2026 ECNP Congress

PS01-1182

A meta-analysis of two phase 3 randomised placebo-controlled trials of zuranolone for the treatment of postpartum depression

Andreas Reif — B. Maximos, J.A. Ramos-Quiroga, S. Rosenberger, F. Forrestal, T. Sun, V. Nguyen, A. Artemyeva, M. Adams · University Hospital Frankfurt – Goethe University, Department of Psychiatry- Psychomatic Medicine and Psychotherapy, Frankfurt, Germany

2026 ECNP Congress

Introduction

Conventional antidepressant therapies may provide symptom relief for individuals with postpartum depression (PPD). However, these treatments can require several weeks to achieve full therapeutic benefit[1] and treatments with earlier onset of action are needed, especially as this time is highly important for mother-child bonding. Zuranolone, a GABA(A) receptor positive allosteric modulator approved for the treatment of PPD, was found in two phase 3 randomised placebo-controlled trials to provide symptom relief relative to placebo.[2,3] This meta-analysis aimed to provide further assessment of the efficacy and safety of zuranolone in PPD using pooled data from these trials.

Methods

This meta-analysis used pooled patient-level data from two randomised controlled trials of zuranolone for PPD (ROBIN [NCT02978326] and SKYLARK [NCT04442503]). Both studies were similarly designed but used different once daily doses of zuranolone (SKYLARK: 50 mg [capsule formulation]; ROBIN: 30 mg [a different capsule formulation with higher bioavailability]).[2,3] The primary endpoint in both studies was change from baseline in 17-item Hamilton Depression Rating Scale (HAMD-17) total scores at Day 15 (Day 3 was a key secondary endpoint). Continuous variables were analysed using a mixed-effects model for repeated measures (MMRM). Time to first response (≥50% reduction in HAMD-17 total score) and remission (HAMD-17 total score ≤7) were assessed using the Kaplan-Meier product-limit method and Cox proportional hazards models, with participants censored at last available assessment if the event was not observed. Responder analyses were performed using generalised estimating equations with unstructured covariance structure, log link function, and binomial or Poisson distribution.

Results

Baseline demographics and clinical characteristics were similar between patients receiving zuranolone (n=176) or placebo (n=177). Consistent with study-level findings, significant improvements were demonstrated in LSM difference in change from baseline in HAMD-17 total scores between zuranolone and placebo at Day 15 (least squares mean [LSM], -16.6 vs -12.5 points; LSM difference [95% CI], -4.1 [-5.9, -2.4]; P<0.0001) and Day 3 [LSM, -10.8 vs -7.7 points; LSM difference [95% CI], -3.1 [-4.6, -1.6]; P<0.0001). Responder rates on Day 15 favoured zuranolone (61% vs 40%; relative risk [95% CI], 1.51 [1.22, 1.86]). Median time to first response was shorter with zuranolone versus placebo (median [95% CI], 8 [8, 9] vs 20 [15, 44] days; hazard ratio [95% CI], 1.85 [1.44, 2.39]; P<0.0001) and median time to firstremissionwas also shorter (median [95% CI], 29 [21, 45] vs 50 [48, not estimable] days; hazard ratio [95% CI], 1.75 [1.28, 2.40]; P=0.0004). Overall, 63.6% and 52.6% of participants receiving zuranolone and placebo, respectively, experienced ≥1 treatment-emergent adverse event (TEAE) (relative risk [95% CI] for zuranolone vs placebo; 1.21 [1.01, 1.45]; P=0.0396); TEAEs occurring in ≥10% of participants and at a higher rate than placebo included somnolence (zuranolone, 21.6%; placebo, 7.6%) and dizziness (zuranolone, 10.8%; placebo, 8.2%).

Conclusions

This meta-analysis demonstrated efficacy and safety consistent with study-level findings. Time to clinically meaningful response and remission with zuranolone was significantly shorter for zuranolone relative to placebo. These findings further support zuranolone as a rapid-acting treatment option for PPD.

References

  1. Brown J.V., Wilson C.A., Ayre K., et al, 2021. Antidepressant treatment for postnatal depression. Cochrane Database of Systematic Reviews 2(2), CD013560.
  2. Deligiannidis K.M., Meltzer-Brody S., Gunduz-Bruce H., et al, 2021. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry 78(9), 951-959.
  3. Deligiannidis K.M., Meltzer-Brody S., Maximos B., et al, 2023. Zuranolone for the treatment of postpartum depression. Am J Psychiatry 180(9), 668-675.