Effect of Zuranolone on Concurrent Anxiety and Insomnia Symptoms in Women With Postpartum Depression

J Clin Psychiatry 2023;84(1):22m14475

To cite: Deligiannidis KM, Citrome L, Huang M-Y, et al. Effect of zuranolone on concurrent anxiety and insomnia symptoms in women with postpartum depression. J Clin Psychiatry. 2023;84(1):22m14475.
To share: https://doi.org/10.4088/JCP.22m14475

© 2023 Physicians Postgraduate Press, Inc.

^aZucker Hillside Hospital, Northwell Health, Glen Oaks, New York
^bFeinstein Institutes for Medical Research, Northwell Health, Manhasset, New York
^cNew York Medical College, Valhalla, New York
^dSage Therapeutics, Inc., Cambridge, Massachusetts
^eAcaster Lloyd Consulting Ltd., London, United Kingdom
^fAMF Consulting, Los Angeles, California
*Corresponding author: Kristina M. Deligiannidis, MD, Zucker Hillside Hospital, Division of Psychiatry Research, Women’s Behavioral Health, 75-59 263rd St, Glen Oaks, NY 11004 ([email protected]).

Postpartum depression (PPD), defined as a major depressive episode with peripartum onset occurring during pregnancy or within 4 weeks postpartum, is one of the most common medical complications associated with pregnancy.^1–4 Many women with PPD experience significantly impaired functioning and well-being, with more severe depression resulting in worse mental functional health.^5–7 Symptoms of PPD can be associated with significant impairment in mother-infant bonding and maternal function,^8–11 including breastfeeding^9,12 and caring for the child.^13,14 In addition to depressive symptoms, women with PPD often experience other symptoms/comorbidities that can adversely affect their psychological well-being and overall functioning. For example, anxiety symptoms may be prominent in women with PPD, with prevalence estimates as high as approximately 70% of patients.^10,15–17 In women with PPD, anxiety symptoms have been associated with more severe depression,^18–20 longer time to treatment response,¹⁶ and an increased risk of self-harm ideation.²¹ Similarly, sleep problems are also common in women during the peripartum period.²² Insomnia (difficulty falling asleep when baby is sleeping or returning to sleep after waking to care for baby) can be both a risk factor for and a symptom of PPD, and its presence may predict both the development and severity of PPD.^9,23,24 Sleep disturbance and poor sleep quality are also associated with frequent self-harm thoughts and poor mental health status in women with PPD.^5,21 Furthermore, poor sleep quality has been associated with postpartum anxiety symptoms.²⁵ Therefore, it is important to address anxiety symptoms, as well as insomnia and other symptoms of depression, to improve the function and psychological health of women with PPD.

Multiple factors may contribute to the pathophysiology of PPD.^26,27 Altered neuroactive steroid (NAS) levels^28–30 and dysregulation of γ-aminobutyric acid (GABA) signaling and, thus, disruption of excitatory-inhibitory balance in key brain networks (eg, those controlling mood)^31–35 are implicated in PPD. Endogenous NASs such as allopregnanolone are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress, acting via interactions with GABA_A receptors.³⁶ Administration of allopregnanolone has been shown to exert anxiolytic and antidepressant effects in mice, likely through enhancement of GABA_A receptor–mediated tonic inhibition.³⁷ Zuranolone is an investigational NAS and a positive allosteric modulator of GABA_A receptors in clinical development as an oral, once-daily, 14-day treatment course for adults with PPD.^38–41 Zuranolone binds to both synaptic (containing γ subunit) and extrasynaptic (containing δ subunit) GABA_A receptors in vitro, leading to potentiation of phasic and tonic postsynaptic currents, respectively, which is hypothesized to play a role in restoring brain network function in regions thought to be involved in depression.^39,40 By increasing phasic and tonic inhibitory GABAergic signaling, zuranolone may rapidly restore and maintain excitatory-inhibitory balance in brain networks, thereby improving depressive and anxiety symptoms in women with PPD.

