Mechanisms of Brexanolone Therapeutics in Postpartum Depression
2020 Award: $48,070
Depression is associated with abnormal activation of inflammatory immune signals in the blood and the brain. We recently discovered that the endogenous steroid allopregnanolone inhibits these signals and therefore we hypothesize that this mechanism explains the therapeutic effects of the new drug Zulresso, which is a proprietary form of allopregnanolone. We will test this idea in women with postpartum depression in hopes of discovering new ways to treat all forms of depression.
Need/Problem: The first FDA-approved medication for post-partum depression is brexanolone, but it requires IV infusion for 60 hours in a medically supervised setting with oxygen monitoring. We need to understand the mechanism of action of brexanolone to allow development of a more affordable and convenient bioavailable treatment for post-partum depression.
Grant Summary: We will examine whether the anti-depressant effects of brexanolone in patients with post-partum depression involve the inhibition of inflammatory signaling, the elevation of anti-inflammatory signaling and/or altered sensitivity of macrophages to immune challenge with pathogens.
Goals and Projected Outcomes: We predict that baseline measures of pro-inflammatory markers as well as pathogen-induced macrophage signaling will be decreased by brexanolone while anti-inflammatory markers will be increased by brexanolone. We further predict that persistent suppression of inflammatory markers after brexanolone will predict the magnitude and duration of antidepressant efficacy. If these mechanisms predict the therapeutic effects of brexanolone, we can screen for other compounds with comparable therapeutic effects that will not require IV administration.
A. Leslie Morrow, PhD
Grant Details: Post-partum depression patients will be evaluated for depression severity using the HAM-D instrument prior to treatment, following treatment at 12 hours post-infusion, and at follow-up after 24 days. Inflammatory vs. anti-inflammatory markers, the macrophage pathogen response and allopregnanolone serum levels will be assessed at the same time points. Depression score changes from baseline will be correlated with markers of inflammatory vs. anti-inflammatory signaling and macrophage pathogen response at each time point. Serum allopregnanolone levels will be analyzed as a co-variate to ascertain if variation in serum allopregnanolone is related to changes in depression scores, immune biomarker expression or inhibition of pathogen response in the patients.
