Zuranolone Concentrations in the Breast Milk of Healthy, Lactating Individuals: Results From a Phase 1 Open-Label Study.

PURPOSE/BACKGROUND: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the United States. This study assessed zuranolone transfer into breast milk. METHODS/PROCEDURES: Healthy, nonpregnant, lactating adult female participants received once-daily 30 mg zuranolone from day (D)1 through D5 in this phase 1 open-label study. The relative infant dose (RID; weight-adjusted proportion of the maternal dose in breast milk over 24 hours) for 30 mg zuranolone was assessed at D5. An RID for 50 mg zuranolone was estimated using a simulation approach across a range of infant ages and weights. FINDINGS/RESULTS: Of 15 enrolled participants (mean age, 30.1 years), 14 completed the study. The mean RID for 30 mg zuranolone at D5 was 0.357%; the mean steady-state milk volume over D3 to D5 decreased from baseline by 8.3%. Overall unbound zuranolone in plasma was low (≤0.49%). Plasma concentrations peaked at D5 before decreasing in a biexponential manner. There was strong concordance between the temporal profiles of zuranolone concentrations in plasma and breast milk. The estimated mean RID for 50 mg zuranolone based on a milk intake of 200 mL/kg per day was 0.984%. All treatment-emergent adverse events reported by participants were mild, the most common being dizziness (n = 3). IMPLICATIONS/CONCLUSIONS: Zuranolone transfer into the breast milk of healthy, nonpregnant, lactating adult female participants was low; the estimated RID for 50 mg zuranolone was <1%, well below the <10% threshold generally considered compatible with breastfeeding.

Bidirectional associations between perinatal allopregnanolone and depression severity with postpartum gray matter volume in adult women.

BACKGROUND: Perinatal depression (PND) is a debilitating condition affecting maternal well-being and child development. Allopregnanolone (ALLO) is important to perinatal neuroplasticity, however its relationship with depression severity and postpartum structural brain volume is unknown. METHOD: We examined perinatal temporal dynamics and bidirectional associations between ALLO and depression severity and the association between these variables and postpartum gray matter volume, using a random intercept cross-lagged panel model. RESULTS: We identified a unidirectional predictive relationship between PND severity and ALLO concentration, suggesting greater depression severity early in the perinatal period may contribute to subsequent changes in ALLO concentration (ß = 0.26, p = 0.009), while variations in ALLO levels during the perinatal period influences the development and severity of depressive symptoms later in the postpartum period (ß = 0.38, p = 0.007). Antepartum depression severity (Visit 2, ß = 0.35, p = 0.004), ALLO concentration (Visit 2, ß = 0.37, p = 0.001), and postpartum depression severity (Visit 3, ß = 0.39, p = 0.031), each predicted the right anterior cingulate volume. Antepartum ALLO concentration (Visit 2, ß = 0.29, p = 0.001) predicted left suborbital sulcus volume. Antepartum depression severity (Visit 1, ß = 0.39, p = 0.006 and Visit 2, ß = 0.48, p < 0.001) predicted the right straight gyrus volume. Postpartum depression severity (Visit 3, ß = 0.36, p = 0.001) predicted left middle-posterior cingulate volume. CONCLUSION: These results provide the first evidence of bidirectional associations between perinatal ALLO and depression severity with postpartum gray matter volume.

Antenatal Antidepressant Prescription Associated With Reduced Fetal Femur Length but Not Estimated Fetal Weight: A Retrospective Ultrasonographic Study.

PURPOSE/BACKGROUND: Antidepressants are among the most frequently prescribed medications during pregnancy and may affect fetal weight. Associations between antenatal antidepressant use and ultrasonographic measures of fetal development have rarely been examined. We hypothesized that the prescription of an antenatal antidepressant would be associated with lower estimated fetal weight (EFW). METHODS/PROCEDURES: A retrospective analysis of routine ultrasonographic data extracted from electronic medical records was performed on a cohort of pregnant women with psychiatric diagnoses and grouped according to the presence of an antenatal antidepressant prescription (n = 32 antidepressant-prescribed and n = 44 antidepressant prescription-free). After stratifying for gestational age, comparisons included 13 ultrasonographic parameters, frequency of oligohydramnios and polyhydramnios and growth deceleration, and maternal serum protein markers assessed per routine care, including α-fetoprotein, free ß-human chorionic gonadotropin, and unconjugated estriol levels, using t tests, nonparametric and Fisher tests, and effect sizes (ESs) were computed. FINDINGS/RESULTS: No statistically significant EFW differences between groups at any time point were detected (P > 0.05). Antenatal antidepressant prescription was associated with lower femur length at weeks 33 to 40 (P = 0.046, ES = 0.75) and greater left ventricular diameter at weeks 25 to 32 (P = 0.04, ES = 1.18). No differences for frequency of oligohydramnios or polyhydramnios or growth deceleration were observed (P > 0.05). We did not detect group differences for maternal proteins (P > 0.05). IMPLICATIONS/CONCLUSIONS: Our evidence suggested a lack of association between antenatal antidepressant prescription and lower EFW but indicated an association with lower femur length and greater left ventricular diameter in mid-late gestation. Future research should examine the clinical implications of these findings.

