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Journal of Medical Economics 2024Estimate relative efficacy of zuranolone, a novel oral, Food and Drug Administration-approved treatment for postpartum depression (PPD) in adults vs. selective serotonin... (Meta-Analysis)
Meta-Analysis
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 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.
Topics: Adult; Female; Humans; Selective Serotonin Reuptake Inhibitors; Depression, Postpartum; Pregnanolone; Pyrazoles
PubMed: 38523596
DOI: 10.1080/13696998.2024.2334160 -
Clinical Pharmacology in Drug... Mar 2024Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABA ) receptors, is in development for...
Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median T of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median T of approximately 1 and 3 hours, respectively. C was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.
Topics: Adult; Humans; Child, Preschool; Seizures; Administration, Intravenous; Anticonvulsants; Epileptic Syndromes; Receptors, GABA-A; Pregnanolone
PubMed: 38231434
DOI: 10.1002/cpdd.1365 -
Acta Obstetricia Et Gynecologica... Oct 2023The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABA ) receptors...
INTRODUCTION
The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABA ) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relation between GABA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABA receptor, in the participating women.
MATERIAL AND METHODS
15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom-free, control women, aged 18-40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection.
RESULTS
Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels.
CONCLUSIONS
Women with painful endometriosis show altered GABA receptor function, depicted as a muted response to an exogenous GABA receptor agonist.
Topics: Female; Humans; Receptors, GABA-A; Pregnanolone; Endometriosis; gamma-Aminobutyric Acid; Diazepam; Gonadal Steroid Hormones; Pelvic Pain
PubMed: 36944570
DOI: 10.1111/aogs.14559 -
The Journal of Pharmacology and... Jan 2024Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine...
Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.
Topics: Rats; Male; Animals; Midazolam; Ketamine; Pregnanolone; Soman; Anticonvulsants; Neuroinflammatory Diseases; Neurosteroids; Status Epilepticus; Seizures; Benzodiazepines; Cholinergic Agents; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 37770198
DOI: 10.1124/jpet.123.001784 -
Virologica Sinica Dec 2023Influenza A virus (IAV) poses a global public health concern and remains an imminent threat to human health. Emerging antiviral resistance to the currently approved...
Influenza A virus (IAV) poses a global public health concern and remains an imminent threat to human health. Emerging antiviral resistance to the currently approved influenza drugs emphasizes the urgent need for new therapeutic entities against IAV. Allopregnanolone (ALLO) is a natural product that has been approved as an antidepressant drug. In the present study, we repurposed ALLO as a novel inhibitor against IAVs. Mechanistic studies demonstrated that ALLO inhibited virus replication by interfering with the nucleus translocation of viral nucleoprotein (NP). In addition, ALLO showed significant synergistic activity with compound 16, a hemagglutinin inhibitor of IAVs. In summary, we have identified ALLO as a novel influenza virus inhibitor targeting NP, providing a promising candidate that deserves further investigation as a useful anti-influenza strategy in the future.
Topics: Animals; Dogs; Humans; Nucleoproteins; Pregnanolone; Madin Darby Canine Kidney Cells; Influenza A virus; Influenza, Human; Virus Replication
PubMed: 37741571
DOI: 10.1016/j.virs.2023.09.003 -
Archives of Women's Mental Health Feb 2024Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug...
OBJECTIVE
Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug reactions (ADRs) associated with its use is limited. The main aim of this study was to explore the postmarketing safety profile of brexanolone.
METHODS
In our case/non-case pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS), the reporting odds ratio and information component with 95% confidence intervals were estimated as measures of disproportionate reporting. Primary disproportionality analyses were performed by comparing brexanolone with all other drugs or selective serotonin reuptake inhibitors (SSRIs). Sensitivity analyses were performed on a subset of perinatal depression.
RESULTS
We identified 267 cases using brexanolone. Brexanolone was reported as a primary or secondary suspect drug in most cases (n = 260, 97.38%). Of the total brexanolone cases, positive dechallenge and discontinuation accounted for 12.36% (n = 33) and 26.22% (n = 70), respectively. Serious outcomes were reported in 11.61% (n = 31) patients. Compared to all the other drugs or SSRIs within the same time window, the reporting risks of brexanolone were mainly from psychiatric and nervous systems. Sensitivity analyses indicated that these significant disproportionalities were mostly retained.
CONCLUSION
Our pharmacovigilance analysis showed a high reporting frequency of psychiatric and nervous system ADRs associated with the use of brexanolone. In additional prospective research, these signals urgently need to be clarified.
