Mechanisms of Brexanolone Therapeutics in Post-Partum Depression: Expanded follow-up study

2023 Award: $100,000

Brexanolone is the first FDA approved medication for postpartum depression. This medication has a different mechanism of action than typical antidepressants and we will be investigating brexanolone’s impact on the systemic inflammatory pathways. Better understanding of why brexanolone is so effective for postpartum depression may provide a better understanding of postpartum depression itself and development of more accessible therapeutics.

Need/Problem: Brexanolone is recently the first FDA approved medication for postpartum depression, which happens to be the most common complication of childbirth. This medication is an exciting development in psychiatry, in that it is rapidly acting, given by IV infusion over 60 hours, and has a vastly different mechanism of action than typical antidepressants. Despite these successes, there are limitations in that it requires a multiple day hospital admission, time away from family, and is expensive. We thus hope to better understand the mechanism of action of brexanolone and why this is so effective for PPD to allow for development of more affordable bioavailable compounds and better understanding of this common illness.

Grant Summary: Over the past several years, we have been fortunate to form a partnership between UNC’s Clinical Brexanolone Treatment Program and UNC’s Molecular Neuropharmacology Lab. Our collaboration provides the first human data showing that brexanolone inhibits inflammatory pathways which contributes to the therapeutic effects of brexanolone.

We will now follow additional cases, to determine if the inhibition of systemic inflammatory pathways persists as long as the anti-depressant and therapeutic effects of brexanolone remain.

Goals and Projected Outcomes: This study will provide follow up data on the inflammatory pathways and how they are altered after receiving brexanolone infusion for the treatment of postpartum depression. Data derived from this study will support additional funding to develop interventions to target postpartum depression.

Riah Patterson, MD

Grant Details: The first aim will be to increase the power of our studies by increasing the number of participants by an additional 25 and to determine if the anti-inflammatory effects of brexanolone are sustained for 30- and 90-days post infusion. Prior to this proposal, cases were only followed 6-12 hours after infusion and yet prior data indicates that the therapeutic effects of brexanolone remain present at 7, 30 and 90 days (Kanes et al., 2017; Meltzer-Brody et al., 2018; Patterson et al., 2022). We will examine HAM-D results at 30 and 90 days and at those same time points we will gather whole blood to capture the pro-inflammatory markers TNF-a and IL6, and the anti-inflammatory marker IL10 to examine if these changes in inflammatory pathways correlate with continued therapeutic benefit of the brexanolone treatment (Balan et al., 2023). Brexanolone is synthetic allopregnanolone, and we know that allopregnanolone levels return to control levels shortly after the infusion, so we want to know what else has changed and what accounts for this sustained clinical improvement.

This research is important because it will 1) advance our understanding of the biological mechanisms underlying both the triggering of and susceptibility to PPD; and 2) potentially permit the identification of those at risk for PPD well before illness expression, which would allow for a personalized medicine approach to prevention and treatment, a goal with obvious implications for public health.