The phase 3 ROBIN study (NCT02978326) was a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of zuranolone in adult women with PPD. The study demonstrated a statistically significant and clinically meaningful improvement in depressive symptoms (defined in adults with PPD as a minimal important difference [MID] in 17-item Hamilton Depression Rating Scale [HDRS-17]⁴² total score of −2.1)⁴³ at day 15 with a once-daily, 14-day course of zuranolone versus placebo.⁴¹ Greater and nominally significant improvement in anxiety symptoms as assessed by Hamilton Anxiety Rating Scale (HARS) was also observed at day 15 with zuranolone versus placebo.⁴¹ The present report describes prespecified exploratory and post hoc analyses assessing concurrent remission of depressive and anxiety symptoms, anxiety symptoms, insomnia symptoms, and patient-perceived functional health from the ROBIN study. For an indirect comparison with standard-of-care (SOC) antidepressant therapy (ADT), treatment benefits and risks with zuranolone versus placebo are described by the number needed to treat (NNT) for HDRS-17 response and remission and the number needed to harm (NNH) for adverse events (AEs), respectively.

METHODS

Trial Design and Clinical Analyses

The trial design and patient inclusion/exclusion criteria have been described previously.⁴¹ Briefly, the study enrolled women aged 18–45 years, ≤ 6 months postpartum, with a diagnosis of PPD (onset of DSM-5–defined major depressive episode in the third trimester or ≤ 4 weeks postpartum) and a HDRS-17 total score ≥ 26 at baseline (N = 153).⁴¹ Use of psychotropic medications intended to treat depressive symptoms was permitted, provided that patients were on a stable dose for ≥ 30 days prior to day 1 with intent to remain at the same dose until completion of the day 15 assessments. A new ADT could be initiated during the follow-up period based on the patient’s clinical needs as per investigator judgment. The first informed consent was received on January 4, 2017, and the final poststudy observation was on December 11, 2018. Women were randomized 1:1 to receive oral zuranolone 30 mg (n = 77) or placebo (n = 76) once daily for 14 days as outpatients, with follow-up through day 45 (30 days after cessation of treatment). The trial received institutional review board approval and was performed in compliance with the Declaration of Helsinki, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, and Good Clinical Practice guidelines and all applicable regulatory requirements. All patients provided written informed consent prior to enrollment.

The primary and secondary endpoints have been reported previously.⁴¹ The primary endpoint was the change from baseline (CFB) in HDRS-17 total score at day 15. Secondary endpoints included CFB in HDRS-17 total score at days 3, 8, 21, and 45; CFB in the HARS⁴⁴ and the Montgomery-Asberg Depression Rating Scale (MADRS)⁴⁵ total scores; and rates of HDRS-17 response and remission at all measured time points. Safety and tolerability, reported previously, were evaluated by AEs, vital signs, clinical laboratory evaluations, electrocardiogram parameters, and the Columbia-Suicide Severity Rating Scale.^41,46

Concurrent remission of depressive and anxiety symptoms (defined as HARS total score ≤ 7 plus either HDRS-17 total score ≤ 7 or MADRS total score ≤ 10) was analyzed post hoc. Results are reported as percentage of patients achieving concurrent remission of depressive and anxiety symptoms.

The effect of zuranolone on anxiety symptoms was evaluated using CFB in the HDRS-17 Anxiety/Somatization (A/S) subscale score^47,48 and the patient-reported Edinburgh Postnatal Depression Scale anxiety (EPDS-3A) subscale score over time⁴⁹; the rate of HARS, HDRS-17 A/S, and EPDS-3A response (defined as ≥ 50% reduction from baseline in total scores); and the rate of sustained HARS, HDRS-17 A/S, and EPDS-3A response (defined as achievement of response at both days 15 and 45). The HDRS-17 A/S subscale, which reflects the severity of anxiety symptoms in patients with depression, includes HDRS-17 items 10 (psychic anxiety), 11 (somatic anxiety), 12 (gastrointestinal somatic symptoms), 13 (general somatic symptoms), 15 (hypochondriasis), and 17 (insight).^47,48 The EPDS-3A includes the EPDS items 3 (self-blame), 4 (anxious/worried), and 5 (scared/panicky).⁴⁹ Insomnia was evaluated using CFB in HDRS-17 insomnia subscale (HDRS-17 Ins), MADRS item 4 (reduced sleep), and EPDS item 7 (difficulty sleeping) over time. These analyses were conducted post hoc.

