Effect of esketamine on serum neurotransmitters in patients with postpartum depression: a randomized controlled trial.

BACKGROUND: The development of postpartum depression has been linked to fluctuations in the levels of neurotransmitters in the human body, such as 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (Norepinephrine, NE), and brain derived neurotrophic factor (BDNF). Research has indicated that the antidepressant effect of esketamine are mediated by monoamine transmitters and neurotrophic factors. Therefore, we postulate that intravenous administration of esketamine in patients with postpartum depression may alter the serum concentrations of these neurotransmitters. METHODS: Three hundred fifteen patients with postpartum depression were selected and divided into two groups based on randomized numerical expression: esketamine (E) group (0. 25 mg/kg esketamine) and control (C) group (a same volume of 0.9% saline), all the drugs were pumped for 40 min. After the end of drug pumping, all patients were continuously observed for 2 h. Changes in serum levels of 5-HT, DA, NE, BDNF were recorded before drug administration and on the 3rd day after drug administration. The scores of Edinburgh Postnatal Depression Scale (EPDS) were calculated before drug administration, and on the 3rd day and on the 30th day after drug administration. Dizziness, headache, nausea, vomiting, drowsiness, and feeling of detachment occurred were recorded within 2 h after drug administration. RESULTS: Before drug administration, the serum concentrations of 5-HT,DA,BDNF,NE in Group E and Group C were namely (0. 91 ± 0. 19 vs. 0. 98 ± 0. 21, P = 0. 181), (2. 38 ± 0. 35 vs. 2. 32 ± 0. 32, P = 0. 491), (3. 07 ± 0. 89 vs 3. 02 ± 0. 88, P = 0. 828), (39. 79 ± 7. 78 vs 41. 34 ± 10. 03, P = 0. 506). On the third day post-medication, the serum concentrations of 5-HT,DA,BDNF,NE in Group E and Group C were namely (1. 42 ± 0. 35 vs. 0. 96 ± 0. 24, P < 0. 001), (3. 99 ± 0. 17 vs. 2. 41 ± 0. 28, P < 0. 001),(5. 45 ± 0. 81 vs 3. 22 ± 0. 76, P < 0. 001),(44. 36 ± 9. 98 vs 40. 69 ± 11. 75, P = 0. 198). Before medication, the EPDS scores were (16. 15 ± 3. 02 vs 17. 85 ± 3. 89, P = 0. 064). on the third day after medication, the Group E had significantly reduced scores (12. 98 ± 2. 39 vs 16. 73 ± 3. 52, P < 0. 001). On the 30rd day after medication, EPDS scores between the two groups were (16. 34 ± 3. 43 vs 16. 91 ± 4. 02, p = 0. 203). Within 2 h of medication, the rate of adverse events was similar between the two groups. CONCLUSIONS: Small doses of esketamine can increase the serum concentration of 5-HT,DA,BDNF, and in the short term, decrease EPDS scores, and improve postpartum depressive symptoms. TRIAL REGISTRATION: Retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2300078343, 2023/12/05).

Antidepressant Medication Use During Lactation: A Review for Providers.

This article presents a summary of information found within the existing medical literature on the pharmacological treatment options for maternal depression during lactation and the concurrent effects on the breastfeeding infant. Existing data on safety and efficacy varies by treatment modality. Medications used to treat depression are all secreted in breast milk to some extent; however, most antidepressants are considered relatively safe to use during breastfeeding. The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine are present in low levels and are considered preferred agents. Safety data for other antidepressants varies, however. monoamine oxidase inhibitors (MAOIs) should generally be avoided. Available references and resources can help providers optimize treatment of maternal depression while mitigating risk to the infant. Optimizing treatment of maternal depression is a complicated undertaking, which should be made in conjunction with the provider through shared decision making with the patient. Specific properties of any proposed medication, such as the relative infant dose and side effect profile, should always be taken into account during the decision-making process.

