Medical Policy

Policy Num:       05.001.036
Policy Name:     Brexanolone for Postpartum Depression

Policy ID:          [05.001.036]  [Ac / B / M+/ P+]  [5.01.33]

Last Review:       September 10, 2024
Next Review:       September 20, 2025
 

Related Policies: None

Brexanolone for Postpartum Depression

summary

Description

Postpartum depression (PPD) is a serious and debilitating condition that is characterized by a major depressive episode temporally and pathophysiologically related to pregnancy. It is similar to other forms of depression and characterized by sadness and/or anhedonia and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation. Brexanolone is chemically similar to the endogenous hormone allopregnanolone, which is a positive allosteric modulator of GABAA (γ aminobutyric acid-ligand gated chloride channel) receptors. The level of endogenous allopregnanolone increases during pregnancy, reaches a peak during the third trimester but falls abruptly after delivery. It is hypothesized that a one-time administration of brexanolone infusion ameliorates symptoms of PPD via positive allosteric modulation of both synaptic and extrasynaptic GABAA receptors.

Summary of Evidence

For individuals with PPD who receive brexanolone, the evidence includes 3 randomized, placebo-controlled trials in which 247 patients with Hamilton Rating Scale for Depression (HAM-D) scores ≥20 were randomized to brexanolone 60 μg/kg/h (n=38), brexanolone 90 μg/kg/h (n=102), and placebo (n=107). Relevant outcomes are change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The primary efficacy endpoint of change from baseline in the 17-item HAM-D total score at 60 hours resulted in significant and clinically meaningful reductions in the total score compared with placebo. Brexanolone was associated with a greater frequency of sedation-related side effects than placebo including sudden loss of consciousness in 6 patients. Characterization of the safety of brexanolone was inadequate due to notable study limitations. These include exposure to study drug in a limited number of patients in a controlled setting and a relatively short follow-up of 30 days. The observed loss of consciousness during drug infusion is part of the basis for a Risk Evaluation and Mitigation Strategy requirement. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with PPD who receive zuranolone, the evidence includes 2 RCTs in which 346 patients with HAM-D scores ≥26 were randomized to zuranolone 30 mg orally once daily (n=76), zuranolone 50 mg orally once daily (n=98), and placebo (n=172). Relevant outcomes are change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The primary efficacy endpoint of change from baseline in the 17-item HAM-D total score at 15 days resulted in significant and clinically meaningful reductions in the total score compared with placebo. Zuranolone was associated with a greater frequency of somnolence and sedation than placebo, but no loss of consciousness was reported. Notable relevance gaps include a relatively short follow-up of 45 days and inclusion of only patients with severe PPD, which may limit its utility to that population. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to assess whether treatment with brexanolone or zuranolone improves the net health outcome in individuals with postpartum depression.

policy statements

Individuals may be considered for a 1 time use of brexanolone per pregnancy if they meet all of the following criteria:

1. Individual is 15 years of age or older and ≤6 months postpartum at the time of infusion.

2. Individual meets the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) criteria for a major depressive episode (See Table 1) by a structured clinical interview for DSM-5 disorders.

3. Individual has a onset of depressive episode between 3^rd trimester through 4 weeks postpartum.

4. Individual has a diagnosis of moderate to severe postpartum depression based on either of the following:

   1. Hamilton Rating Scale for Depression (HAM-D) score ≥ 20 (see policy guidelines) OR

   2. Edinburgh Postnatal Depression Scale (EPDS) score ≥ 13 (see policy guidelines)

5. Individual meets 1 of the following:

   1. Has tried and had an inadequate response to 2 antidepressant agents from 2 different antidepressant classes (i.e. SSRIs, SNRIs, TCAs, bupropion, or mirtazapine). An adequate trial of an antidepressant is defined by BOTH of the following:

      • The trial length was at least 6 weeks at generally accepted doses or of sufficient duration as determined by the treating physician at the generally accepted doses; and

      • Individual was ≥80% adherent to the agent during the trial; OR

   2. Has a documented intolerance or U.S. Food and Drug Administration (FDA) labeled contraindication, to major classes of antidepressant agents; OR

   3. Shows a potential risk of immediate harm to self and/or others as determined by the treating physician and supported by documentation.

6. Individual does NOT have any FDA labeled contraindications to the requested agent and is intended to be used consistently with the FDA approved label (see policy guidelines).

7. The prescriber is a specialist in the area of the individual's diagnosis (e.g. psychiatrist) or the prescriber has consulted with a specialist in the area of the individual's diagnosis.

Brexanolone is considered investigational when the above criteria are not met.