Improvements in general health status were assessed in a prespecified analysis using the 36-item Short-Form Health Survey, version 2 (SF-36v2), which measures adult patients’ perceptions of their own functional health and well-being that are not directly reflected in HDRS-17, HARS, or other metrics.^50,51 The survey evaluates the person’s functioning in 8 domains, including Physical Functioning, Role Limitations due to Physical Problems, Role Limitations due to Emotional Problems, Bodily Pain, General Health Perceptions, Vitality, Social Functioning, and General Mental Health.⁵⁰

Clinical benefits and risks were evaluated post hoc by assessing NNT, NNH, and the likelihood to be helped or harmed (LHH).^52,53 NNTs were estimated for response, remission, sustained response, and sustained remission and NNHs for discontinuation due to an AE, experiencing ≥ 1 treatment-emergent AE (TEAE), and AEs with an incidence ≥ 2% with zuranolone and higher than with placebo. LHH, defined as the NNH-to-NNT ratio, was calculated if both NNT and NNH were significant for a specific event.

Statistical Analysis

The CFB at each time point was evaluated using the least squares (LS) mean from a mixed model for repeated measures (MMRM). Concurrent remission rates were derived using the generalized estimating equation models for repeated measures, adjusting for baseline covariates. Secondary, exploratory, and post hoc endpoints were evaluated using an MMRM and were not adjusted for multiplicity. SF-36v2 domain or summary scores of 50 represent the normative level of the general population.⁵¹ In line with the SF-36v2 manual,⁵¹ the MIDs for SF-36v2 domain and summary scores are 2 points for Vitality, General Health, and Physical Component Summary; 3 points for Role Physical, Physical Functioning, Bodily Pain, Social Functioning, Mental Health, and Mental Component Summary; and 4 points for Role Emotional. NNT and NNH were calculated based on the proportions of patients (P) for a specific outcome (1/[P_treatment − P_placebo]). The 95% confidence intervals (CIs) for NNT and NNH were calculated based on Wilson score intervals. The analyses are exploratory. All P values are nominal, with P < .05 indicating statistical significance. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Of 153 women randomized, 150 were evaluable and included in the efficacy analyses (zuranolone, N = 76; placebo, N = 74) as previously described.⁴¹ Demographic and baseline patient characteristics (ie, age, race, ADT use, HDRS-17 total score) were well balanced between the 2 treatment arms.⁴¹ At baseline, 16/76 (21.1%) and 13/74 (17.6%) patients in the zuranolone and placebo groups, respectively, were receiving stable doses of ADTs.⁴¹ In the zuranolone group, 12 patients were receiving a selective serotonin reuptake inhibitor (SSRI), 3 were receiving a norepinephrine/dopamine-reuptake inhibitor (NDRI), and 1 was receiving a serotonin and norepinephrine reuptake inhibitor. In the placebo group, 12 patients were receiving an SSRI and 1 patient was receiving an NDRI. A small proportion (6 patients [7.9%] and 4 patients [5.4%] in the zuranolone and placebo groups, respectively) initiated ADT during the follow-up period.⁴¹

Concurrent Remission of Depressive and Anxiety Symptoms

As assessed by the combined criteria of HDRS-17 total score ≤ 7 and HARS total score ≤ 7, a greater proportion of women receiving zuranolone achieved concurrent remission of depressive and anxiety symptoms compared with those receiving placebo as early as day 3 (18.9% vs 2.7%; P = .003) and at day 15 (40.5% vs 19.2%; P = .007) and day 45 (52.1% vs 23.2%; P < .001; Figure 1A). Similarly, as assessed by the combined criteria of MADRS total score ≤ 10 and HARS total score ≤ 7, a higher rate of concurrent remission was achieved with zuranolone versus placebo at day 3 (23.0% vs 6.8%; P = .010), day 15 (43.2% vs 23.3%; P = .014), and day 45 (53.4% vs 26.1%; P = .001; Figure 1B). The rate of sustained concurrent remission of depressive and anxiety symptoms (ie, at both days 15 and 45) was higher with zuranolone versus placebo using the criteria of either the combined HDRS-17/HARS (P < .001; odds ratio [OR; 95% CI], 6.2 [2.2 to 17.4]) or the combined MADRS/HARS (P = .003; OR [95% CI], 3.7 [1.5 to 8.9]; Figure 1C).

