betadex and brexanolone

To review the pharmacology, efficacy, and safety of Brexanolone and define its role in the treatment of postpartum depression.. A MEDLINE/PubMed search was conducted (1980-May 2020) using the following keywords: postpartum depression, antidepressants, pharmacologic therapy, drug therapy, and brexanolone to identify relevant articles.. Literature search was limited to human studies published in the English language. Phase I, II, and III studies evaluating the pharmacology, efficacy, safety of brexanolone for postpartum depression were included. Bibliographies of relevant articles evaluating postpartum depression and treatment were reviewed for additional citations and background information.. Brexanolone is a soluble, proprietary, injectable formulation of allopregnanolone, a neuroactive steroid that modulates neuronal excitability. Allopregnanolone levels increase during pregnancy and decrease substantially after birth. These fluctuations have profound effects on anxiety and depression. Three clinical trials established the efficacy and safety of brexanolone in the treatment of postpartum depression. In all 3 trials, brexanolone had an acceptable safety profile and was well tolerated. The most common adverse effects were loss of consciousness, sedation, dry mouth, headache, dizziness, and flushing. Due to sudden loss of consciousness and excessive sedation, continuous pulse oximetry is recommended.. Brexanolone has a novel mechanism of action and appears to be safe and effective for the treatment of moderate to severe postpartum depression. At present, high cost, serious adverse effects, and restricted access may limit its use in clinical practice.

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnancy; Pregnanolone; Unconsciousness

Topics: Adult; beta-Cyclodextrins; Clinical Decision-Making; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone; Treatment Outcome

ZULRESSO (Brexanolone) is a novel FDA-approved treatment for moderate-to-severe postpartum depression. Postpartum depression may be diagnosed in women experiencing depressive symptoms which can manifest as cognitive, behavioral, or emotional disturbances as early as the third trimester to 4 weeks following delivery. The efficacy of brexanolone suggests that neurosteroids such as allopregnanolone are important to treat PPD. However, it is currently unclear if brexanolone provides lasting relief of depressive symptoms at or beyond 30 days following administration. Further studies are necessary to make this determination.

Topics: Adult; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone

This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy.. A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website.. One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache.. Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed.. Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.

Topics: Antidepressive Agents; beta-Cyclodextrins; Bipolar Disorder; Depression, Postpartum; Depressive Disorder; Drug Combinations; Female; Humans; Pregnancy; Pregnanes; Pregnanolone; Psychiatric Status Rating Scales; Pyrazoles

Topics: Antidepressive Agents; beta-Cyclodextrins; Clinical Trials as Topic; Depression, Postpartum; Drug Combinations; Female; Humans; Infusions, Intravenous; Pregnanolone; Quality of Life; Severity of Illness Index; Treatment Outcome; United States; United States Food and Drug Administration

Postpartum depression (PPD) is defined as a major depressive episode occurring during pregnancy or within 4 weeks of delivery that may have significant consequences for mother and infant. Antidepressants are used to treat PPD, but their effectiveness may be limited by a slow time to peak effect. Brexanolone is Food and Drug Administration-approved for the management of PPD; its use requires patient participation in a risk evaluation and mitigation strategies (REMS) program. This review evaluates the efficacy and safety of brexanolone in PPD.. Four completed studies, 1 quasi-experimental study and 3 randomized controlled trials (RCTs), were reviewed. Females who had moderate or severe PPD during the third trimester or within 4 weeks of delivery and were less than 6 months postpartum at initiation of therapy were included. Improvement in Hamilton Rating Scale for Depression (HAM-D) scores was assessed in addition to safety outcomes and scores on other depression rating scales. All studies demonstrated statistical improvement in HAM-D scores from baseline with brexanolone vs placebo use at the end of infusions (ie, hour 60). Results with regard to sustained HAM-D score improvements were mixed in the RCTs at 30-day follow-up. The most frequent adverse events in brexanolone-treated patients were sedation, dizziness, somnolence, and headache. The severe or serious adverse effect of presyncope, syncope, or loss of consciousness was reported by 4% of participants.. With a rapid onset of action, brexanolone could be considered advantageous over traditional therapies for PPD in patients for whom a rapid response is required due to severity of disease. Significant concerns remain regarding sustained effect and use in patients outside of the clinical trial setting.