Peripartum depression: Does risk versus diagnostic status impact mother-infant bonding and perceived social support?

BACKGROUND: Peripartum depression (PND) impairs mother-infant boding and perceived social support, yet limited research has examined if women at-risk for PND (AR-PND) also experience impairment. We examined if pregnant women AR-PND, women with PND, and healthy comparison women (HCW) differed in their mother-infant bonding and social support. As PND is highly comorbid with anxiety, we also examined if peripartum anxiety impacted postpartum diagnosis of PND. METHODS: A total of 144 pregnant women AR-PND or euthymic were assessed twice antepartum and twice postpartum. We utilized regression models to examine the impact of PND risk group status and diagnostic status on mother-infant bonding and perceived social support postpartum. We conducted a sensitivity analysis using a generalized estimating equations model to determine if anxiety (Hamilton Anxiety Rating Scale, HAM-A) across all four time points was associated with the postpartum diagnosis of PND. RESULTS: Women AR-PND experienced significantly worse mother-infant bonding compared to HCW (p = .03). Women diagnosed with PND experienced significantly worse mother-infant bonding and social support compared to HCW (p = .001, p = .002, respectively) and to those who were at-risk for but did not develop PND (p = .02, p = .008, respectively). HAM-A severity at each visit was associated with PND diagnosis status, where each increase in HAM-A was associated with 15% increased odds of being diagnosed with PND postpartum. CONCLUSIONS: Both women AR-PND and those with PND experience worse mother-infant bonding. Peripartum anxiety should also be assessed as it represents a marker for later PND.

Excretion of Antipsychotics Into the Amniotic Fluid, Umbilical Cord Blood, and Breast Milk: A Systematic Critical Review and Combined Analysis.

BACKGROUND: Antipsychotics are being increasingly prescribed during pregnancy and in the postpartum period. However, knowledge regarding the ability of antipsychotics to enter the fetal, newborn, and infant circulation presents inconsistencies. Evidence for penetration ratios in an array of matrices will contribute to further studies examining the mechanistic pathway from antipsychotic use to adverse events. METHODS: A systematic literature search of PubMed and EMBASE was performed to identify studies assessing the concentrations of antipsychotics in maternal blood (serum or plasma), amniotic fluid, umbilical cord blood, and/or breast milk. The penetration ratios were estimated by dividing the antipsychotic concentrations in the target matrix (ie, amniotic fluid, umbilical cord blood or breast milk) by the maternal concentration. Data are provided in means with ranges or SD depending on data availability. RESULTS: Forty-nine eligible studies were identified. For amniotic fluid, the penetration ratios were estimated for quetiapine, clozapine, and flupentixol, with quetiapine displaying the highest ratio (mean 0.59, range 0.09-1.70 versus 0.56, range 0.31-0.82 for clozapine and 0.24, range 0.23-0.24 for flupentixol). For umbilical cord blood, olanzapine had the highest ratio (mean 0.71 ± 0.42) followed by haloperidol (mean 0.66 ± 0.40) and paliperidone (mean 0.53, range 0.50-0.58). In case of breast milk, the highest ratio was observed for amisulpride (mean 14.42, range 11.86-19.50) followed by clozapine (mean 3.19, range 2.79-4.32) and haloperidol (mean 3.11, range 0.59-6.67). CONCLUSIONS: The ability of antipsychotics to enter the fetal, newborn, and infant circulation varies considerably among antipsychotics. Given sampling constraints of other matrices, measuring antipsychotic concentrations in maternal blood may represent the least expensive, most readily available, and reliable estimate of fetal/infant exposure.

Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression. METHODS: We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 µg/kg per h (BRX90), brexanolone 60 µg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). FINDINGS: Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. INTERPRETATION: Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. FUNDING: Sage Therapeutics, Inc.

Examining the relationship between perinatal depression and neurodevelopment in infants and children through structural and functional neuroimaging research.