Brexanolone is considered investigational for all other indications.

policy guidelines

Brexanolone

Brexanolone should be administered as a continuous intravenous infusion over 60 hours (2.5 days) as follows:

• 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour

• 4 to 24 hours: Increase dosage to 60 mcg/kg/hour

• 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (alternatively consider a dosage of 60 mcg/kg/hour for those who do not tolerate 90 mcg/kg/hour)

• 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour

• 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour

Brexanolone has a boxed warning because individuals are at risk of excessive sedation or sudden loss of consciousness during administration. Individuals must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. Individuals must be accompanied during interactions with their child(ren). In addition, a healthcare provider must be available on-site to continuously monitor the individuals, and intervene as necessary, for the duration of the infusion.

Brexanolone is available only through a restricted program called the ZULRESSO REMS. Notable requirements include the following:

• Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to individuals who are enrolled in the ZULRESSO REMS.

• Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the ZULRESSO REMS.

• Individuals must be enrolled in the ZULRESSO REMS prior to administration of brexanolone.

• Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies.

Because of the low amounts of brexanolone secreted in milk and low oral bioavailability, brexanolone would not be expected to cause any adverse effects in breastfed infants. There are no data on the effects of brexanolone on a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition.

The safety and effectiveness of brexanolone has not been established in pediatric patients.

Zuranolone

The recommended dose of zuranolone is 50 mg taken orally once daily in the evening for 14 days. It should be taken with fat-containing food (eg, 400 to 1000 calories, 25% to 50% fat). If the individual experiences central nervous system (CNS) effects within the 14-day period, the dosage may be reduced to 40 mg once daily in the evening for the remainder of the 14-days.

Zuranolone has a boxed warning because individuals taking zuranolone are at risk of impaired ability to drive or engage in other potentially hazardous activities due to CNS depressant effects. Individuals should be advised not to drive or engage in other potentially hazardous activities until at least 12 hours after zuranolone administration for the duration of the 14-day treatment course. Additionally, individuals may not be able to assess their own driving competence, or the degree of driving impairment caused by zuranolone.

Because of the low amounts of zuranolone secreted in milk, zuranolone would not be expected to cause any adverse effects in breastfed infants, however, there are no data on the effects of zuranolone on a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for zuranolone and any potential adverse effects on the breastfed child from zuranolone or from the underlying maternal condition.

The safety and effectiveness of zuranolone has not been established in pediatric patients.

Depression Scales

Hamilton Rating Scale for Depression (HAM-D)

HAM-D is a 17-item rating scale to determine the severity level of depression in an individual before, during, and after treatment. The total score ranges from 0 to 52, with the score corresponding to the following classifications:

• 0-7: No depression (normal)

• 8- 13: Mild depression

• 14-18: Moderate depression

• 19-22: Severe depression

• ≥23: Very severe depression

Edinburgh Postnatal Depression Scale (EPDS)

EPDS is a self-report instrument containing 10 items that are ranked from 0 to 3 that reflect the individual's experience over the past week. The total score ranges from 0 to 30. An EPDS ≥13 is an acceptable cut-point for identifying women at risk for major depression in clinical settings.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Postpartum Depression

Postpartum depression (PPD ) is a temporal major depressive episode that may occur during pregnancy or within 4 weeks of delivery with an estimated prevalence of approximately 12% of births.^1, As per estimates by Sage Therapeutics, the sponsor of brexanolone, PPD may affect 1 in 9 women who give birth in the U. S. per year which translates to 400000 incident cases annually.^2,3, 

PPD depression is similar to other forms of depression and characterized by sadness and/or anhedonia and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation (see Table 1 for the diagnostic criteria for a major depressive episode). However, PPD is distinguishable from postpartum blues (baby blues) where sadness and anxiety are milder, are time-limited (lasting for a few hours to a few days in the first week postpartum) and have few negative sequelae.^4,PPD can have serious implications as suicide is the leading cause of maternal death after childbirth in the developed world. PPD has been reported to be one of the strongest predictors of suicidal ideation in new mothers^5, and carries an increased risk for suicide.^6,7, Recent studies suggest that postpartum suicidal ideation occurs in 19% to 30% of women with PPD.^8,9,

Table 1. Diagnostic Criteria for a Major Depressive Episode

Adapted from FDA Briefing Document10, and Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed., American Psychiatry Association, 2013.7,

Current Treatment

The following therapies are currently being used to manage patients with PPD.

Psychotherapy alone is considered first-line treatment for mild to moderate peripartum depression, whereas psychotherapy is often combined with medication in patients with severe symptoms.^11, Cognitive behavior therapy has the most evidence supporting its effectiveness.^12, Evidence is equivocal regarding the use of exercise to treat peripartum depression,^13, and hypnosis has no demonstrated benefit.^14, In patients with severe peripartum depression that is refractory to medication or who have contraindica­tions to medication use, electroconvulsive therapy is effective.^11,

No drugs had been specifically approved by the U.S. Food and Drug Administration for treatment of PPD prior to the approval of brexanolone.^10, Drugs generally approved for the treatment of major depression are used to treat PPD, but data on their effectiveness is limited. Non-drug treatments such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and psychotherapy are also used. All available depression treatments show a delayed effectiveness response. Antidepressant drugs typically take 4 to 6 weeks to demonstrate efficacy. Similarly, a course of electroconvulsive therapy is typically twice per week for 4 or 5 weeks, transcranial magnetic stimulation is given daily for 4 to 6 weeks, and psychotherapy usually involves 8 to 20 weekly sessions.^3,

Prior to the approval of brexanolone, there was no U.S. Food and Drug Administration approved treatments for PPD.