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnancy; Pregnanolone; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Risk Evaluation and Mitigation; Severity of Illness Index

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Depressive Disorder, Major; Drug Combinations; Drug Monitoring; Estrogens; Female; Humans; Oxytocin; Pregnanolone; Randomized Controlled Trials as Topic; Transcranial Magnetic Stimulation; Treatment Outcome; United States

Perinatal care, including the management of mental health issues, often falls under the auspices of primary care providers. Postpartum depression (PPD) is a common problem that affects up to 15% of women. Most women at risk can be identified before delivery based on psychiatric history, symptoms during pregnancy, and recent psychosocial stressors. Fortunately, there have been a variety of treatment studies using antidepressants, nonpharmacologic interactions, and most recently, allopregnanolone (Brexanolone) infusion that have shown benefits. The most commonly used screening scale, Edinburgh Postnatal Depression Scale, a 10-item self-rated scale, has been translated into a variety of languages.

Topics: Adult; Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Infant; Mass Screening; Neurosteroids; Perinatal Care; Postpartum Period; Pregnancy; Pregnanolone; Prevalence; Psychiatric Status Rating Scales; Psychotherapy; Risk Factors; Selective Serotonin Reuptake Inhibitors; Surveys and Questionnaires

Our aim was to review the efficacy, safety, and pharmacology of brexanolone (Zulresso), a new antidepressant with a novel mechanism of action, in the treatment of postpartum depression (PPD). Pertinent data and information were obtained via PubMed (1993 to August 2018). Articles published in English that evaluated the safety and efficacy of brexanolone and other off-label PPD treatments were included. Literature regarding epidemiology and pathophysiology of PPD was also selected. Brexanolone, administered as an intravenous infusion over 60 hours, produced a statistically significant and clinically meaningful reduction in Hamilton Depression Rating Scale (HAM-D) scores compared with placebo at both 60 and 90 μg/kg/hour in patients with moderate to severe PPD. Brexanolone groups had higher response and remission rates compared with placebo. Common adverse effects were somnolence, dizziness, and headache. A small percentage (4%) of patients required cessation of therapy due to excessive sedation or loss of consciousness. Although the evidence for brexanolone as a novel treatment for PPD looks promising, a Risk Evaluation and Mitigation Strategies (REMS) program requirement and the logistics of prolonged infusions serve as barriers to treatment. A discussion of these obstacles as well as pharmacokinetics, monitoring, and dosing is provided. Brexanolone is a novel antidepressant indicated for the treatment of PPD. Clinical trials demonstrated that brexanolone significantly reduces depression scores in women with moderate to severe PPD. Due to risk of oversedation and loss of consciousness, a REMS program will be put in place to mitigate the risk of adverse events.

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; GABA Modulators; Humans; Pregnancy; Pregnanolone; Psychiatric Status Rating Scales; Severity of Illness Index

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 3β-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.

Topics: Animals; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Drug Development; Female; GABA Modulators; Humans; Neurosteroids; Pregnanes; Pregnanolone; Pyrazoles; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

Topics: beta-Cyclodextrins; Brain; Depression, Postpartum; Drug Combinations; Drug Development; Drug Discovery; Female; Humans; Mental Disorders; Molecular Targeted Therapy; National Institute of Mental Health (U.S.); Neurobiology; Neurosteroids; Pregnanolone; Psychiatry; Psychotropic Drugs; Translational Research, Biomedical; United States

The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABA

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression; Depression, Postpartum; Drug Combinations; Female; GABA Modulators; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A

To systematically examine the effectiveness, tolerability, and safety of brexanolone infusion in treating postpartum depression (PPD).. Randomized controlled trials (RCTs) were included.. Two articles reporting 3 RCTs with 4 active arms (n = 267) covering 156 women with PPD receiving brexanolone infusion and 111 women with PPD on placebo were included. Compared with placebo, women suffering from PPD who received brexanolone had significantly greater response that started after 24 h (risk ratio (RR)=1.34, 95%CI 1.03-1.73), peaked at 36 h (RR = 1.50, 95%CI 1.06-2.13, P = 0.02) and lasted until Day 7 (RR = 1.32, 95%CI 1.01-1.73). Similarly, PPD women treated with brexanolone had significantly greater remission starting at 24 h (RR = 1.86, 95%CI 1.03-3.34), peaking at 60 h (RR = 2.20, 95%CI 1.31-3.70) and lasting until 72 h (RR = 1.96, 95%CI 1.41-2.72). Brexanolone infusion led to significantly higher rate of discontinuation for any reasons (RR = 2.68, 95%CI 1.35-5.32). Discontinuation due to intolerability and adverse drug reactions was similar between the active agent and placebo.. A single brexanolone infusion appears to have ultra-rapid antidepressant effect for PPD, lasting for up to 1 week. The short and long-term therapeutic effect of brexanolone needs to be examined in large-scale RCTs.