An update on approved and emerging drugs for the treatment of postpartum depression.

Depression, anxiety and psychotic disorders are common perinatal mental health disorders in the postpartum period. Depressive symptoms that occur postpartum are also present in the prenatal period in 50% of patients. Risk factors for the development of postpartum depression include poor relationship with the partner, lack of social support, mother’s low socioeconomic status and multiparity. It has been determined that reproductive hormones change significantly during peripartum. Progesterone is one of these hormones and acts on the central nervous system starting from the fetal period; neurogenesis, neuromodulation, sedation are some of these effects. It has also been observed that progesterone has positive effects on learning, memory and mood. Progesterone exerts its effects on the central nervous system by converting into its metabolite allopregnanolone. Allopregnanolone is one of the neuroactive steroids, and found in similar amounts in the circulation of pregnant women and fetuses. It acts on synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors and is a positive allosteric modulator of the GABAA receptor. Allopregnanolone increases both the receptor’s opening frequency and its open duration and improves GABAergic current. Low serum allopregnanolone levels in the second trimester are predictive of postpartum depression. Each 1 ng/mL increase in serum allopregnanolone level reduces the risk of development of postpartum depression by 63%. Brexanolone and zuranolone are synthetic allopregnanolone preparations approved by the FDA for use in female patients with postpartum depression. They act via positive allosteric modulation on the GABAA receptor. Brexanolone is administered via intravenous infusion at varying infusion rates in a healthcare facility over 60 hours. Its effect starts immediately after treatment and continues until the 30th day of follow-up, and depressive mood does not recur. Zuranolone was developed for oral use, and administered as a single dose of 50 mg after a fatty meal. Their effectiveness has been demonstrated in patients with treatment-resistant depression. The development of other novel agents that act on the GABAA receptor and other pathways for the treatment of postpartum depression is in progress.

Efficacy and safety of peri-partum Esketamine for prevention of post-partum depression in women undergoing caesarian section: A meta-analysis and systematic review of randomized controlled trials.

Postpartum depression (PPD) is a psychiatric condition affecting women post-childbirth. Medication combined with psychotherapy, is the current protocol for its treatment. A meta-analysis was conducted using RevMan 5.4 to explore the efficacy and safety of peri-partum administration of esketamine for preventing PPD. After searching several databases to retrieve the relevant RCTs, seven were included in this analysis, with dichotomous data presented as risk ratio and continuous data as mean difference. The study found a lower incidence of PPD in the esketamine group compared to the control group (RR= 0.37), with significant difference in EPDS scores between the two groups (MD= -1.23) in the first week postpartum. The esketamine group reported a lower prevalence of PPD 4-6 weeks postpartum (RR= 0.48), and no significant difference in EPDS scores after 4 weeks postpartum (MD = -0.10). The esketamine group had a significantly higher incidence of hallucination (RR= 13.85). Other adverse effects, such as dizziness (RR= 4.09), nausea (RR= 0.88), vomiting (RR=0.74), headache (RR=1.52), nightmares (RR=1.22), pruritus (RR=0.29), and drowsiness (RR=1.57) did not show significant differences between the two groups. The study found that esketamine, with manageable side effects, reduces the prevalence of post-partum depression (PPD) after one week as well as after four to six weeks. However, the findings are limited by the limited number of available RCTs, and future research should determine the ideal dosage, the most effective method of administration and the long-term safety profile of esketamine so that it may be considered as an adjunct therapy or a potential sole treatment option.

Consensus Panel Recommendations for the Pharmacological Management of Breastfeeding Women with Postpartum Depression.