De Crescenzo et al (2014) published a systematic review of RCTs comparing selective serotonin reuptake inhibitors to placebo and/or other treatments for PPD that included 6 RCTs with 595 patients.^15, Comparators included cognitive-behavioral intervention, psychosocial community-based intervention, psychodynamic therapy, a second-generation tricyclic antidepressant, and placebo. Limitations in the evidence precluded meta-analytic pooling of data and included small sample size, heterogeneity in interventions, outcomes, duration of follow-up, and a high dropout rate. The response was defined as a reduction of at least 50% from baseline on the HAM-D or Edinburgh Postnatal Depression Scale and calculated on the primary endpoint. Only 1 of the 6 included studies reported a statistically significant difference in response rate with selective serotonin reuptake inhibitors vs the comparator.

Molyneaux et al (2018) published a Cochrane systematic review of antidepressants for preventing postnatal depression.^16, The authors identified 2 RCTs trials with a total of 81 participants. The first trial compared nortriptyline with a placebo and did not find any evidence that nortriptyline was effective in preventing postnatal depression.^17, In this study, 23% (6/26) of women who took nortriptyline and 24% (6/25) of women who took placebo experienced postnatal depression (relative risk [RR] 0.96, 95% confidence interval [CI] 0.36 to 2.59, very low-quality evidence) in the first 17 weeks postpartum. The second study compared sertraline with a placebo.^18, In this study, 7% (1/14) of women who took sertraline developed postnatal depression in the first 17 weeks postpartum compared with 50% (4/8) of women who took a placebo. It is uncertain whether sertraline reduces the risk of postnatal depression (RR 0.14, 95% CI 0.02 to 1.07, very low-quality evidence). Authors failed to draw any clear conclusions about the effectiveness of antidepressants for the prevention of postnatal depression because of the limited sample size in both trials.

regulatory status

On March 19, 2019, brexanolone (Zulresso) injection for intravenous use was approved by the FDA for the treatment of PPD in adults. On June 16, 2022, the labeled indication was expanded to patients 15 years and older.

On August 4, 2023, zuranolone (Zurzuvae) capsule for oral use was approved by the FDA for the treatment of PPD in adults.

Potential benefits of these agents may include the following:

• Treatment offers a novel mechanism of action or approach that may allow the successful treatment of many individuals for whom other available treatments have failed.

• Successful treatment may reduce the potential for significant morbidity and mortality and allow more positive interactions with mother and baby.

• Treatment offers an opportunity to alleviate symptoms faster (known response within 60 hours [brexanolone] or as early as 3 days [zuranolone]) than conventional treatments (weeks to months with selective serotonin reuptake inhibitors or non-drug treatments).

RATIONALE

This evidence review was created in June 2019 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through July 9, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Brexanolone for Postpartum Depression

Clinical Context and Therapy Purpose

The purpose of brexanolone in individuals who have postpartum depression (PPD) is to provide a treatment option that is an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a diagnosis of PPD (See Table 1).

Interventions

The therapy being considered is brexanolone, which is chemically identical to endogenous allopregnanolone, a positive allosteric modulator of γ aminobutyric acid-ligand gated chloride (GABAA) channel receptors.

Allopregnanolone is an endogenous hormone derived from progesterone and formed in the brain and corpus luteum, and during pregnancy, in the placenta. Levels of allopregnanolone increase during pregnancy, reach a peak during the third trimester, then fall abruptly after delivery. Although the mechanism of action is unknown, it is thought to be related to the positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors.^19,

Comparators

The relevant comparators are standard medical management (psychotherapy and/or pharmacotherapy).

Outcomes

The general outcomes of interest are change in disease status, functional outcomes, quality of life, treatment-related mortality, and treatment-related morbidity. The primary efficacy outcomes measure used in the 3 clinical trials of brexanolone was the 17-Item Hamilton Rating Scale for Depression (HAM-D). It is a validated instrument used to rate the severity of depression in individuals who are already diagnosed as depressed^20, and has been used in a number of registration studies of approved oral antidepressants.^2, It is summarized in Table 2. Sage Therapeutics also collected information on other secondary outcomes using the Clinical Global Impression, the Montgomery-Åsberg Depression Rating Scale, and Edinburgh Postnatal Depression Scale. While Clinical Global Impression is a validated measure often utilized in clinical trials to allow clinicians to integrate several sources of information into a single rating of the individual's condition, it is not a disease-specific measure and was only used to corroborate the results of the primary outcome measure.^3, Therefore, such outcome measures are not summarized further in this Report. The onset of symptoms of PPD generally occurs at a discrete time point in the third trimester of pregnancy or after childbirth. The intention of a 1-time infusion of brexanolone postpartum for the onset of PPD during pregnancy or after delivery is to achieve acute relief from depressive symptoms. Therefore, assessment of early efficacy outcomes after completion of the 60-hour infusion is appropriate. Further, to assess the durability of efficacy at 30 days is also appropriate.