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone; Randomized Controlled Trials as Topic; Treatment Outcome

Brexanolone injection, the first therapy approved by the US FDA for the treatment of postpartum depression (PPD) in adults, has been shown to produce a significantly greater decrease in the Hamilton Rating Scale for Depression (HAM-D) total score than placebo in randomised controlled trials (RCTs) of women with PPD.. Given the rapid effect of brexanolone injection (within 60 h) sustained throughout the length of the trials (30 days), we sought to compare its efficacy data against selective serotonin reuptake inhibitors (SSRIs), the class of antidepressants most commonly prescribed for PPD, using HAM-D and Edinburgh Postnatal Depression Scale (EPDS) outcomes from currently available RCTs.. We extracted data from 26 studies identified in a systematic literature review of pharmacological and pharmacological/nonpharmacological combination therapies in PPD. Six studies were suitable to form evidence networks through which to perform indirect treatment comparisons (ITCs) of HAM-D and EPDS outcomes between brexanolone and SSRIs. Having assessed the comparability and suitability of the available evidence for analysis, we discovered significant heterogeneity in the study designs, most notably in the placebo arms of the trials. We therefore conducted matching-adjusted indirect comparisons (MAICs) between brexanolone and the placebo arms of comparator studies, subsequently using the MAIC results of brexanolone versus placebo, and results for SSRIs versus placebo, to form ITCs of brexanolone versus SSRIs at three separate time points-day 3, week 4 and last observation. ITCs were calculated as the differences in change from baseline (CFB) in HAM-D and, separately, CFB in EPDS, between treatments, and reported with 95% confidence intervals (CIs).. For all time points, MAICs showed larger differences in CFB for brexanolone compared with SSRIs. Differences (95% CIs) between brexanolone and SSRIs were 12.79 (8.04-17.53) [day 3], 5.87 (- 1.62 to 13.37) [week 4] and 0.97 (- 6.35 to 8.30) [last observation] for the HAM-D. For the EPDS, the differences in CFB were 7.98 (5.32-10.64) [day 3], 6.35 (3.13-9.57) [week 4] and 4.05 (0.79-7.31) [last observation]. Other analytical approaches are also presented to demonstrate the similarity of results, using a network meta-analysis approach, and the importance of using the MAIC method to control for the important heterogeneity between placebo arms.. Acknowledging the limitations of ITCs and this evidence base, when compared with SSRIs, these analyses suggest that brexanolone demonstrated larger differences in CFB for both patient- and clinician-reported PPD outcomes and at all investigated time points after adjusting for differences between placebos in the included studies.

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Male; Meta-Analysis as Topic; Network Meta-Analysis; Pregnanolone; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Serotonin

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 (GABA. 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).. 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.. 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.. Sage Therapeutics, Inc.

Topics: Adult; beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; GABA Agonists; Humans; Injections, Intravenous; Pregnancy; Pregnancy Trimester, Third; Pregnanolone; Psychiatric Status Rating Scales; Receptors, GABA; Severity of Illness Index; Treatment Outcome; Young Adult

Preclinical evidence indicates that rapid changes in levels of allopregnanolone, the predominant metabolite of progesterone, confer dramatic behavioral changes and may trigger postpartum depression (PPD) in some women. Considering the pathophysiology of PPD (i.e., triggered by reproductive steroids), the need for fast-acting, efficacious treatments and the negative consequences of untreated PPD, there is an increasing focus on developing PPD therapies. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, was evaluated as a treatment for severe PPD in a proof-of-concept, open-label study.. Four women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD) score of ≥20, received brexanolone, titrated to a dose reflecting third-trimester allopregnanolone levels. After a 36-hour maintenance infusion, tapering occurred over 12 hours. Primary outcomes were measures of safety. Secondary outcomes were assessments of efficacy, including HAMD.. All enrolled patients completed the study. Fourteen adverse events were reported, of which none was severe. Starting at the first measure after infusion initiation and continuing through Hour 84, mean HAMD total scores were reduced to levels consistent with remission of symptoms. All other efficacy assessments showed similar improvements.. Brexanolone was well tolerated and demonstrated activity in severe PPD. Larger, double-blind trials are needed for further evaluation.

