INTRODUCTION: One proposed etiology of postpartum depression (PPD) involves dysfunctional GABAergic signaling. Brexanolone injection (BRX) and SAGE-217, two neuroactive steroid GABAA receptor positive allosteric modulators, have been evaluated in a total of 4 double-blind, randomized, placebo-controlled trials (RCTs). METHODS: Inclusion criteria: adult women, ≤6 months postpartum, diagnosed with PPD, and a qualifying HAM-D total score (BRX Studies A and B, ≥26; BRX Study C, 20–25; SAGE-217, ≥26). BRX randomization: 1:1:1 BRX 90 ug/kg/h (BRX90): BRX 60 ug/kg/h: placebo in Study B and 1:1 BRX90: placebo in Studies A/C, as 60-hour infusions, with follow-up through Day 30. SAGE-217 randomization: 1:1 SAGE-217 30 mg capsules or placebo for 14 days, with 4 weeks follow-up. Primary endpoints were change in HAM-D total score at Hour 60 (BRX) or Day 15 (SAGE-217). Adverse events (AEs) were recorded throughout the studies. RESULTS: Both BRX90 and SAGE-217 achieved their primary endpoints (P<.0001 and P=.0028 respectively). Significant improvements versus placebo were sustained through Day 30 (BRX90, P=.0252) and Day 45 (SAGE-217, P=.0027). AEs in all BRX (n=140) occurring in ≥5% of BRX and ≥2x the rate of placebo were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. The most common AEs (≥5%) with SAGE-217 were somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, and sedation. CONCLUSION: BRX and SAGE-217 achieved their primary endpoints of statistically significant and clinically meaningful reductions in depressive symptoms versus placebo in PPD RCTs and were generally well tolerated. These results support the role of GABAergic signaling in PPD.
Recurrent pancreatitis in pregnancy after a preconception Whipple procedure can be managed conservatively without surgical intervention.
INTRODUCTION: Brexanolone injection (BRX), an investigational, intravenous formulation of the GABAA receptor positive allosteric modulator allopregnanolone is in development for postpartum depression (PPD) pharmacotherapy. Allopregnanolone levels were evaluated in breast milk and plasma from healthy lactating women administered BRX. METHODS: IRB approval was obtained. Informed consent was required for enrollment. Subjects (n=12) received a 60-hour inpatient BRX infusion (titration to 90 µg/kg/h followed by a taper phase) and were followed through Day 7 as outpatients. Breast milk and plasma allopregnanolone were quantified using liquid chromatography-mass spectrometry (limits of quantitation: milk = 5 ng/mL, plasma = 1 ng/mL). Subjects pumped breast milk as needed. All breast milk was collected. PopPK model structures were considered to account for milk sample frequency and the lack of strict alignment between pumping and plasma collection. The most parsimonious model was used to describe milk concentrations as the product of a constant partition coefficient and plasma allopregnanolone concentration. Modeling accounted for milk and plasma values below the limit of quantitation. RESULTS: The model characterized milk and plasma data well; allopregnanolone concentrations increased during titration and declined during taper for plasma and milk, in parallel. Milk concentrations were 1.36 times higher than plasma. Modeling predicts that 95% of patients with 90 µg/kg/h dosing will have milk allopregnanolone levels <10 ng/mL 36 hours after treatment cessation. The calculated relative infant dose (RID) was 1.3%. CONCLUSION: Following BRX dosing, PopPK modeling characterized allopregnanolone concentrations in milk and plasma and suggests that the RID for BRX is associated with low risk to breastfed infants.
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