Table 2. Health Outcome Measures Relevant to Postpartum Depression

HAM-D: Hamilton Rating Scale for Depression ; EPSD: Edinburgh Postnatal Depression Scale.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The clinical development program of brexanolone for patients with PPD is summarized in Table 3 and includes 3 randomized, placebo-controlled trials. Trial characteristics and results are summarized in Tables 4 and 5, respectively. All 3 trials were independent but conducted under an umbrella protocol with similar trial designs, there were some differences and similarities. These are summarized below:

• While all 3 trials randomized patients to a 60-hour infusion of intravenous (IV) brexanolone or placebo and included the proposed 90 μg/kg/h dose regimen, trial 202B also included an arm to evaluate a 60 μg/kg/h dose regimen.

• Trials 202A and 202B enrolled patients with severe PPD (baseline HAM-D score of ≥26) while trial 202C enrolled patients with moderate PPD (baseline HAM-D score of 20 to 25).

• The primary endpoint in all 3 trials was the change from baseline in the HAM-D total score at the end of infusion (hour 60).

• Pre-specified key secondary endpoints varied between the trials and included a change from baseline in HAM-D total score at the end of day 30, HAM-D change over time, change in HAM-D individual items, HAM-D response, HAM-D remission, and Clinical Global Impression-I.

A total of 267 patients were randomized in the 3 trials but 20 were not dosed and withdrew for personal reasons (n=10) or were withdrawn because they no longer met study criteria in the time between randomization and scheduled treatment (n=10). Overall, 94.7% of all patients completed the study. All 3 trials demonstrated a statistically and clinically significant difference in the least mean square change in HAM-D score at 60 hours after the infusion. However, the larger phase 3 trials (202B and 202C) revealed a smaller treatment effect than what was observed in the initial phase 2 trial (202A) (3.7 and 2.5 vs. 12.2 respectively). The placebo-subtracted difference in HAM-D scores for both the 60 and 90 μg/kg/h doses (-5.5 and -3.7, respectively) are consistent with the efficacy results of other approved antidepressants. Clinically significant improvement in depression was also observed in the placebo arm. This was likely due to increased attention and care received from trained health professionals, as well as supportive care for babies while staying in the hospital.

Post hoc analyses of pooled data of 127 patients from the pivotal 202B and 202C studies showed that the baseline health-related quality of life and health utility as assessed with the Short Form-36 Health Survey version 2 (SF-36-v2) among patients with PPD was significantly below normative values and those patients who responded to treatment also experienced rapid improvement in health-related quality of life to levels similar to those observed in the general population.^24, Excluding the physical summary measure, the mean improvement in scores ranged from 4.76 to 25.44 points on day 7 and from 6.20 to 29.56 on day 30, which are all larger than the minimal important change in scores established for these SF-36-v2 scales. Score improvements of this magnitude are in the moderate to large effect size range. Since SF-36-v2 was added to the trials as an exploratory endpoint by protocol amendment, data were only available for a subset of patients in the clinical trials.

Overall, the incidence of adverse events was similar between the brexanolone and placebo arms (50% vs 50.5% respectively). Two cases of serious adverse events were reported in brexanolone-treated patients compared to none in placebo. In 1 patient in the 202B trial, a patient who received brexanolone 60 μg/kg/h reported suicidal ideation 2 days after the infusion while another patient in the 202C trial who received brexanolone 90 μg/kg/h suffered from syncope/altered consciousness. In general, the incidence of sedation-related adverse events was observed at a higher frequency in brexanolone versus placebo-treated patients, which is reflective of the primary pharmacology of brexanolone. The incidence of sedation/somnolence was 6% and 15% in patients treated with placebo and brexanolone (any dose), respectively. The incidence of dizziness, lightheadedness, presyncope, or vertigo was 7% and 12%, respectively.

The major safety concern observed with brexanolone was 6 participants experienced loss of consciousness/syncope/presyncope during the infusion. Of these 6, 1 fainted with blood draw (fear of needles), 1 suffered presyncope/vertigo standing, which was resolved after sitting, and 4 appeared to have suddenly fallen asleep. These effects were resolved with dose interruption and all patients recovered in 10 to 60 minutes after loss of consciousness. As per the U.S. Food and Drug Administration (FDA),^10, the loss of consciousness can be abrupt and there is no known way to predict the risk of loss of consciousness, which could result in serious harm, accident, or injury to the mother and, potentially to the infant. The observed incidence of loss of consciousness occurred in a clinical trial setting that required overnight accommodations for patients for approximately 72 hours, IV infusion capabilities, and the presence of a healthcare professional on-site at all times. While the healthcare professional credentials varied between sites such as emergency medical technicians, nurses, and physicians, the majority of patients (85%) were dosed in a variety of non-hospital clinical research environments and 15% were dosed at units that were part of a hospital environment.^25, In order to mitigate the risk of a sudden loss of consciousness, the FDA has mandated a Risk Evaluation and Mitigation Strategy that requires administration of brexanolone only in medically-supervised settings and is detailed in the section “Tentative Inclusion Guidelines”.

