Onset of Reduction in Depressive Symptoms in Postpartum Depression (PPD): Pivotal Studies of Two Neuroactive Steroid GABAA Receptor Positive Allosteric Modulators, Brexanolone Injection and Zuranolone
Background: Brexanolone injection (BRX) and the investigational compound, zuranolone (SAGE-217; ZRN), two neuroactive steroid (NAS) GABAA receptor positive allosteric modulators, were evaluated in four PPD randomized-controlled trials (RCTs). Both NASs achieved their primary endpoints (BRX:Hour 60; ZRN:Day 15).
Methods: Adult women, ≤6 months postpartum, with PPD, and qualifying 17-item Hamilton Rating Scale for Depression total scores (HAMD-17; BRX Studies A/B:≥26, C:20-25; ZRN:≥26), were enrolled. BRX randomization: 1:1:1 BRX 90µg/kg/h (BRX90):BRX 60µg/kg/h (BRX60):placebo in B; 1:1 BRX90:placebo in A/C, as 60-hour infusions, with follow-up through Day 30. ZRN randomization: 1:1 ZRN 30mg capsules:placebo for two-weeks, with four-weeks follow-up. Change from baseline in depressive symptoms versus placebo was measured by HAMD-17. Adverse events (AEs) were assessed.
Results: In a pooled 24-hour analysis, the BRX group (N=140) demonstrated numerically larger decreases in HAMD-17 versus placebo starting at Hour 4 and all subsequent time points measured. Statistically significant improvements versus placebo were achieved at Hour 8 (p=0.0402) and 24 (p<0.0001). BRX common AEs (‚â•5% of BRX and ‚â•2x placebo rate) included sedation and/or somnolence, dry mouth, flushing/hot flush, and loss of consciousness. ZRN (N=76) demonstrated significant HAMD-17 reduction versus placebo at Days 3 (p=0.0252), 8 (p=0.0106), and 15 (p=0.0028). ZRN common AEs (‚â•5%) included somnolence, headache, dizziness, upper respiratory tract infection, diarrhea, and sedation.
Conclusions: In secondary analyses, BRX and ZRN achieved statistically significant reductions in depressive symptoms versus placebo in PPD RCTs as early as 8-hours and 3-days, respectively. These results support the continued clinical development of NASs in the treatment of PPD.
