

Have you used brexanolone or zuranolone in your patients? Tell us about it at PTEditor@MMHGroup.com!

References

1. Gentile S. Untreated depression during pregnancy: short- and long-term effects in offspring. A systematic review. Neuroscience. 2017:342:154-166.

2. Lahti M, Savolainen K, Tuovinen S, et al. Maternal depressive symptoms during and after pregnancy and psychiatric problems in children. J Am Acad Child Adolesc Psychiatry. 2017;56(1):30-39.

3. McKee K, Admon LK, Winkelman TNA, et al. Perinatal mood and anxiety disorders, serious mental illness, and delivery-related health outcomes, United States, 2006-2015. BMC Womens Health. 2020;20(1):150.

4. Netsi E, Pearson RM, Murrary L, et al. Association of persistent and severe postnatal depression with child outcomes. JAMA Psychiatry. 2018;75(3):247-253.

5. Ross LE, Dennis C-L. The prevalence of postpartum depression among women with substance use, an abuse history, or chronic illness: a systematic review. J Womens Health (Larchmt). 2009;18(4):475-486.

6. Hoffmann E, Nomikos GG, Kaul I, et al. SAGE-217, A novel GABAA receptor positive allosteric modulator: clinical pharmacology and tolerability in randomized phase I dose-finding studies. Clin Pharmacokinet. 2020;59(1):111-120.