Depression is the most common perinatal psychiatric disorder, but little is known about how it may impact offspring neurodevelopment, as well as the mechanisms by which it may confer transgenerational psychiatric risk. This review presents imaging studies conducted to evaluate the relationship between perinatal depression (PND) and infant and child neurodevelopment. Altered structural and functional connectivity is implicated in children exposed to PND and anxiety. Overall, there are changes in connectivity between amygdala and the prefrontal cortex. Studies suggest decreased hippocampal growth in the first 6 months after birth, decreased cortical thickness in children, and increased amygdala volumes, that are more pronounced in female offspring. Future research is needed to understand the impact of PND on development so that early interventions which promote mother-infant bonding and cognitive development may improve developmental outcomes in children exposed to PND, reducing later risk of psychopathology.

Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.

BACKGROUND: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. METHODS: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. FINDINGS: This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference -12·2, 95% CI -20·77 to -3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). INTERPRETATION: In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. FUNDING: Sage Therapeutics, Inc.

Association of peripartum synthetic oxytocin administration and depressive and anxiety disorders within the first postpartum year.

BACKGROUND: Due to its potent effects on social behavior, including maternal behavior, oxytocin has been identified as a potential mediator of postpartum depression and anxiety. The objective of this study was to examine the relationship between peripartum synthetic oxytocin administration and the development of depressive and anxiety disorders within the first year postpartum. We hypothesized that women exposed to peripartum synthetic oxytocin would have a reduced risk of postpartum depressive and anxiety disorders compared with those without any exposure. METHODS: Population-based data available through the Massachusetts Integrated Clinical Academic Research Database (MiCARD) were used to retrospectively (2005-2014) examine this relationship and calculate the relative risk of peripartum synthetic oxytocin for the development of postpartum depressive and anxiety disorders in exposed (n = 9,684) compared to unexposed (n = 37,048) deliveries. RESULTS: Among deliveries to women with a history of prepregnancy depressive or anxiety disorder, exposure to peripartum oxytocin increased the risk of postpartum depressive or anxiety disorder by 36% (relative risk (RR): 1.36; 95% confidence interval (95% CI): 1.20-1.55). In deliveries to women with no history of prepregnancy depressive or anxiety disorder, exposure to peripartum oxytocin increased the risk of postpartum depressive or anxiety disorder by 32% compared to those not exposed (RR: 1.32; 95% CI: 1.23-1.42). CONCLUSIONS: Contrary to our hypothesis, results indicate that women with peripartum exposure to synthetic oxytocin had a higher relative risk of receiving a documented depressive or anxiety disorder diagnosis or antidepressant/anxiolytic prescription within the first year postpartum than women without synthetic oxytocin exposure.

The Prevalence of Bipolar Disorders and Association With Quality of Life in a Cohort of Patients With Multiple Sclerosis.

Clinical observations of mood instability in multiple sclerosis (MS) have led to the hypothesis that bipolar disorder (BD) may be more prevalent in persons with MS than in the general population. This cross-sectional study assesses the prevalence of BD among patients with MS using standardized psychiatric diagnostic interviews and evaluates quality of life. This study demonstrates a higher prevalence of BD in patients with MS compared with the general population. It also reveals the negative impact of BD on quality of life, raises the concern that BD can occur before the onset of neurological symptoms in MS, and suggests that, in some cases, BD may delay diagnosis of MS.

Understanding Peripartum Depression Through Neuroimaging: a Review of Structural and Functional Connectivity and Molecular Imaging Research.

PURPOSE OF REVIEW: Imaging research has sought to uncover brain structure, function, and metabolism in women with postpartum depression (PPD) as little is known about its underlying pathophysiology. This review discusses the imaging modalities used to date to evaluate postpartum depression and highlights recent findings. RECENT FINDINGS: Altered functional connectivity and activity changes in brain areas implicated in executive functioning and emotion and reward processing have been identified in PPD. Metabolism changes involving monoamine oxidase A, gamma-aminobutyric acid, glutamate, serotonin, and dopamine have additionally been reported. To date, no studies have evaluated gray matter morphometry, voxel-based morphometry, surface area, cortical thickness, or white matter tract integrity in PPD. Recent imaging studies report changes in functional connectivity and metabolism in women with PPD vs. healthy comparison women. Future research is needed to extend these findings as they have important implications for the prevention and treatment of postpartum mood disorders.

Cortisol response to the Trier Social Stress Test in pregnant women at risk for postpartum depression.