INTRODUCTION: Our consensus statement aims to clarify the use of antidepressants and anxiolytics during breastfeeding amidst clinical uncertainty. Despite recent studies, potential harm to breastfed newborns from these medications remains a concern, leading to abrupt discontinuation of necessary treatments or exclusive formula feeding, depriving newborns of benefits from mother's milk. METHODS: A panel of 16 experts, representing eight scientific societies with a keen interest in postpartum depression, was convened. Utilizing the Nominal Group Technique and following a comprehensive literature review, a consensus statement on the pharmacological treatment of breastfeeding women with depressive disorders was achieved. RESULTS: Four key research areas were delineated: (1) The imperative to address depressive and anxiety disorders during lactation, pinpointing the risks linked to untreated maternal depression during this period. (2) The evaluation of the cumulative risk of unfavorable infant outcomes associated with exposure to antidepressants or anxiolytics. (3) The long-term impact on infants' cognitive development or behavior due to exposure to these medications during breastfeeding. (4) The assessment of pharmacological interventions for opioid abuse in lactating women diagnosed with depressive disorders. CONCLUSIONS: The ensuing recommendations were as follows: Recommendation 1: Depressive and anxiety disorders, as well as their pharmacological treatment, are not contraindications for breastfeeding. Recommendation 2: The Panel advocates for the continuation of medication that has demonstrated efficacy during pregnancy. If initiating an antidepressant during breastfeeding is necessary, drugs with a superior safety profile and substantial epidemiological data, such as SSRIs, should be favored and prescribed at the lowest effective dose. Recommendation 3: For the short-term alleviation of anxiety symptoms and sleep disturbances, the Panel determined that benzodiazepines can be administered during breastfeeding. Recommendation 4: The Panel advises against discontinuing opioid abuse treatment during breastfeeding. Recommendation 5: The Panel endorses collaboration among specialists (e.g., psychiatrists, pediatricians, toxicologists), promoting multidisciplinary care whenever feasible. Coordination with the general practitioner is also recommended.

Allopregnanolone in the peripartum: Correlates, concentrations, and challenges - A systematic review.

BACKGROUND: Allopregnanolone (ALLO) is a metabolite of progesterone and a neuroactive steroid hormone. As a positive allosteric modulator of gamma-aminobutyric acid (GABA) receptors, ALLO seems to have antidepressant and anxiolytic effects, and was therefore approved as a specific medication for the treatment of postpartum depression in 2019. Despite the growing number of publications investigating ALLO levels, results on the biological and psychological correlates in the peripartum period remain inconsistent, possibly due to methodological challenges regarding measurement. To date, however, there is no systematic review examining the correlates, concentrations, and challenges in measuring ALLO in peripartum women. METHOD: A systematic literature search of PubMed and PsycINFO was conducted in August 2023. Original research articles that measured ALLO concentrations in peripartum women were included. Reports were excluded if they were not original research, included non-human subjects, did not include peripartum women, did not include ALLO measurement as an outcome, included (pharmacological) interventions, constituted method validations, or used the same cohort as another study. RESULTS: The literature search yielded 234 articles, and two articles were identified from other sources. After full-text screening, 19 articles (N = 1401) met the inclusion criteria, of which seven focused on biological correlates of ALLO and 12 on mood correlates. Of the latter, six found no association between ALLO and mood, four found a negative association, and two found a positive association. Overall, the results show an increase in ALLO levels during pregnancy and a decrease after birth, with levels then remaining low until six months postpartum. ALLO was most commonly measured in blood plasma and by gas chromatography-mass spectrometry (GC-MS). A significant matrix effect was found for blood serum and a significant method effect for radioimmunoassays (RIAs). A significant effect of time of measurement was found. CONCLUSION: ALLO measurement shows method and matrix effects. ALLO levels are higher when measured in serum compared to in plasma, and when measured using RIA compared to other methods. Time of measurement, study design, and standardization of measurement also influence the reliability of measurement and the interpretation of results.

Zuranolone: A Narrative Review of a New Oral Treatment for Postpartum Depression.