Topics: Adult; beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Infusions, Intravenous; Pregnanolone; Proof of Concept Study; Treatment Outcome

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 (GABA. 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.. 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).. 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 GABA. Sage Therapeutics, Inc.

Topics: Adult; Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Infusions, Intravenous; Pregnanolone; Psychiatric Status Rating Scales; Treatment Outcome; Young Adult

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Female; Humans; Pregnanolone

A series of prodrugs of brexanolone, the synthetic version of the endogenously produced γ-aminobutyric acid A receptors positive allosteric modulator allopregnanolone, were designed, synthesized, and evaluated in vitro and in vivo. The effect of different function groups connecting to brexanolone C3 hydroxyl as well as those at the chain terminals of prodrug moieties were explored. Through these efforts, prodrugs that can efficiently release brexanolone in vitro and in vivo, and possess a potential for sustained delivery of a long acting brexanolone were discovered.

Topics: beta-Cyclodextrins; Drug Combinations; Pregnanolone; Prodrugs; Receptors, GABA

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone

Postpartum depression (PPD) is a serious complication of childbearing affecting ∼1 in 7 mothers. Left unrecognized and untreated, it is associated with negative outcomes for mothers and their infants. Building upon research suggesting that, for some women, hormonal fluctuations after childbirth contribute to the onset of depression, clinical trials have found promise in a novel treatment approach, brexanolone infusion. In 2019, the Food and Drug Administration (FDA) approved brexanolone as the first medication with an indication specifically for PPD. Delivering brexanolone treatment to patients in need requires overcoming some logistical and clinical challenges that are unique to this approach. This brief report describes the process by which a university-affiliated obstetric-gynecologic hospital in the northeast United States successfully implemented a program to administer this novel treatment to women with PPD.

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Hospitals; Humans; Pregnancy; Pregnanolone

Topics: Antidepressive Agents; beta-Cyclodextrins; Depressive Disorder, Treatment-Resistant; Drug Combinations; Humans; Neurosteroids; Pregnanes; Pregnanolone; Pyrazoles

Postpartum depression (PPD) is a serious and common complication of childbirth that can have deleterious effects not only on the mother but on the cognitive and behavioral development of exposed children. Brexanolone is a novel, soluble synthetic formulation of the natural hormone allopregnanolone and acts as a positive allosteric modulator of the gamma-aminobutyric acid A receptor (GABAA). Allopregnanolone levels dramatically decrease during the postpartum time-period and some studies indicate lower serum levels of allopregnanolone during pregnancy in women that go on to develop PPD.Areas covered: The author provides an overview of brexanolone as a treatment option for PPD including coverage of its pharmacokinetics, efficacy, safety, and tolerability. Furthermore, the author gives her expert perspectives on its use and its standing in the treatment armamentarium moving forward.Expert opinion: Brexanolone represents a breakthrough for psychiatry due to its novel mechanism of action, its rapid onset of action, and its sustained effects without continued administration. It is appropriate for use in women with moderate to severe PPD. Experience with the medication and further research is needed to clarify whether the current recommended dosing regimen is required for efficacy.

Topics: beta-Cyclodextrins; Child; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnancy; Pregnanolone

On March 19, 2019, Brexanolone (Zulresso ™) was released as the first-ever FDA-approved medication specifically for the treatment of postpartum depression by Sage Therapeutics, Inc. Unfortunately, its use in breastfeeding mothers was not evaluated and is being restricted. An efficacious drug for postpartum depression stands to benefit many families. However, the lack of guidance for breastfeeding patients, and the resultant restrictions on breastfeeding by insurance companies is deeply troubling. Conversely, withholding this medication from a lactating mother is ethically problematic. From a public health perspective, we aim to foster continuous breastfeeding among depressed women while they are being treated for depression. We therefore aim to address concerns about Brexanolone's effects on the breastfed child, as exposed through breastmilk, as well as the impact this medication may have on lactation.