Antepartum depression and anxiety are risk factors for postpartum depression (PPD). Postpartum abnormalities in hypothalamic-pituitary-adrenal (HPA) reactivity are associated with PPD. It is not known if antepartum HPA abnormalities exist in women at risk for PPD (AR-PPD). We measured salivary cortisol response to the Trier Social Stress Test (TSST) in 44 (24 AR-PPD, 20 healthy comparison) pregnant women. Depression and anxiety were measured using the Edinburgh Postnatal Depression Scale (EPDS) and Spielberger State-Trait Anxiety Inventory-State (STAI-S). We analyzed longitudinal changes in cortisol using generalized estimating equation methods to control for the correlation within subjects at the six TSST time points. Group differences in area under the curve (AUC) were examined. A majority (70.8 %) of the AR-PPD had prior depression. EPDS total score was higher in AR-PPD vs. comparison women (mean EPDS = 9.8 ± 4.9 vs. mean EPDS = 2.4 ± 2.0 respectively, p < 0.001). Mean STAI-S total score was higher in AR-PPD vs. comparison women at all TSST time points and over time (z = 2.71, df = 1, p = 0.007). There was no significant difference in cortisol concentration over time between groups. We observed no detectable difference in cortisol response to psychosocial stress induced by the TSST despite clinically significant between-group differences in current/past depression and current symptomatology.

Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring.

OBJECTIVE: Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations. METHODS: The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period. RESULTS: Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period. CONCLUSIONS: Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.

The cost-effectiveness of zuranolone versus selective serotonin reuptake inhibitors for the treatment of postpartum depression in the United States.

AIMS: The objective of this research is to evaluate the cost-effectiveness of zuranolone, the first oral treatment indicated for postpartum depression (PPD) in adults approved by the United States Food and Drug Administration. METHODS: Zuranolone and selective serotonin reuptake inhibitor (SSRI) trial-based efficacy was derived from an indirect treatment comparison. Long-term efficacy outcomes were based on a large longitudinal cohort study. Maternal health utility values were derived from trial-based, short-form 6-D responses. Other inputs were derived from literature and economic data from the US Bureau of Labor Statistics. We estimated costs (2023 US dollars) and quality-adjusted life-years (QALYs) for patients with PPD treated with zuranolone (14-day dosing) or SSRIs (chronic dosing). The indirect costs and QALYs of the children and partners were also estimated. RESULTS: The incremental cost-effectiveness ratio for zuranolone versus SSRIs was $94,741 per QALY gained over an 11-year time horizon. Maternal total direct medical costs averaged $84,318 in the zuranolone arm, compared to $86,365 in the SSRI arm. Zuranolone-treated adults averaged 6.178 QALYs compared to 6.116 QALYs for the SSRI arm. Costs and utilities for the child and partner were also included in the base case. Drug and administration costs for zuranolone averaged $15,902, compared to $30 for SSRIs over the studied time horizon. Results were sensitive to the model time horizon. LIMITATIONS: As head-to-head trials were not available to permit direct comparison, efficacy inputs were derived from an indirect treatment comparison which can be confounded by cross-trial differences. The data used are reflective of a general PPD population rather than marginalized individuals who may be at a greater risk for adverse PPD outcomes. The model likely excludes unmeasured effects for patient, child, and partner. CONCLUSIONS: This economic model's results suggest that zuranolone is a more cost-effective therapy compared to SSRIs for treating adults with PPD.

QUESTION: Is zuranolone cost-effective compared to selective serotonin-reuptake inhibitors for the treatment of postpartum depression (PPD) in adults in a United States (US) health care setting? FINDINGS: The model, which incorporated clinical trial data, long-term longitudinal cohort data, US Bureau of Labor Statistics data on compensation, and other peer-reviewed literature, projects that zuranolone is cost-effective compared to selective serotonin-reuptake inhibitors for the treatment of PPD at a willingness-to-pay threshold of $150,000 (USD).Meaning: For adults with PPD requiring pharmacological intervention, zuranolone may be a cost-effective treatment option with the potential to confer quality-of-life benefits for these patients and their families as well as economic benefits for society.

Management of Premenstrual Dysphoric Disorder: A Scoping Review.

Premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS) refer to physical, cognitive, or affective symptoms that arise in the late luteal phase and remit with menses. The present work is a clinically focused scoping review of the last twenty years of research on treatment for these disorders. A search of key terms using the PubMed/Medline, the Cochrane Library, Embase, and Web of Science databases was performed, and 194 studies of adult women met initial inclusion criteria for review. Research studies concerning medications, pharmacological and non-pharmacological complementary and alternative medicine treatments, and surgical interventions with the most available evidence were appraised and summarized. The most high-quality evidence can be found for the use of selective serotonin reuptake inhibitors (SSRIs) and combined oral contraceptives (COCs), with gonadotropin releasing hormone (GnRH) agonists and surgical interventions showing efficacy for refractory cases. While there is some evidence of the efficacy of alternative and complementary medicine treatments such as nutraceuticals, acupuncture, and yoga, variability in quality and methods of studies must be taken into account. Reprinted from Int J Womens Health 2022; 14:1783-1801, with permission from Dove Medical Press Ltd. Copyright © 2022.

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.