PURPOSE: Postpartum depression is a prevalent and overlooked mental disorder. Pathophysiology is thought to originate from a combination of biological and social factors, including hormones, and genetics. The consequences of untreated postpartum depression can be severe and negatively impact maternal and infant health. Zuranolone was approved as an oral agent in August 2023 for the treatment of postpartum depression in adults. The purpose of this article is evaluating the clinical aspects of zuranolone, including safety and efficacy pertaining to the drug and the clinical data that led to its approval. METHODS: A literature search was conducted using PubMed, Web of Science, and EMBASE with the terms postpartum depression, postpartum depression management, and zuranolone to locate relevant data for this narrative review. The prescribing information of zuranolone and clinicaltrials.gov were also utilized. FINDINGS: Two Phase III trials (Study 1-NCT04442503 and Study 2-NCT02978326) led to the approval of zuranolone by the Food and Drug Administration (FDA) based on clinically meaningful improvement in depressive symptoms. The trials met their primary endpoint, a change from baseline in HAM-D total score at day 15 (Study 1; 95% CI -6.3 to -1.7, P = 0.001: Study 2; 95% CI (-6.9 to -1.5, P = 0.003). IMPLICATIONS: Zuranolone, an oral and rapidly acting antidepressant, represents a promising new oral treatment option for individuals with postpartum depression.

Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial.

OBJECTIVE: To determine whether a single low dose of esketamine administered after childbirth reduces postpartum depression in mothers with prenatal depression. DESIGN: Randomised, double blind, placebo controlled trial with two parallel arms. SETTING: Five tertiary care hospitals in China, 19 June 2020 to 3 August 2022. PARTICIPANTS: 364 mothers aged ≥18 years who had at least mild prenatal depression as indicated by Edinburgh postnatal depression scale scores of ≥10 (range 0-30, with higher scores indicating worse depression) and who were admitted to hospital for delivery. INTERVENTIONS: Participants were randomly assigned 1:1 to receive either 0.2 mg/kg esketamine or placebo infused intravenously over 40 minutes after childbirth once the umbilical cord had been clamped. MAIN OUTCOME MEASURES: The primary outcome was prevalence of a major depressive episode at 42 days post partum, diagnosed using the mini-international neuropsychiatric interview. Secondary outcomes included the Edinburgh postnatal depression scale score at seven and 42 days post partum and the 17 item Hamilton depression rating scale score at 42 days post partum (range 0-52, with higher scores indicating worse depression). Adverse events were monitored until 24 hours after childbirth. RESULTS: A total of 364 mothers (mean age 31.8 (standard deviation 4.1) years) were enrolled and randomised. At 42 days post partum, a major depressive episode was observed in 6.7% (12/180) of participants in the esketamine group compared with 25.4% (46/181) in the placebo group (relative risk 0.26, 95% confidence interval (CI) 0.14 to 0.48; P<0.001). Edinburgh postnatal depression scale scores were lower in the esketamine group at seven days (median difference -3, 95% CI -4 to -2; P<0.001) and 42 days (-3, -4 to -2; P<0.001). Hamilton depression rating scale scores at 42 days post partum were also lower in the esketamine group (-4, -6 to -3; P<0.001). The overall incidence of neuropsychiatric adverse events was higher in the esketamine group (45.1% (82/182) v 22.0% (40/182); P<0.001); however, symptoms lasted less than a day and none required drug treatment. CONCLUSIONS: For mothers with prenatal depression, a single low dose of esketamine after childbirth decreases major depressive episodes at 42 days post partum by about three quarters. Neuropsychiatric symptoms were more frequent but transient and did not require drug intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04414943.

Postpartum Depression: A Clinical Review of Impact and Current Treatment Solutions.