Topics: beta-Cyclodextrins; Breast Feeding; Depression, Postpartum; Drug Combinations; Female; Humans; Lactation; Milk, Human; Postpartum Period; Pregnanolone

Topics: Animals; Anticonvulsants; beta-Cyclodextrins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Drug Therapy, Combination; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Midazolam; Neurosteroids; Patch-Clamp Techniques; Pregnanolone; Receptors, GABA-A; Seizures; Tiagabine

Brexanolone recently became the first medication to be approved by the US Food and Drug Administration specifically for treating postpartum depression. In contrast to traditional antidepressants, however, brexanolone is a neurosteroid that is believed to mimic allopregnanolone, a product of endogenous progesterone. Although early clinical trials have shown success, the medication remains largely unavailable due to its extremely high cost and formulation (it must be given as a continuous intravenous infusion over 3 days in a monitored, inpatient setting). The efficacy data surrounding brexanolone are encouraging; there is also evidence, however, that postpartum depression may be mitigated by a number of social policies that provide support to new parents. We suggest a comprehensive approach to postpartum wellness that includes investing in evidence-based social interventions that may be much more accessible to the millions of Americans experiencing postpartum mood disturbance.

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Neurosteroids; Postpartum Period; Pregnancy; Pregnanolone

Topics: beta-Cyclodextrins; Depression; Depressive Disorder, Treatment-Resistant; Drug Combinations; Humans; Ketamine; Pregnanolone; United States; United States Food and Drug Administration

Brexanolone injection (BRX) was approved by the FDA in 2019 for the treatment of adult patients with postpartum depression (PPD), but its cost-effectiveness has not yet been evaluated.. To estimate the cost-effectiveness of BRX compared with treatment with selective serotonin reuptake inhibitors (SSRIs) for PPD.. We projected costs (2018 U.S. dollars) and health (quality-adjusted life-years [QALYs]) for mothers treated with BRX or SSRIs and their children. A health state transition model projected clinical and economic outcomes for mothers based on the Edinburgh Postnatal Depression Scale, from a U.S. payer perspective. The modeled population consisted of adult patients with moderate to severe PPD, similar to BRX clinical trial patients. Short-term efficacy for BRX and SSRIs came from an indirect treatment comparison. Long-term efficacy outcomes over 4 weeks, 11 years (base case), and 18 years were based on results from an 18-year longitudinal study. Maternal health utility values came from analysis of trial-based short-form 6D responses. Other inputs were derived from the literature.. The incremental cost-effectiveness ratio for BRX versus SSRIs was $106,662 per QALY gained over an 11-year time horizon. Drug and administration costs for BRX averaged $38,501, compared with $25 for SSRIs over the studied time horizon. Maternal total direct medical costs averaged $65,908 in the BRX arm, compared with $73,653 in the SSRI arm. BRX-treated women averaged 6.230 QALYs compared with 5.979 QALYs for the SSRI arm. Adding partner costs and utilities in a sensitivity analysis further favored BRX. Results were sensitive to the severity of PPD at baseline and the model time horizon. Probabilistic sensitivity analyses indicated that BRX was cost-effective at the $150,000-per-QALY threshold with 58% probability.. Analysis using a state transition model showed BRX to be a cost-effective therapy compared with SSRIs for treating women with PPD.. This study was funded by Sage Therapeutics, Cambridge, MA. Eldar-Lissai, Gerbasi, and Hodgkins are employees of Sage Therapeutics and own stock or stock options in the company. Gerbasi also reports previous employment with Policy Analysis Inc. Cohen contributed to this work as an independent consultant. Meltzer-Brody has a sponsored clinical research agreement with Sage Therapeutics to the University of North Carolina, as well as a sponsored research agreement from Janssen to the University of North Carolina, unrelated to this work. Meltzer-Brody has also received personal consulting fees from Cala Health and MedScape, unrelated to this work. Johnson, Chertavian, and Bond are employees of Medicus Economics, which was paid fees by Sage to conduct the research for this study. Study findings do not necessarily represent the views of CEVR or Tufts Medical Center.