Anxiety Symptoms

Greater CFB in HARS score at days 3 through 45 with zuranolone versus placebo (P < .05 at all measured time points) in this population has been reported previously.⁴¹ At baseline, mean (SD) HDRS-17 A/S subscale total score was 9.0 (1.5) and 9.4 (1.7) for women receiving zuranolone and placebo, respectively. Women demonstrated an improvement in anxiety/somatization symptoms as assessed by CFB in HDRS-17 A/S subscale score (LS mean [SE; 95% CI]) with zuranolone versus placebo starting at day 3 (−3.8 [0.3; −4.5 to −3.2] vs −2.7 [0.3; −3.3 to −2.0]; P = .007) and continuing at all measured time points through day 45 (−5.7 [0.4; −6.4 to −5.0] vs −4.3 [0.4; −5.0 to −3.5]; P = .003; Figure 2A). Reductions in EPDS-3A score were greater with zuranolone versus placebo at day 8 (−2.2 [0.3] vs −1.5 [0.3]; P = .032) through day 45 (−3.6 [0.3] vs −2.1 [0.3]; P < .001; Figure 2B).

Higher rates of HARS response (71.6% vs 49.3%, P = .007; Figure 3A) and HDRS-17 A/S response (68.9% vs 46.6%, P = .008; Figure 3B) were observed in women treated with zuranolone versus placebo at day 15 and continued at all measured timepoints through day 45. EPDS-3A response rates were numerically higher with zuranolone versus placebo at all measured time points from day 8 through day 45, with a nominally significant difference at day 45 (56.2% vs 26.1%, P < .001; Figure 3C). Rates of sustained response (ie, at both days 15 and 45) on HARS (58.7% vs 42.3%, P = .068), HDRS-17 A/S (53.3% vs 34.3%, P = .029), and EPDS-3A (29.3% vs 16.9%, P = .082) were numerically higher with zuranolone versus placebo (Figure 4).

Insomnia Symptoms

Numerically greater improvement in symptoms of insomnia was achieved by women receiving zuranolone versus placebo as assessed by HDRS-17 Ins (Figure 5A), MADRS reduced sleep item (Figure 5B), and EPDS difficulty sleeping item (Figure 5C); nominally significant benefits were observed for zuranolone versus placebo at all measured time points on HDRS-17 Ins, all time points except day 21 on MADRS reduced sleep item, and at day 45 on EPDS difficulty sleeping item.

Patient-Reported Functional Health and Well-Being

At day 45, women receiving zuranolone achieved improvements compared with placebo across 5 domains of the SF-36v2, including Social Functioning (LS mean [SE; 95% CI], 18.27 [1.37; 15.56 to 21.0] vs 13.53 [1.44; 10.69 to 16.37]; P = .008), Mental Health (19.39 [1.58; 16.27 to 22.51] vs 13.93 [1.64; 10.69 to 17.17]; P = .008), Physical Functioning (6.38 [0.95; 4.51 to 8.26] vs 3.8 [0.99; 1.85 to 5.74]; P = .038), Role Physical (11.75 [1.11; 9.56 to 13.94] vs 8.85 [1.16; 6.56 to 11.13]; P = .045), and Bodily Pain (8.19 [1.17; 5.87 to 10.51] vs 4.0 [1.23; 1.56 to 6.40]; P = .007), and in the Mental Component Summary score (23.59 [1.83; 19.97 to 27.21] vs 18.45 [1.90; 14.68 to 22.21]; P = .030); CFB in other SF-36v2 domains was numerically greater with zuranolone versus placebo (Supplementary Figure 1A). In women receiving zuranolone, mean scores at day 45 for Physical Functioning, Bodily Pain, and General Health domains and for Physical Component Summary reached the US population normative levels; mean Role Physical domain score was within 1 MID from population normative levels (Supplementary Figure 1B).