Depression during the first year postpartum (postpartum depression) impacts millions of women and their families worldwide. In this narrative review, we provide a summary of postpartum depression, examining the etiology and consequences, pharmacological and psychological treatments, and potential mechanisms of change and current barriers to care. Psychological treatments are effective and preferred by many perinatal patients over medications, but they often remain inaccessible. Key potential mechanisms underlying their effectiveness include treatment variables (e.g., dosage and therapeutic alliance) and patient behaviors (e.g., activation and avoidance and emotional regulation). Among pharmacological treatments, the selective serotonin reuptake inhibitor (SSRI) sertraline is generally the first-line antidepressant medication recommended to women in the postpartum period due to its minimal passage into breastmilk and the corresponding decades of safety data. Importantly, most antidepressant drugs are considered compatible with breastfeeding. Neurosteroids are emerging as an effective treatment for postpartum depression, although currently this treatment is not widely available. Barriers to widespread access to treatment include those that are systematic (e.g., lack of specialist providers), provider-driven (e.g., lack of flexibility in treatment delivery), and patient-driven (e.g., stigma and lack of time for treatment engagement). We propose virtual care, task-sharing to non-specialist treatment providers, and collaborative care models as potential solutions to enhance the reach and scalability of effective treatments to address the growing burden of postpartum depression worldwide and its negative impact on families and society.

First Oral Treatment Specific for Postpartum Depression.

Postpartum depression is one of the most common perinatal mood disorders. The U.S. Food and Drug Administration approved the first oral medication developed specifically for the treatment of postpartum depression in August 2023. Zuranolone, marketed under the brand name Zurzuvae (Sage Therapeutics, Inc. and Biogen), is thought to work similarly to other positive allosteric modulators of gamma-aminobutyric acid A receptors such as benzodiazepines. It can be used alone or as an adjunct to other oral antidepressant medication. Its 2-week regimen of once-daily oral administration provides women with postpartum depression the opportunity to maintain their daily routines in an outpatient setting. This article provides an overview of zuranolone, including indications, mechanism of action, potential adverse reactions, and implications for nursing practice.

The comparison of the effect of non-pharmacological pain relief and pharmacological analgesia with remifentanil on fear of childbirth and postpartum depression: a randomized controlled clinical trial.

INTRODUCTION: Childbirth may be associated with psychological, social, and emotional effects and provide the background for women's health or illness throughout their life. This research aimed at comparing the impact of non-pharmacological pain relief and pharmacological analgesia with remifentanil on childbirth fear and postpartum depression. MATERIALS AND METHOD: This randomized clinical trial with two parallel arms was conducted on 66 women with term pregnancy referred to Taleghani Hospital in Tabriz for vaginal delivery during September 2022 to September 2023. First, all of the eligible participants were selected through Convenience Sampling. Then, they were randomly assigned into two groups of pharmacological analgesia with remifentanil and non-pharmacological analgesia with a ratio of 1:1 using stratified block randomization based on the number of births. Before the intervention, fear of childbirth (FOC) was measured using Delivery Fear Scale (DFS) between 4 and 6 cm cervical dilatation. Pain and fear during labor in dilatation of 8 cm were measured in both groups using VAS and DFS. After delivery, FOC was assessed using Delivery Fear Scale (W DEQ Version B) and postpartum depression using the Edinburgh's postpartum depression scale (EPDS). Significance level was considered 0.05. Mean difference (MD) was compared with Independent T-test and ANCOVA pre and post intervention. RESULTS: The mean score of FOC in the non-pharmacological analgesia group was significantly lower than that in the pharmacological analgesia group after the intervention by controlling the effect of the baseline score (MD: -6.33, 95%, Confidence Interval (CI): -12.79 to -0.12, p = 0.04). In the postpartum period, the mean score of FOC in the non-pharmacological analgesia group was significantly lower than that in the pharmacological analgesia group after controlling the effect of the baseline score (MD: -21.89; 95% CI: -35.12 to -8.66; p = 0.002). The mean score of postpartum depression in the non-pharmacological analgesia group was significantly lower than that in the pharmacological analgesia group (MD: -1.93, 95% CI: -3.48 to -0.37, p = 0.01). TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT): IRCT20170506033834N10. Date of registration: 05/07/2022 Date of first registration: 05/07/2022. URL: https://www.irct.ir/trial/61030; Date of recruitment start date05/07/2022. CONCLUSION: The study results indicated a reduction in FOC and postpartum depression among parturient women receiving non-pharmacological strategies with active participation in childbirth compared to women receiving pharmacological analgesia. Owing to the possible side effects of pharmacological methods for mother and fetus, non-pharmacological strategies with active participation of the mother in childbirth are recommended to reduce the FOC and postpartum depression.

