BACKGROUND AND PURPOSE:

• Evidence suggests that GABAergic signaling plays a role in the development of postpartum depression (PPD)
• Zuranolone is a neuroactive steroid (NAS) GABA_A receptor (GABA_AR)–positive allosteric modulator (PAM) with a similar method of action to other NAS GABA_AR PAMs, but can be taken orally
• Deligiannidis et al. (JAMA Psychiatry, 2021) assessed the efficacy and safety of zuranolone in PPD

METHODS:

• Phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial
• Participants
  • ≤6 months postpartum | 18 to 45 years
  • With PPD: Major depressive episode beginning third trimester or ≤4 weeks postdelivery
  • Baseline score of ≥26 on the 17-item Hamilton Rating Scale for Depression (HAMD-17)
• Interventions
  • Zuranolone: 30 mg orally every evening for 2 weeks
  • Placebo
• Study design
  • 1:1 randomization
  • Analysis was by intention to treat
• Primary outcome
  • Change from baseline in HAMD-17 score at day 15
• Secondary outcomes
  • Changes from baseline in HAMD-17 score at other time points
  • HAMD-17 response (≥50% score reduction)
  • Remission rates (score ≤7)
  • Montgomery-Åsberg Depression Rating Scale score
  • Hamilton Rating Scale for Anxiety score

RESULTS:

• Zuranolone: 76 patients | Placebo: 77 patients
  • Mean (SD) age 28.3 (5.4) years
  • 98.7% completed treatment
• Patients who received zuranolone had significant day 15 HAMD-17 score improvements from baseline, compared to placebo
  • Zuranolone: −17.8
  • Placebo: −13.6
  • Difference −4.2 (95% CI, −6.9 to −1.5); P=0.003
• Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 through day 45
  • Day 3: Difference −2.7 (95% CI, −5.1 to −0.3); P=0.03
  • Day 45: Difference −4.1 (95% CI, −6.7 to −1.4); P=0.003
• Sustained differences at day 15 favoring zuranolone were observed in
  • HAMD-17 response
    • Odds ratio (OR) 2.63 (95% CI, 1.34 to 5.16); P=0.005
  • HAMD-17 score remission
    • OR 2.53 (95% CI, 1.24 to 5.17); P = 0.01
  • Change from baseline for Montgomery-Åsberg Depression Rating Scale score
    • Difference −4.6 (95% CI, −8.3 to −0.8); P=0.02
  • Hamilton Rating Scale for Anxiety score
    • Difference −3.9 (95% CI, −6.7 to −1.1); P=0.006
• One patient per group experienced a serious adverse event
  • Zuranolone group: confusional state
  • Placebo: pancreatitis

CONCLUSION:

• Compared to placebo, zuranolone significantly improved depressive symptoms in women with PPD
• Adverse events were minimal
• The authors state

Zuranolone has the potential to become a novel treatment for patients with PPD

Moreover, the findings of this study, along with prior PPD studies, support the potential for the development and therapeutic use of NAS GABA_AR PAMs in the treatment of PPD

Learn More – Primary Sources:

Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial

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