NNT and NNH Estimates

A greater proportion of women achieved sustained HDRS-17 response (59% vs 39%; P = .020) and sustained HDRS-17 remission (37% vs 13%, P < .001) with zuranolone versus placebo. The NNT estimates (95% CI) were similar for HDRS-17 response (5 [3 to 13]) and remission (5 [3 to 17]) at day 15, sustained response (5 [3 to 27]), and sustained remission (5 [3 to 10]; Supplementary Table 1). The NNH estimates were ≥ 10 for incidence of TEAEs and discontinuation due to an AE (Supplementary Table 1). LHH estimates were not calculated for this population as the NNH estimates were nonsignificant.

DISCUSSION

Results from ROBIN prespecified exploratory and post hoc analyses presented here show that women with PPD achieved concurrent improvements in both depressive and anxiety symptoms with zuranolone; the proportion of women achieving concurrent remission of both symptoms was greater with zuranolone versus placebo as early as day 3, and the benefit was maintained at days 15 and 45. Sustained (at both days 15 and 45) concurrent remission was observed in approximately 30% of women receiving zuranolone based on either the HDRS-17/HARS or the MADRS/HARS criteria; the rate was higher than that of women receiving placebo (7% on HDRS-17/HARS criteria and 11% on MADRS/HARS criteria). Improvements in anxiety symptoms as assessed by HDRS-17 A/S and EPDS-3A with zuranolone versus placebo are consistent with previous similar findings based on HARS assessments.⁴¹ Beneficial effects of zuranolone on insomnia symptoms and patient-perceived functional health were also observed.

Given the high rate of concurrent anxiety and/or insomnia symptoms in women with PPD, these findings are potentially clinically impactful, as rapid improvements in depressive, anxiety, and insomnia symptoms may be achieved without a need for polypharmacy. In clinical practice, pharmacotherapies targeting anxiety and/or insomnia symptoms are often used in addition to SOC ADT, increasing risk for adverse effects, drug-drug interactions, and poor adherence,⁵⁴ as only a few SOC ADTs have been shown to improve both depressive and anxiety symptoms in clinical studies of women with PPD.^55–58 Additionally, it often takes 4 to 6 weeks for SOC ADTs to demonstrate clinical benefit,^59–61 with women experiencing transient increases in jitteriness/anxiety during the early treatment period⁶² at greater rates than men.⁶³

Women with PPD experience significant impairments in physical functioning and psychosocial well-being beyond the mood and neurovegetative symptoms associated with PPD.^5,7,64 Patient-reported outcome measures such as SF-36v2 are increasingly incorporated into clinical trials to evaluate how treatment impacts the overall functioning and well-being of patients.^65,66 The present results of nominally significant improvements in 5 domains of the SF-36v2 (including 3 of the 4 physical health domains) and in the Mental Component Summary score suggest that women receiving zuranolone as treatment for their PPD perceive improvements in their own functional health and well-being.

When medications are compared with placebo, the resultant NNT and NNH estimates can serve as a basis of indirect comparisons within a class of agents, as recently demonstrated for ADTs.⁶⁷ In general, NNT values < 10 for efficacy measures suggest that the intervention is potentially clinically beneficial.⁶⁸ NNTs of 6–9 are commonly reported when comparing SOC ADTs with placebo. In addition, NNH values ≥ 10 are desirable for AE outcomes.⁶⁸ Our analyses found an NNT of 5 for response and remission at day 15 and NNH estimates ≥ 10 for both incidence of AEs and discontinuation due to an AE.

Study Limitations

The analyses were for non-primary endpoints in the study and therefore were not controlled for multiplicity. Additionally, results may not be generalizable to patients outside the confines of a clinical trial because of the strict inclusion/exclusion criteria used in this registrational study. Furthermore, reasons for clinical trial discontinuation can be complex, so the NNH for discontinuation due to AEs in this study may not always generalize to overall tolerability in clinical practice. The brief duration of the study limits the sensitivity of calculating NNH for delayed AEs, and the relatively small sample sizes limit sensitivity of calculating NNH for uncommon AEs and subpopulation effects. Finally, the NNH results for zuranolone were nonsignificant, likely because of the small sample size. Estimates for LHH were therefore not calculated for this population.