Table 3. Summary of the Clinical Development Program for Brexanolone

HAM-D; Hamilton Rating Scale for Depression; NCT: National Clinical Trial.

Table 4. Summary of Key Randomized Trials of Brexanolone

DSM: Diagnostic and Statistical Manual of Mental Disorders; HAM-D; Hamilton Rating Scale for Depression.

Table 5. Summary of Key Randomized Trials of Brexanolone

CI: confidence interval; HAM-D: Hamilton Rating Scale for Depression ; LS: least square; NA: not applicable; NR: not reported; SE: standard error.aHAM-D remission is ≤ 7 HAM-D total score.bHAM-D response is ≥ 50% reduction from baseline in HAM-D total score.

The purpose of the study limitations table (Table 6) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. No limitations in study design and conduct were noted. Notable relevance limitations include a relatively short follow-up of 30 days and exposure of drugs in a limited number of patients under controlled settings to adequately characterize the safety of brexanolone. The FDA has proposed the creation of a registry to enroll all patients treated with brexanolone to better characterize the risk of loss of consciousness and management of the risk.

Table 6. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Brexanolone for Postpartum Depression

The evidence for use of brexanolone for PPD consists of 3 RCTs in which 247 patients were randomized to brexanolone 60 μg/kg/h (n=38), brexanolone 90 μg/kg/h (n=102), and placebo (n=107). The primary efficacy endpoint of change from baseline in the HAM-D total score at 60 hours resulted in significant and clinically meaningful reductions in HAM-D total score compared with placebo. Brexanolone was associated with a greater frequency of sedation-related side effects than placebo including sudden loss of consciousness in 6 patients. Therefore, brexanolone has been approved with a Risk Evaluation and Mitigation Strategy program to monitor and manage the risk of loss of consciousness. Notable relevance gaps include a relatively short follow-up of 30 days and exposure of drugs in a limited number of patients under controlled settings to adequately characterize the safety of brexanolone.

For individuals with PPD who receive brexanolone, the evidence includes 3 randomized, placebo-controlled trials in which 247 patients with HAM-D scores ≥20 were randomized to brexanolone 60 μg/kg/h (n=38), brexanolone 90 μg/kg/h (n=102) and placebo (n=107). Relevant outcomes are change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The primary efficacy endpoint of change from baseline in the 17-item HAM-D total score at 60 hours resulted in significant and clinically meaningful reductions in the total score compared with placebo. Brexanolone was associated with a greater frequency of sedation-related side effects than placebo including sudden loss of consciousness in 6 patients. Characterization of the safety of brexanolone was inadequate due to notable study limitations. These include exposure to study drug in a limited number of patients in a controlled setting and a relatively short follow-up of 30 days. The observed loss of consciousness during drug infusion is part of the basis for a Risk Evaluation and Mitigation Strategy requirement. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Zuranolone for Postpartum Depression

Clinical Context and Therapy Purpose

The purpose of zuranolone in individuals who have PPD is to provide a treatment option that is an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a diagnosis of PPD (See Table 1).

Interventions

The therapy being considered is zuranolone, which is chemically identical to endogenous allopregnanolone, a positive allosteric modulator of GABAA channel receptors.

Allopregnanolone is an endogenous hormone derived from progesterone and formed in the brain and corpus luteum, and during pregnancy, in the placenta. Levels of allopregnanolone increase during pregnancy reach a peak during the third trimester, then fall abruptly after delivery. Although the mechanism of action is unknown, it is thought to be related to the positive allosteric modulation of both synaptic and extrasynaptic GABAA receptors.^19,

Comparators

The relevant comparators are standard medical management (psychotherapy and/or pharmacotherapy).

