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Introduction Postpartum depression (PPD) is a serious illness where patients (pts) experience depressive symptoms that start during or after pregnancy. Concurrent anxiety symptoms in PPD are common and are associated with poorer outcomes. The Edinburgh Postnatal Depression Scale (EPDS) is a patient-reported instrument used for PPD and may be used concurrently with the clinician-administered Hamilton Rating Scale for Anxiety (HAM-A). Zuranolone (ZRN) is an investigational oral positive allosteric modulator of synaptic and extrasynaptic GABA A receptors and neuroactive steroid for the treatment of PPD and major depressive disorder in adults. The phase 3, double blind, randomized, placebo (PBO)-controlled SKYLARK study evaluating the efficacy and safety of ZRN 50 mg (ZRN50) in pts with severe PPD met its primary endpoint of change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day (D)15 (−15.6 vs −11.6 for placebo; p<0.001). The percentages of pts achieving HAMD-17 response (≥50% CFB in HAMD-17 total score) and remission (HAMD-17 total score ≤7) were higher in the ZRN group vs PBO. We report a post hoc analysis of the EPDS and HAM-A response and remission rates to assess the effects of ZRN50 on depressive and anxiety symptoms in the SKYLARK study. Methods Adults aged 18-45 years with severe PPD (baseline HAMD-17 ≥26) were randomized 1:1 to oral once-daily ZRN50 or PBO for 14 days and followed through D45. EPDS and HAM-A response (≥50% CFB in EPDS or HAM-A total score, respectively) and remission (EPDS total score <10 or HAM-A total score ≤7) rates were recorded at D3, D8, D15, D21, D28, and D45. Response and remission rates were modeled using generalized estimating equations for binary responses. Statistical testing was not adjusted for multiplicity; p values and statements of significance are considered nominal. D15 and D45 results are reported. Results Among 196 pts randomized and dosed, 170 completed the 45-day study. Significantly greater percentages of pts treated with ZRN achieved EPDS response (52.7% vs 33.7%; p=0.0178) and remission (49.5% vs 33.7%; p=0.0192) at D15 vs PBO and achieved HAM-A response (54.3% vs 37.8%, p=0.0338) and remission (34.8% vs 15.6%; p=0.0050) at D15 vs PBO. Numerically greater percentages of pts achieved EPDS response (57.1% vs 50.6%; p=0.3020) and remission (56.0% vs 47.1%; p=0.0812) at D45 with ZRN vs PBO and achieved HAM-A response (65.5% vs 60.0%; p=0.3066) and remission (44.0% vs 37.6%; p=0.3662) at D45 with ZRN vs PBO. Conclusions ZRN50 was associated with improvements in both depressive and anxiety symptoms, which commonly co-occur in individuals with PPD. These results suggest treatment with ZRN may lead to improvements in measures of both depression and anxiety and support the potential role of ZRN as a novel, oral, rapid-acting, 14-day treatment course for PPD. Funding Sage Therapeutics, Inc. and Biogen Inc. Medical writing and editorial support were provided by Meditech Media, Ltd. and Parexel, and funded by Sage Therapeutics, Inc. and Biogen Inc.