919 granules improve postpartum depression through the regulation of abnormal peripheral blood IL-1ß.

Postpartum depression (PPD) has a significant impact on the physical and mental health of mothers, potentially leading to symptoms such as low mood, fatigue, and decreased appetite. It may also affect the healthy growth of the infant. The onset of PPD is closely related to abnormalities in inflammation and the immune system. PPD patients exhibit abnormalities in the proportion of peripheral blood immune cells, along with an increase in pro-inflammatory cytokines. Excessive pro-inflammatory cytokines in peripheral blood can disrupt the blood-brain barrier (BBB) by activating astrocytes and reducing transendothelial electrical resistance (TEER), allowing peripheral immune cells or cytokines to enter the brain and trigger inflammation, ultimately leading to the onset of depression. In addition, PPD lacks safe and effective treatment medications. In this study, we collected peripheral blood from both healthy postpartum women and those with PPD, conducted single cell RNA sequencing (scRNA-seq), and used an in-house analytical tool scSTAR to reveal that PPD patients exhibit elevated proportions of peripheral blood cDC2 and Proliferation B cells, which are significantly correlated with IL-1ß. Additionally, animal experiments were designed to validate that 919 granules can improve PPD by modulating the levels of peripheral blood IL-1ß, providing a potential therapeutic mechanism for PPD treatment.

The efficacy of zuranolone versus placebo in postpartum depression and major depressive disorder: a systematic review and meta-analysis.

BACKGROUND: Zuranolone, an oral version of allopregnanolone and neurosteroid, is a novel drug for the treatment of major depressive disorder (MDD) and postpartum depression (PPD). AIM: The purpose of this systematic review and meta-analysis was to assess the efficacy of zuranolone in the treatment of MDD and PPD. METHOD: A systematic search was conducted using EBSCOhost to simultaneously search Academic Search Premier, APA PsycArticles, APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL Ultimate, and MEDLINE with Full Text. Two independent reviewers screened the articles and completed a full-text review using Covidence. The quality of each study was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2). A meta-analysis was then conducted using Review Manager (RevMan v5.4) software. RESULTS: The initial search yielded 127 results, with 6 articles fitting our inclusion and exclusion criteria. All 6 studies, comprising 1707 participants, had an overall low risk of bias. There was a significant decrease in HAM-D scores for MDD at 15 days versus placebo (MD - 2.40, 95% CI - 3.07 to - 1.63; p < .001). When pooling data for PDD, there was an overall significant decrease in HAM-D scores at 15 days versus placebo (MD - 4.06, 95% CI - 4.25 to - 3.87; p < .001). CONCLUSION: The results suggest that zuranolone can improve symptoms of PPD at 15 days; however, results were not clinically significant for MDD. Future research is needed to evaluate the long-term efficacy of zuranolone in PPD and the treatment efficacy in MDD.

Brexanolone Treatment in a Real-World Patient Population: A Case Series and Pilot Feasibility Study of Precision Neuroimaging.