Topics: Adolescent; Adult; beta-Cyclodextrins; Cost-Benefit Analysis; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnancy; Pregnanolone; Prenatal Care; Psychometrics; Quality-Adjusted Life Years; Selective Serotonin Reuptake Inhibitors; United States; Young Adult

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; GABA Modulators; Humans; Pregnanolone

The FDA has approved brexanolone specifically for treatment of adults with postpartum depression (PPD). Administered I.V., it can relieve severe signs and symptoms of PPD within days rather than weeks. This article discusses the benefits and risks of brexanolone as a treatment for PPD, including nursing considerations and patient teaching.

Topics: Adult; beta-Cyclodextrins; Depression, Postpartum; Drug Approval; Drug Combinations; Female; Humans; Patient Education as Topic; Pregnanolone; Risk Assessment; United States; United States Food and Drug Administration

Topics: beta-Cyclodextrins; Depression; Drug Combinations; Excitatory Amino Acid Antagonists; GABA Modulators; Humans; Ketamine; Pregnanolone

The objective of this study is to explore the associations between the patient-reported Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire (PHQ)-9 and clinician-reported 17-item Hamilton Depression Rating Scale (HAMD-17) in order to facilitate clinical decision-making. An integrated efficacy dataset of three randomized placebo-controlled trials (NCT02614547, NCT02942004, and NCT02942017) evaluating brexanolone injection, a neuroactive steroid chemically identical to allopregnanolone, in women with postpartum depression was used for this post hoc analysis. Data were pooled across treatment arms. Associations were assessed at day 30 (end-of-trial follow-up). Pearson correlation assessed the relationship between EPDS and PHQ-9 item and total scores and HAMD-17 total score. Cohen's kappa assessed agreement of EPDS remission (score < 10) and PHQ-9 remission (score < 5) with HAMD-17 remission (score ≤ 7). Ordinary least squares (OLS) regression models were used to develop equations estimating HAMD-17 total scores from EPDS and PHQ-9 scores, respectively. The total scores showed large correlations (HAMD-17/EPDS: r = 0.71, p < 0.001; HAMD-17/PHQ-9: r = 0.75, p < 0.001). Individual EPDS and PHQ-9 items significantly correlated (r= 0.35 to 0.67, all p < 0.001) with HAMD-17 total score. EPDS had 79% sensitivity and 67% specificity to detect HAMD-17 remission; corresponding estimates for PHQ-9 were 76% and 78%. OLS models yielded the following equations: HAMD-17 total = 2.66 + (EPDS total × 0.87) and HAMD-17 total = 3.99 + (PHQ-9 total × 0.97). There were large and statistically significant associations between patient-reported outcomes (EPDS, PHQ-9) and clinician-reported outcomes (HAMD-17) as clinical improvements were associated with patient-reported symptom improvement. These results provide tools to help translate clinical trial data to clinical practice, thus aiding shared decision-making for this critical population.

Topics: Adult; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Mass Screening; Patient Health Questionnaire; Patient Reported Outcome Measures; Pregnanolone; Psychiatric Status Rating Scales; Sensitivity and Specificity; Severity of Illness Index; Surveys and Questionnaires

This article reviews eight drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.

Topics: Aminophenols; Antibodies, Monoclonal, Humanized; Azabicyclo Compounds; Benzodioxoles; beta-Cyclodextrins; Cilastatin; Drug Approval; Drug Combinations; Ethinyl Estradiol; Genetic Vectors; Humans; Imipenem; Indoles; Nitroimidazoles; Pregnanolone; Pregnenediones; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Retinoids; United States; United States Food and Drug Administration

Topics: Administration, Intravenous; Adult; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Guidelines as Topic; Humans; Infant, Newborn; Maternal-Child Health Services; Patient Safety; Pregnanolone

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Health Personnel; Humans; Infant, Newborn; Infusions, Intravenous; Length of Stay; Mothers; Patient Safety; Pregnanolone; Severity of Illness Index; Workforce

Postpartum depression is a mood disorder that affects up to 20% of women in the first year after childbirth. Symptoms can range from mild depression and anxiety to severe mood alterations and psychosis. A mainstay of treatment has included selective serotonin reuptake inhibitors. However, it can take 2 to 6 weeks for clinical improvement with this approach. In March 2019, the U.S. Food and Drug Administration approved brexanolone, the first medication specifically indicated for the treatment of postpartum depression. Given as an intravenous infusion over the course of 60 hr, brexanolone has the potential to fill an unmet need for women with postpartum depression. In this column, I will provide an overview of brexanolone and discuss administration, adverse effects, and practice implications for nurses who work with childbearing women.