Outcomes

The general outcomes of interest are change in disease status, functional outcomes, quality of life, treatment-related mortality, and treatment-related morbidity. The primary efficacy outcomes measure used in the 2 clinical trials of zuranolone was the HAM-D. It is a validated instrument used to rate the severity of depression in individuals who are already diagnosed as depressed^20, and has been used in a number of registration studies of approved oral antidepressants. It is summarized in Table 2, above. Sage Therapeutics also collected information on other secondary outcomes using the Clinical Global Impression, the Montgomery-Åsberg Depression Rating Scale, and Edinburgh Postnatal Depression Scale. While Clinical Global Impression is a validated measure often utilized in clinical trials to allow clinicians to integrate several sources of information into a single rating of the individual's condition, it is not a disease-specific measure and was only used to corroborate the results of the primary outcome measure. Therefore, such outcome measures are not summarized further in this Report. The onset of symptoms of PPD generally occurs at a discrete time point in the third trimester of pregnancy or after childbirth. The intention of a 14-day course of oral zuranolone postpartum for the onset of PPD during pregnancy or after delivery is to achieve acute relief from depressive symptoms. Therefore, assessment of early efficacy outcomes after completion of the 14-day course is appropriate. Further, to assess the durability of efficacy at 30 days is also appropriate.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought;

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The efficacy of zuranolone for the treatment of PPD in adults was demonstrated in 2 randomized, placebo controlled trials in women with PPD with onset of symptoms in the third trimester or within 4 weeks of delivery.^28,29, Trial characteristics and results are summarized in Tables 7 and 8, respectively. The studies were conducted by the same study group but investigated differing doses of zuranolone versus placebo. Deligiannidis et al (2021) compared zuranolone 30 mg daily (dose not FDA-approved) to placebo and Deligiannidis et al (2023) compared zuranolone 50 mg daily to placebo. The only FDA-approved dose of zuranolone is 50 mg once daily. A total of 150 patients were included in analysis in the 2021 study and 196 included in analysis in the 2023 study. Both trials demonstrated a statistically and clinically significant difference in the least mean square difference in HAM-D score at day 15 after the completion of the 14-day regimen. In the 2023 study investigating the FDA-approved dose of 50 mg, clinically meaningful improvements in symptoms were evident as early as day 3 of treatment and were maintained through day 45. Notably, in both studies, only women with severe PPD (baseline HAM-D score ≥26) were included. Clinically significant improvement in depression was also observed in the placebo arms. This was likely due to increased attention and care received from trained health professionals, as well as supportive care for babies while staying in the hospital.

In the 2023 study, zuranolone was generally well tolerated.^29, During the 14-day treatment course, adverse events were reported by 60.2% (n=59) and 41.8% (n=41) of patients receiving zuranolone and placebo, respectively. In the zuranolone group, 16.3% experienced adverse events leading to dosage reduction. Specific adverse events leading to dosage reduction in more than 1 patient receiving zuranolone included somnolence (7.1%), dizziness (6.1%), and sedation (3.1%). Four patients in the zuranolone group compared to 2 patients in the placebo group experienced an adverse event leading to discontinuation of the study drug. Overall, the most common adverse events reported by patients were somnolence (26.5% zuranolone vs. 5.1% placebo), dizziness (13.3% zuranolone vs. 10.2% placebo), sedation (11.2% zuranolone vs. 1.0% placebo), and headache (9.2% zuranolone vs. 13.3% placebo). Two cases of serious adverse events, both in the zuranolone grouop, were reported, 1 during the treatment course and one post-treatment, but were considered unrelated to the study drug. There was no loss of consciousness reported.

Table 7. Summary of Key Randomized Trials of Zuranolone

DSM: Diagnostic and Statistical Manual of Mental Disorders; HAM-D; Hamilton Rating Scale for Depression; NCT: National Clinical Trial.

Table 8. Summary of Key Randomized Trials of Zuranolone

CI: confidence interval; HAM-D: Hamilton Rating Scale for Depression; LS: least square; NCT: National Clinical Trial; NR: not reported; OR: odds ratio; SE: standard error.aHAM-D remission is ≤ 7 HAM-D total score.bHAM-D response is ≥ 50% reduction from baseline in HAM-D total score.

The purpose of the study limitations table (Tables 9 and 10) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. Notably, in both studies, only women with severe PPD (baseline HAM-D score ≥26) were included. Other limitations include a relatively short follow-up of 45 days.

Table 9. Study Relevance Limitations

PPD: Postpartum depression. The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 10. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Zuranolone for Postpartum Depression

The evidence for use of zuranolone for PPD consists of 2 RCTs in which 346 patients with severe PPD (baseline HAM-D score ≥26) were randomized to zuranolone 30 mg orally once daily (n=76), zuranolone 50 mg orally once daily (n=98), and placebo (n=172). The primary efficacy endpoint of change from baseline in the HAM-D total score at day 15 resulted in significant and clinically meaningful reductions in HAM-D total score compared with placebo. Zuranolone was associated with a greater frequency of somnolence and sedation than placebo, but no loss of consciousness was reported. Notable relevance gaps include a relatively short follow-up of 45 days.