PURPOSE/BACKGROUND: Brexanolone is approved for postpartum depression (PPD) by the United States Food and Drug Administration. Brexanolone has outperformed placebo in clinical trials, but less is known about the efficacy in real-world patients with complex social and medical histories. Furthermore, the impact of brexanolone on large-scale brain systems such as changes in functional connectivity (FC) is unknown. METHODS/PROCEDURES: We tracked changes in depressive symptoms across a diverse group of patients who received brexanolone at a large medical center. Edinburgh Postnatal Depression Scale (EPDS) scores were collected through chart review for 17 patients immediately prior to infusion through approximately 1 year postinfusion. In 2 participants, we performed precision functional neuroimaging (pfMRI), including before and after treatment in 1 patient. pfMRI collects many hours of data in individuals for precision medicine applications and was performed to assess the feasibility of investigating changes in FC with brexanolone. FINDINGS/RESULTS: The mean EPDS score immediately postinfusion was significantly lower than the mean preinfusion score (mean change [95% CI]: 10.76 [7.11-14.40], t (15) = 6.29, P < 0.0001). The mean EPDS score stayed significantly lower at 1 week (mean difference [95% CI]: 9.50 [5.23-13.76], t (11) = 4.90, P = 0.0005) and 3 months (mean difference [95% CI]: 9.99 [4.71-15.27], t (6) = 4.63, P = 0.0036) postinfusion. Widespread changes in FC followed infusion, which correlated with EPDS scores. IMPLICATIONS/CONCLUSIONS: Brexanolone is a successful treatment for PPD in the clinical setting. In conjunction with routine clinical care, brexanolone was linked to a reduction in symptoms lasting at least 3 months. pfMRI is feasible in postpartum patients receiving brexanolone and has the potential to elucidate individual-specific mechanisms of action.

Indirect comparisons of relative efficacy estimates of zuranolone and selective serotonin reuptake inhibitors for postpartum depression.

AIMS: Estimate relative efficacy of zuranolone, a novel oral, Food and Drug Administration-approved treatment for postpartum depression (PPD) in adults vs. selective serotonin reuptake inhibitors (SSRIs) and combination therapies used for PPD in the United States. MATERIALS AND METHODS: Randomized controlled trials (RCTs) for zuranolone and SSRIs, identified from systematic review, were used to construct evidence networks, linking via common comparator arms. Due to heterogeneity in placebo responses, matching-adjusted indirect comparison (MAIC) was applied, statistically weighting the zuranolone treatment arm of Phase 3 SKYLARK Study (NCT04442503) to the placebo arm of RCTs investigating SSRIs for PPD. MAIC outputs were applied in Bucher indirect treatment comparisons (ITCs) and network meta-analysis (NMA), using Edinburgh Postnatal Depression Scale (EPDS) and 17-item Hamilton Rating Scale for Depression (HAMD-17) change from baseline (CFB) on Days 3, 15, 28 (Month 1), 45, and last observation (Day 45, Week 12/18). RESULTS: Larger EPDS CFB was observed among zuranolone-treated vs. SSRI-treated patients from Day 15 onward. Zuranolone-treated (vs. SSRI-treated) patients exhibited 4.22-point larger reduction in EPDS by Day 15 (95% confidence interval: -6.16, -2.28) and 7.43-point larger reduction at Day 45 (-9.84, -5.02) with Bucher ITC. NMA showed EPDS reduction for zuranolone was 4.52 (-6.40, -2.65) points larger than SSRIs by Day 15 and 7.16 (-9.47, -4.85) larger at Day 45. Lack of overlap between study populations substantially reduced effective sample size post-matching, making HAMD-17 CFB analysis infeasible. LIMITATIONS: Limited population overlap between SKYLARK Study and RCTs reduced feasibility of undertaking HAMD-17 CFB ITCs and may introduce uncertainty to EPDS CFB ITC results. CONCLUSIONS: Analysis showed zuranolone-treated patients with PPD experienced greater symptom improvement than SSRI-treated patients from Day 15 onward, with largest mean difference at Day 45. Adjusting for differences between placebo arms, zuranolone may be associated with greater PPD symptom improvement (measured by EPDS) vs. SSRIs.