Effect of Zuranolone vs Placebo in Postpartum Depression

Abstract

IMPORTANCE Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child.OBJECTIVE To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD. DESIGN, SETTING, AND PARTICIPANTSThis phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or Յ4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019.INTERVENTIONS Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks. MAIN OUTCOMES AND MEASURESPrimary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (Ն50% score reduction) and remission (score Յ7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments. RESULTSOf 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (−17.8 vs −13.6; difference, −4.2; 95% CI, −6.9 to −1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, −2.7; 95% CI, −5.1 to −0.3; P = .03) through day 45 (difference, −4.1; 95% CI, −6.7 to −1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, −4.6; 95% CI, −8.3 to −0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, −3.9; 95% CI, −6.7 to −1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD.

Development of neuroactive steroids for the treatment of postpartum depression

“…85 At the last assessment point (day 45), a statistically significant separation between zuranolone and placebo was still observed (P = .003). 85 In addition, day 15 response and remission rates were significantly greater in the zuranolone group (72% and 45%, respectively) compared to the placebo group (48% and 23%, respectively; both P < .05). 85 These positive findings have encouraged further development of zuranolone for the treatment of PPD.…”

“…The first randomised, double‐blind, placebo‐controlled clinical trial of zuranolone in PPD included 153 women age 18‐44 years who were up to 6 months postpartum and who had an onset of symptoms no earlier than the last trimester and up to 4 weeks after delivery 85 . Key entry criteria included a total HAMD‐17 score ≥ 26 and medical stability 85 . Patients were randomised 1:1 to receive either 30 mg of zuranolone or matching placebo capsules for 14 days and were followed for another 4 weeks remaining blind to treatment 85 .…”

Advances in pharmacotherapy for postpartum depression: a structured review of standard-of-care antidepressants and novel neuroactive steroid antidepressants

“… 89 , 90 A recent double-blind, placebo-controlled phase 3 trial randomized 153 participants to a 14 day course of zuranolone 30 mg or placebo. 34 Participants were then followed for 4 weeks. Participants receiving zuranolone had a significant reduction in least-squares mean HAM-D 17 total score versus those receiving placebo (-17.8 versus -13.6, p = 0.003).…”

New Molecular Targets for Antidepressant Drugs

“…administration of brexanolone, a neuroactive steroid (SAGE-547) with gamma-aminobutyric acid (GABA) A receptor-positive allosteric modulatory activity, shows a rapid antidepressant effect that lasts more than a week in postpartum depression [ 8 , 9 ]. Zuranolone, an orally available neuroactive steroid with a comparable mechanism of action (SAGE-217), also shows antidepressant effects on MDD [ 10 ] and postpartum depression [ 11 ]. In addition, there are a number of other compounds, each with different molecular targets and potential antidepressant effects, that are currently being evaluated [ 12 ].…”