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 PARTICIPANTS This 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 4 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
INTERVENTIONS Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each
evening for 2 weeks.
MAIN OUTCOMES AND MEASURES Primary 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 (50% score
reduction) and remission (score 7) rates, Montgomery-Åsberg Depression Rating Scale
score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events
and clinical assessments.
RESULTS Of 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 RELEVANCE In 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