For individuals with PPD who receive zuranolone, the evidence includes 2 RCTs in which 346 patients with HAM-D scores ≥26 were randomized to zuranolone 30 mg orally once daily (n=76), zuranolone 50 mg orally once daily (n=98), and placebo (n=172). Relevant outcomes are change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The primary efficacy endpoint of change from baseline in the 17-item HAM-D total score at 15 days resulted in significant and clinically meaningful reductions in the total score compared with placebo. Zuranolone was associated with a greater frequency of somnolence and sedation than placebo, but no loss of consciousness was reported. Notable relevance gaps include a relatively short follow-up of 45 days and inclusion of only patients with severe PPD, which may limit its utility to that population. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Obstetricians and Gynecologists

In June 2023, the American College of Obstetricians and Gynecologists (ACOG) published a clinical practice guideline on treatment and management of mental health conditions during pregnancy and postpartum.^30, The following relevant recommendation was made regarding brexanolone:

• "ACOG recommends consideration of brexanolone administration in the postpartum period for moderate-to-severe perinatal depression with onset in the third trimester or within 4 weeks postpartum. The decision to use brexanolone should balance the benefits (eg, rapid onset of action) with the risks and challenges (eg, limited access, high cost, lack of data supporting safety with breastfeeding, requirement for inpatient monitoring during the infusion, lack of efficacy data bayond 30 days) (strong recommendation, moderate-quality evidence)."

In August 2023, after the US Food and Drug Administration-approval of zuranolone for the treatment of postpartum depression, ACOG published a Practice Advisory on the new agent meant to serve as an update to the Clinical Practice Guideline published in June 2023.^31, In this Advisory, ACOG recommended "consideration of zuranolone in the postpartum period (ie, within 12 months postpartum) for depression that has onset in the third trimester or within 4 weeks postpartum. The decision to use zuranolone should balance the benefits (eg, significantly improved and rapidly resolved symptoms) with the risks and challenges (eg, potential suicidal thoughts or behavior, sedation that precludes performing some activities of daily living like driving, and lack of efficacy beyond 45 days)."

American Psychiatric Association

No evidence-based guideline specifically related to the treatment of postpartum depression was identified. Relevant excerpts from “Practice Guideline for the Treatment of Patients with Major Depressive Disorder” published in 2010^32, are summarized here.

Depression During Pregnancy

• “Depression-focused psychotherapy or other nonmedication therapies may be considered first for some women, and psychotherapy should be considered as part of the treatment plan whenever possible.”

• “Although there is little controlled research, psychotherapies appear efficacious in antenatal and postpartum depression, with inter-personal therapy for depression being the best studied.”^33,34,

• “Antidepressant efficacy has not been determined for pregnant women, and questions remain as to whether medications have equivalent efficacy during pregnancy, compared with the nonpregnant state.”

• “Electroconvulsive therapy is also recommended as a treatment option for major depressive disorder during pregnancy.”

Postpartum Depression

“Antidepressants are often prescribed for postpartum depression, according to the same principles delineated for other types of major depressive disorder, despite a limited number of controlled studies.”

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force Recommendations (USPSTF) recommendations apply to pregnant persons and persons who are less than 1 year postpartum who do not have a current diagnosis of depression but are at increased risk of developing depression.^31,

The USPSTF recommends (category B recommendation) screening for depression in the general adult population, including pregnant and postpartum women. The USPSTF also recommends screening for depression in adolescents aged 12 to 18 years and found insufficient evidence to recommend for or against screening in children 11 years or younger.

The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions (category B recommendation).