Topics: Administration, Intravenous; Adult; beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Mothers; Postpartum Period; Pregnanolone; Selective Serotonin Reuptake Inhibitors

On March 19, 2019, the United States Food and Drug Administration (FDA) approved Zulresso (brexanolone) for intravenous use for the treatment of postpartum depression (PPD) in adult women. The decision was based on three recent clinical trials following an FDA priority review and breakthrough therapy designation. Brexanolone is now available through a restricted process called the Zulresso Risk Evaluation and Mitigation Strategy Program that requires the drug to be administered by a healthcare provider in a certified healthcare facility. Brexanolone represents an important new treatment option to address treatment-resistant depressive symptoms. In this article, we discuss the current critical need for PPD treatments, the mechanisms of brexanolone action, and the efficacy and drug safety studies that led to FDA approval. Additionally, we discuss some limitations of the current formulation, specific populations of women that might benefit from this treatment, and how new drugs on the horizon may increase the ability to treat PPD in a variety of patient populations.

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Approval; Drug Combinations; Female; Humans; Pregnanolone; United States; United States Food and Drug Administration

In 2019, the FDA approved several new drugs for use in primary care. This article highlights the following new drugs: risankizumab-rzaa (Skyrizi); halobetasol and tazarotene (Duobrii); dolutegravir and lamivudine (Dovato); romosozumab-aqqg (Evenity); brexanolone (Zulresso); solriamfetol (Sunosi); aclidinium and formoterol (Duaklir Pressair); and siponimod (Mayzent).

Topics: Antibodies, Monoclonal; Azetidines; Benzyl Compounds; beta-Cyclodextrins; Carbamates; Clobetasol; Drug Approval; Drug Combinations; Formoterol Fumarate; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Nicotinic Acids; Oxazines; Phenylalanine; Piperazines; Pregnanolone; Pyridones; Tropanes; United States; United States Food and Drug Administration

Topics: Antidepressive Agents; beta-Cyclodextrins; Depression, Postpartum; Depressive Disorder, Treatment-Resistant; Drug Combinations; Female; Humans; Ketamine; Pregnanolone; United States; United States Food and Drug Administration

Topics: beta-Cyclodextrins; Drug Combinations; Ketamine; Pregnanolone; United States; United States Food and Drug Administration

During the postpartum period, the brain's inhibitory GABAA receptors may not recover in time following their reduced numbers during pregnancy. This is likely the cause of postpartum depression prevalent in ∼12% of childbearing women. A new therapy for this condition consists of administering a synthetic neurosteroid during the postpartum period to alleviate the mood disorder. To view this Bench to Bedside, open or download the PDF.

Topics: Adult; beta-Cyclodextrins; Depression, Postpartum; Depressive Disorder, Major; Drug Combinations; Female; Humans; Mood Disorders; Neurotransmitter Agents; Postpartum Period; Pregnancy; Pregnanolone; Prevalence; Receptors, GABA-A

Brexanolone (ZULRESSO™) is an intravenously administered, small molecule, neuroactive steroid GABA

Topics: Administration, Intravenous; Adolescent; Adult; Allosteric Regulation; beta-Cyclodextrins; Depression, Postpartum; Drug Approval; Drug Combinations; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pregnanolone; Receptors, Steroid; Treatment Outcome; United States; United States Food and Drug Administration

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnancy; Pregnanolone; Receptors, GABA-A

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone

Topics: beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Pregnanolone; United States; United States Food and Drug Administration

Topics: beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Pregnanolone

Topics: beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Pregnanolone

Topics: beta-Cyclodextrins; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; Humans; Pregnanolone

Topics: beta-Cyclodextrins; Depression, Postpartum; Drug Combinations; Female; GABA Modulators; gamma-Aminobutyric Acid; Humans; Pregnanolone