The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

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.

Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder with peripartum onset: A multicenter, open-label, controlled proof-of-concept clinical trial (DELOS-1).

BACKGROUND: Postpartum depression has a high prevalence in the United States (~13 %) and often goes undertreated/untreated. We conducted a multicenter, open-label, proof-of-concept trial to assess the Nesos wearable, non-invasive, transcutaneous auricular vagus nerve stimulation (taVNS) system for the treatment of major depressive disorder with peripartum onset (PPD). METHODS: Women (n = 25), ages 18 to 45, within 9 months postpartum, and diagnosed with PPD were enrolled at 3 sites. The study included 6 weeks open-label therapy and 2 weeks observation. Efficacy outcomes included change from baseline (CFB) in Hamilton Rating Scale for Depression (HAMD17) total scores, HAM-D17 response and remission, and patient and clinician global impression of change (PGIC, CGIC) scores. Analysis included descriptive statistics and mixed-effects models for repeated measures. RESULTS: The most common AEs (≥5 %) were discomfort (n = 5), headache (n = 3), and dizziness (n = 2); all resolved without intervention. No serious AEs or deaths occurred. Baseline mean HAM-D17 score was 18.4. Week 6 least squares (LS) mean CFB in HAM-D17 score was -9.7; 74 % achieved response and 61 % achieved remission. At week 6, at least some improvement was reported by 21 of 22 (95 %) clinicians on CGIC and 22 of 23 (96 %) participants on PGIC. LIMITATIONS: This was a single-arm, open-label study, and enrollment was limited to participants with mild-to-moderate peripartum depression. CONCLUSION: Results from this proof-of-concept study suggest that the Nesos taVNS system is well tolerated and may be an effective non-invasive, non-pharmacological treatment for major depressive disorder with peripartum onset. Further evaluation in larger sham-controlled studies is needed. CLINICALTRIALS: govNCT03972995.

Pharmacotherapy of Postpartum Depression: Current Approaches and Novel Drug Development.

Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of the mother and child, negatively impacting child cognitive, behavioral, and emotional development with lasting consequences. There are a number of therapeutic interventions for postpartum depression including pharmacotherapy, psychotherapy, neuromodulation, and hormonal therapy among others, most of which have been adapted from the treatment of major depressive disorder outside of the peripartum period. Current evidence of antidepressant treatment for postpartum depression is limited by the small number of randomized clinical trials, underpowered samples, and the lack of long-term follow-up. The peripartum period is characterized by rapid and significant physiological change in plasma levels of endocrine hormones, peptides, and neuroactive steroids. Evidence supporting the role of neuroactive steroids and γ-aminobutyric acid (GABA) in the pathophysiology of postpartum depression led to the investigation of synthetic neuroactive steroids and their analogs as potential treatment for postpartum depression. Brexanolone, a soluble proprietary intravenous preparation of synthetic allopregnanolone, has been developed. A recent series of open-label and placebo-controlled randomized clinical trials of brexanolone in postpartum depression demonstrated a rapid reduction in depressive symptoms, and has led to the submission for regulatory approval to the US Food and Drug Administration (decision due in March 2019). SAGE-217, an allopregnanolone analog, with oral bioavailability, was recently tested in a randomized, double-blind, placebo-controlled phase III study in severe postpartum depression, with reportedly positive results. Finally, a 3ß-methylated synthetic analog of allopregnanolone, ganaxolone, is being tested in both intravenous and oral forms, in randomized, double-blind, placebo-controlled phase II studies in severe postpartum depression.

Complementary Health Practices for Treating Perinatal Depression.

This article provides a focused review of the evidence for several complementary health approaches (ie, omega-3 fatty acids, folate, vitamin D, selenium, zinc, magnesium, B vitamins, physical activity, yoga) in the treatment of perinatal depression. There is evidence that some of these treatments may be reasonable to consider in women during pregnancy or the postpartum period. However, there are little data on the comparative safety and efficacy of these relative to traditional treatments (eg, psychotherapy, pharmacotherapy). Adequately powered high-quality studies are necessary to determine the role of complementary health practices for treating perinatal depression.

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.

Complementary and alternative medicine therapies for perinatal depression.

Complementary and alternative medicine therapies are increasingly sought out by people with psychiatric disorders. In this chapter, we review the evidence for several commonly used CAM therapies (i.e. omega-3 fatty acids, folate, S-adenosyl-methionine, St John's Wort, bright light therapy, exercise, massage, and acupuncture) in the treatment of perinatal depression. A number of these treatments may be reasonable to consider for women during pregnancy or postpartum, but the safety and efficacy of these relative to standard treatments must still be systematically determined. Evidence-based use of complementary and alternative medicine therapies treatments for perinatal depression is discussed. Adequately powered systematic studies are necessary to determine the role of complementary and alternative medicine therapies in the treatment of perinatal depression.

Complementary and alternative medicine for the treatment of depressive disorders in women.

Complementary and alternative medicine (CAM) therapies are commonly practiced in the United States and are used more frequently among women than men. This article reviews several CAM treatments for depressive disorders in women, with a focus on major depressive disorder across the reproductive life cycle. The CAM therapies selected for this review (ie, S-adenosylmethionine, omega-3 fatty acids, St John's wort, bright light therapy, acupuncture, and exercise) were based on their prevalence of use and the availability of randomized, placebo-controlled data. Further study is necessary to delineate the role of specific CAM therapies in premenstrual syndrome, premenstrual dysphoric disorder, antepartum and postpartum depression, lactation, and the menopausal transition.