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

References

1. Ko JY, Rockhill KM, Tong VT, et al. Trends in Postpartum Depressive Symptoms - 27 States, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep. Feb 17 2017; 66(6): 153-158. PMID 28207685
2. Sage Presentations for the November 2, 2018 Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. https://public4.pagefreezer.com/content/FDA/08-02-2022T03:01/https://www.fda.gov/media/121351/download. Accessed July 9, 2024.
3. Sage Briefing Information for the November 2, 2018 Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. https://public4.pagefreezer.com/content/FDA/08-02-2022T03:01/https://www.fda.gov/media/121348/download. Accessed July 9, 2024.
4. A-C Bernard-Bonnin, Canadian Paediatric Society, Mental Health and Developmental Disabilities Committee; Maternal depression and child development, Paediatrics & Child Health, Volume 9, Issue 8, 1 October 2004, Pages 575-583, https://doi.org/10.1093/pch/9.8.575.
5. Do T, Hu Z, Otto J, et al. Depression and suicidality during the postpartum period after first time deliveries, active component service women and dependent spouses, U.S. Armed Forces, 2007-2012. MSMR. Sep 2013; 20(9): 2-7. PMID 24093957
6. Savitz DA, Stein CR, Ye F, et al. The epidemiology of hospitalized postpartum depression in New York State, 1995-2004. Ann Epidemiol. Jun 2011; 21(6): 399-406. PMID 21549277
7. American Psychiatric Association. DSM 5. Diagnostic and statistical manual of mental disorders. American Psychiatric Press Inc, (5th edition). 2013; Washington, DC: American Psychiatric Association.
8. Mauri M, Oppo A, Borri C, et al. SUICIDALITY in the perinatal period: comparison of two self-report instruments. Results from PND-ReScU. Arch Womens Ment Health. Feb 2012; 15(1): 39-47. PMID 22215284
9. Wisner KL, Sit DK, McShea MC, et al. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. JAMA Psychiatry. May 2013; 70(5): 490-8. PMID 23487258
10. FDA Briefing Information for the November 2, 2018 Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. https://public4.pagefreezer.com/content/FDA/08-02-2022T03:01/https://www.fda.gov/media/121345/download. Accessed July 9, 2024.
11. Yonkers KA, Vigod S, Ross LE. Diagnosis, pathophysiology, and management of mood disorders in pregnant and postpartum women. Obstet Gynecol. Apr 2011; 117(4): 961-977. PMID 21422871
12. Scope A, Leaviss J, Kaltenthaler E, et al. Is group cognitive behaviour therapy for postnatal depression evidence-based practice? A systematic review. BMC Psychiatry. Nov 28 2013; 13: 321. PMID 24283266
13. Daley A, Jolly K, MacArthur C. The effectiveness of exercise in the management of post-natal depression: systematic review and meta-analysis. Fam Pract. Apr 2009; 26(2): 154-62. PMID 19126829
14. Sado M, Ota E, Stickley A, et al. Hypnosis during pregnancy, childbirth, and the postnatal period for preventing postnatal depression. Cochrane Database Syst Rev. Jun 13 2012; (6): CD009062. PMID 22696381
15. De Crescenzo F, Perelli F, Armando M, et al. Selective serotonin reuptake inhibitors (SSRIs) for post-partum depression (PPD): a systematic review of randomized clinical trials. J Affect Disord. Jan 2014; 152-154: 39-44. PMID 24139299
16. Molyneaux E, Telesia LA, Henshaw C, et al. Antidepressants for preventing postnatal depression. Cochrane Database Syst Rev. Apr 18 2018; 4(4): CD004363. PMID 29669175
17. Wisner KL, Perel JM, Peindl KS, et al. Prevention of recurrent postpartum depression: a randomized clinical trial. J Clin Psychiatry. Feb 2001; 62(2): 82-6. PMID 11247106
18. Wisner KL, Perel JM, Peindl KS, et al. Prevention of postpartum depression: a pilot randomized clinical trial. Am J Psychiatry. Jul 2004; 161(7): 1290-2. PMID 15229064
19. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. Mar 2005; 6(3): 215-29. PMID 15738957
20. HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. Feb 1960; 23(1): 56-62. PMID 14399272
21. Zimmerman M, Martinez JH, Young D, et al. Severity classification on the Hamilton Depression Rating Scale. J Affect Disord. Sep 05 2013; 150(2): 384-8. PMID 23759278
22. Peindl KS, Wisner KL, Hanusa BH. Identifying depression in the first postpartum year: guidelines for office-based screening and referral. J Affect Disord. May 2004; 80(1): 37-44. PMID 15094256
23. Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry. Dec 1990; 47(12): 1093-9. PMID 2244793
24. Gerbasi ME, Kosinski M, Meltzer-Brody S, et al. Achieving clinical response in postpartum depression leads to improvement in health-related quality of life. Curr Med Res Opin. Jul 2021; 37(7): 1221-1231. PMID 33719782
25. FDA Presentations for the November 2, 2018 Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. https://public4.pagefreezer.com/content/FDA/08-02-2022T03:01/https://www.fda.gov/media/121350/download. Accessed July 8, 2024.
26. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. Jul 29 2017; 390(10093): 480-489. PMID 28619476
27. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. Sep 22 2018; 392(10152): 1058-1070. PMID 30177236
28. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry. Sep 01 2021; 78(9): 951-959. PMID 34190962
29. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the Treatment of Postpartum Depression. Am J Psychiatry. Sep 01 2023; 180(9): 668-675. PMID 37491938
30. Treatment and Management of Mental Health Conditions During Pregnancy and Postpartum: ACOG Clinical Practice Guideline No. 5. Obstet Gynecol. Jun 01 2023; 141(6): 1262-1288. PMID 37486661
31. Zuranolone for the treatment of postpartum depression: Practice Advisory. American College of Obstetricians and Gynecologists. August 2023. Updated January 30, 2024. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/08/zuranolone-for-the-treatment-of-postpartum-depression. Accessed July 9, 2024.
32. Practice Guideline for the Treatment of Patients With Major Depressive Disorder (Third Edition). https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed July 9, 2024.
33. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry. Mar 2003; 160(3): 555-62. PMID 12611838
34. Stuart S, O'Hara MW, Gorman LL. The prevention and psychotherapeutic treatment of postpartum depression. Arch Womens Ment Health. Aug 2003; 6 Suppl 2: S57-69. PMID 14615924
35. Curry SJ, Krist AH, Owens DK, et al. Interventions to Prevent Perinatal Depression: US Preventive Services Task Force Recommendation Statement. JAMA. Feb 12 2019; 321(6): 580-587. PMID 30747971

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Policy History