CONCLUSIONS

Adult women with PPD receiving zuranolone experienced improvements in both depressive and anxiety symptoms, with a higher rate of concurrent remission at days 3, 15, and 45 compared with those receiving placebo. Beneficial effects of zuranolone versus placebo on insomnia and patient-reported functional health and well-being were also observed. Together, these findings support further development of zuranolone as a potentially rapid-acting pharmacotherapy for adults with PPD, including those with anxiety and/or insomnia symptoms, potentially without the need for polypharmacy.

Submitted: March 31, 2022; accepted October 31, 2022.
Published online: January 30, 2023.
Relevant financial relationships: Dr Deligiannidis serves as a consultant to Sage Therapeutics, Inc., Brii Biosciences, and GH Research and reports grants awarded to Zucker Hillside Hospital/Feinstein Institutes for Medical Research during the conduct of the brexanolone injection and zuranolone clinical trials. Dr Deligiannidis received grants from National Institutes of Health (NIH) and Vorso Corporation and royalties from an NIH employee invention outside of the submitted work. Dr Citrome serves as a consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Eisai, Enteris BioPharma, HLS Therapeutics, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Lyndra, Medavante-ProPhase, Merck, Neurocrine, Novartis, Noven, Otsuka, Ovid, Relmada, Reviva, Sage, Sunovion, Teva, University of Arizona, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Eisai, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sage, Sunovion, Takeda, and Teva; and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stocks (small number of shares of common stock) in Bristol Myers Squibb, Eli Lilly, J & J, Merck, and Pfizer purchased > 10 years ago; and receives royalties from Wiley (Editor in Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). Drs Huang, Bonthapally, and Lasser are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options. Ms Acaster is an employee of Acaster Lloyd Consulting Ltd, which was paid by Sage Therapeutics, Inc., to conduct the research reported in this work. Dr Fridman is an employee of AMF Consulting, which was paid by Sage Therapeutics Inc., to conduct the research reported in this work. Dr Kanes is a former employee of Sage Therapeutics, Inc., and may hold stock and/or stock options.
Funding/support: The ROBIN Study was funded by Sage Therapeutics, Inc., Cambridge, MA.
Role of the sponsor: Sage Therapeutics, Inc. was involved in the ROBIN Study design; both Sage Therapeutics, Inc., and Biogen Inc. were involved in the post-hoc analyses, interpretation, and writing of this report. During the development process, both Sage Therapeutics, Inc., and Biogen Inc., had the opportunity to review and comment on the manuscript; however, the authors retained full editorial control and provided final approval on all content. All authors had full access to all data, and the corresponding author had final responsibility for the decision to submit for publication.
Previous presentations: Aspects of this post hoc analysis have been presented at the Society for Maternal-Fetal Medicine, 40th Annual Pregnancy Meeting, February 3–8, 2020, Grapevine, TX; the Society of Biological Psychiatry, Virtual Annual Meeting, April 30–May 2, 2020; Psych Congress 2020, Virtual Annual Meeting, September 10–13, 2020; the European College of Neuropsychopharmacology, Annual Virtual Meeting, September 12–15, 2020; the American Society of Clinical Psychopharmacology, Annual Virtual Meeting, 2020; the American College of Neuropsychopharmacology, Annual Virtual Meeting, 2020; and the Society of Biological Psychiatry, Annual Virtual Meeting, April 29–May 1, 2021.
Acknowledgments: Medical writing and editorial assistance were provided by Symbiotix, LLC (Linda M. Ritter, PhD, Medical Director [no conflicts of interest to disclose]), and funded by Sage Therapeutics, Inc., and Biogen Inc. The authors also thank Brian Werneburg, PhD, and Handan Gunduz-Bruce, MD, MBA, for their contributions to earlier versions of the manuscript. Drs Werneburg and Gunduz-Bruce are former employees of Sage Therapeutics, Inc., and may hold stock and/or stock options.
Supplementary material: Available at Psychiatrist.com.

Clinical Points

• Postpartum depression with anxiety symptoms or symptoms of sleep disturbance/insomnia is associated with more severe depression, longer time to treatment response, increased of self-harm ideation, and poor mental health status.
• A once-daily, 14-day treatment course of oral zuranolone was associated with concurrent improvements in depressive and anxiety symptoms, with beneficial effects on insomnia and self-reported functional health in women with postpartum depression.