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The American Journal of Psychiatry Sep 2023Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABA receptors and neuroactive steroid, as an oral, once-daily, 14-day treatment course for patients with severe PPD.
METHODS
In this double-blind phase 3 trial, women with severe PPD were randomized in a 1:1 ratio to receive zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15; key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Adverse events were monitored.
RESULTS
Among 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) completed the 45-day study. Treatment with zuranolone compared with placebo resulted in statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAM-D score, -15.6 vs. -11.6; LSM difference, -4.0, 95% CI=-6.3, -1.7); significant improvement in depressive symptoms was also reported at days 3, 28, and 45. CGI-S score at day 15 significantly improved with zuranolone compared with placebo. The most common adverse events (≥10%) with zuranolone were somnolence, dizziness, and sedation. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed.
CONCLUSIONS
In this trial, zuranolone demonstrated significant improvements in depressive symptoms and was generally well tolerated, supporting the potential of zuranolone as a novel, rapid-acting oral treatment for PPD.
Topics: Pregnancy; Humans; Female; Depression, Postpartum; Treatment Outcome; Pregnanes; Pyrazoles; Double-Blind Method
PubMed: 37491938
DOI: 10.1176/appi.ajp.20220785 -
JAMA Psychiatry Sep 2021Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child.
OBJECTIVE
To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD.
DESIGN, SETTING, AND PARTICIPANTS
This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019.
INTERVENTIONS
Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks.
MAIN OUTCOMES AND MEASURES
Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments.
RESULTS
Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02978326.
Topics: Adolescent; Adult; Depression, Postpartum; Depressive Disorder, Major; Double-Blind Method; Female; GABA Modulators; Humans; Middle Aged; Outcome Assessment, Health Care; Postpartum Period; Pregnancy; Pregnancy Trimester, Third; Pregnanes; Pyrazoles; Young Adult
PubMed: 34190962
DOI: 10.1001/jamapsychiatry.2021.1559 -
Journal of Neuromuscular Diseases 2022Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle... (Review)
Review
Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort.
Topics: Humans; Muscular Dystrophy, Duchenne; Prednisolone; Prednisone; Pregnenediones; Prospective Studies
PubMed: 35723111
DOI: 10.3233/JND-210776 -
CNS Drugs Mar 2019Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of... (Review)
Review
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; 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; beta-Cyclodextrins
PubMed: 30790145
DOI: 10.1007/s40263-019-00605-7 -
The American Journal of Psychiatry Sep 2023This study assessed the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study assessed the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the γ-aminobutyric acid type A (GABA) receptor, for the treatment of major depressive disorder.
METHODS
Patients 18-64 years of age with severe major depressive disorder were enrolled in this randomized, double-blind, placebo-controlled trial. Patients self-administered zuranolone 50 mg or placebo once daily for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15. Safety and tolerability were assessed by incidence of adverse events.
RESULTS
Of 543 randomized patients, 534 (266 in the zuranolone group, 268 in the placebo group) constituted the full analysis set. Compared with patients in the placebo group, patients in the zuranolone group demonstrated a statistically significant improvement in depressive symptoms at day 15 (least squares mean change from baseline HAM-D score, -14.1 vs. -12.3). Numerically greater improvements in depressive symptoms for zuranolone versus placebo were observed by day 3 (least squares mean change from baseline HAM-D score, -9.8 vs. -6.8), which were sustained at all visits throughout the treatment and follow-up periods of the study (through day 42, with the difference remaining nominally significant through day 12). Two patients in each group experienced a serious adverse event; nine patients in the zuranolone group and four in the placebo group discontinued treatment due to adverse events.
CONCLUSIONS
Zuranolone at 50 mg/day elicited a significantly greater improvement in depressive symptoms at day 15, with a rapid time to effect (day 3). Zuranolone was generally well tolerated, with no new safety findings compared with previously studied lower dosages. These findings support the potential of zuranolone in treating adults with major depressive disorder.
Topics: Humans; Adult; Depressive Disorder, Major; Treatment Outcome; Pregnanes; Pyrazoles
PubMed: 37132201
DOI: 10.1176/appi.ajp.20220459 -
Neuropharmacology Dec 2020Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA receptor positive allosteric modulator designed with the pharmacokinetic properties...
Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, αβγ, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.
Topics: Animals; Anticonvulsants; Antidepressive Agents; Binding Sites; Brain; Diazepam; Drug Synergism; Electroencephalography; GABA Modulators; GABA-A Receptor Agonists; Hippocampus; Humans; Male; Mice; Pregnanes; Pyrazoles; Rats, Sprague-Dawley; Receptors, GABA; Seizures; Steroids; gamma-Aminobutyric Acid
PubMed: 32976892
DOI: 10.1016/j.neuropharm.2020.108333 -
Drugs Nov 2023Zuranolone (ZURZUVAE) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABA) receptor being developed by Sage... (Review)
Review
Zuranolone (ZURZUVAE) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABA) receptor being developed by Sage Therapeutics and Biogen for the treatment of mood disorders. In August 2023, zuranolone received its first approval in the USA for the treatment of adults with postpartum depression [pending scheduling by the US Drug Enforcement Administration (DEA)]. This article summarizes the milestones in the development of zuranolone leading to this first approval.
Topics: Adult; Female; Humans; Pregnanes; Pyrazoles; Depression, Postpartum; Pregnanolone
PubMed: 37882942
DOI: 10.1007/s40265-023-01953-x -
British Dental Journal Sep 2021
Topics: Betamethasone; Betamethasone Valerate
PubMed: 34561568
DOI: 10.1038/s41415-021-3487-9 -
The Journal of Pediatrics Jun 2018
Topics: Asthma; Child; Dexamethasone; Humans; Prednisone
PubMed: 29567044
DOI: 10.1016/j.jpeds.2018.01.068 -
Stress (Amsterdam, Netherlands) Nov 2023As the end product of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone coordinate circadian activities,... (Review)
Review
As the end product of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone coordinate circadian activities, stress-coping, and adaptation to change. For this purpose, the hormone promotes energy metabolism and controls defense reactions in the body and brain. This life-sustaining action exerted by glucocorticoids occurs in concert with the autonomic nervous and immune systems, transmitters, growth factors/cytokines, and neuropeptides. The current contribution will focus on the glucocorticoid feedback paradox in the HPA-axis: the phenomenon that stress responsivity remains resilient if preceded by stress-induced secretion of glucocorticoid hormone, but not if this hormone is previously administered. Furthermore, in animal studies, the mixed progesterone/glucocorticoid antagonist RU486 or mifepristone switches to an apparent partial agonist upon repeated administration. To address these enigmas several interesting phenomena are highlighted. These include the conditional nature of the excitation/inhibition balance in feedback regulation, the role of glucose as a determinant of stress responsivity, and the potential of glucocorticoids in resetting the stress response system. The analysis of the feedback paradox provides also a golden opportunity to review the progress in understanding the role of glucocorticoid hormone in resilience and vulnerability during stress, the science that was burned deeply in Mary Dallman's emotions.
Topics: Animals; Glucocorticoids; Feedback; Stress, Psychological; Corticosterone; Hydrocortisone
PubMed: 37589046
DOI: 10.1080/10253890.2023.2247090