Topics: Female; Pregnancy; Humans; United States; Selective Serotonin Reuptake Inhibitors; Pharmacovigilance; Prospective Studies; Pregnanolone; United States Food and Drug Administration; Drug Combinations; beta-Cyclodextrins
PubMed: 37831172
DOI: 10.1007/s00737-023-01378-1 -
Psychoneuroendocrinology Jun 2024Perinatal depression is a major cause of disability for individuals giving birth worldwide, with detrimental effects on short- and long-term parental and child outcomes....
Perinatal depression is a major cause of disability for individuals giving birth worldwide, with detrimental effects on short- and long-term parental and child outcomes. There is emerging evidence that the neuroactive steroid hormone allopregnanolone is implicated in the pathophysiology and course of perinatal mood symptoms. However, no study thus far has examined allopregnanolone levels whilst making use of longitudinal data on depressive symptom trajectories throughout the perinatal period. The present study investigated levels of allopregnanolone at gestational week 17 of 252 participants in relation to perinatal depressive symptom trajectories, with a secondary aim of exploring the role of history of depression as an effect modifier. Four perinatal depressive symptom trajectories were investigated: controls (no depressive symptoms throughout perinatal period) (N=161), antepartum (depressive symptoms prenatally with postpartum remission) (N=31), postpartum-onset (no depressive symptoms during pregnancy, development of depressive symptoms postpartum) (N=23), and persistent (depressive symptoms throughout the perinatal period) (N=37). Results show that for every one nmol/l increase in allopregnanolone, there was 7% higher odds for persistent depressive symptoms (OR 1.07, 95% CI 1.01-1.14) compared to controls. No association was seen for antepartum and postpartum-onset depressive symptoms. History of depression did not modify the association between allopregnanolone and perinatal depressive symptom trajectories. These results show the role of allopregnanolone for persistent depressive symptoms and strengthen the hypothesis of differences in pathophysiology among the trajectories.
Topics: Female; Child; Pregnancy; Humans; Depression; Depression, Postpartum; Pregnanolone; Postpartum Period; Depressive Disorder
PubMed: 38442504
DOI: 10.1016/j.psyneuen.2024.107009 -
Journal of Affective Disorders Jun 2024To investigate the efficacy and safety of different dosage regimens of zuranolone in the treatment of patients with major depressive disorder (MDD). (Review)
Review
OBJECTIVE
To investigate the efficacy and safety of different dosage regimens of zuranolone in the treatment of patients with major depressive disorder (MDD).
METHODS
PubMed, Embase, The Cochrane Library and other databases were searched from inception until July 2019. Randomized controlled trials (RCTs) related to the efficacy and safety of zuranolone in the treatment of MDD were included. The data were extracted independently by 2 investigators and assessed the study quality by the Cochrane risk-of-bias tool. The primary outcome includes the 17-item HAMILTON total score (HAMD-17) and the incidence of adverse events (AEs).
RESULTS
Six high-quality RCTs with 1593 patients were finally included in our analysis. Zuranolone group achieve a notable treatment effect at day15 in HAMD-17 compared with placebo group (MD = -2.69, 95 % CI: -4.45 to -0.94, P < 0.05). For safety, no significant differences existed in the proportion of patients with AEs between zuranolone with placebo (RR = 1.25, 95 % CI: 0.99 to 1.58, P = 0.06).
CONCLUSION
Zuranolone has a significant efficacy in improving depressive symptoms in the short term and is positively correlated with the dosage administered. However, the efficacy of zuranolone decreased significantly when the time of administration was extended. Zuranolone demonstrated a controllable safety issue. But adverse effects increased as the dose of zuranolone was gradually increased to 50 mg.
Topics: Humans; Depressive Disorder, Major; Randomized Controlled Trials as Topic; Pyrazoles; Remission Induction; Pregnanolone
PubMed: 38479510
DOI: 10.1016/j.jad.2024.03.057 -
The Medical Letter on Drugs and... Dec 2023
Topics: Female; Humans; Depression, Postpartum; Pregnanolone; Pyrazoles
PubMed: 38133592
DOI: 10.58347/tml.2023.1692a -
Steroids Oct 2023Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs...
Drugs possessing aryloxypropanamine pharmacophore, duloxetine, dapoxetine and propranolol, increase allopregnanolone in rat brain: Possible involvement of allopregnanolone in their central nervous system effects.
Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs possessing the aryloxypropanamine (AOPA) pharmacophore, such as fluoxetine, exert their central nervous system (CNS) effects by increasing the brain AP. Although duloxetine (DLX), dapoxetine (DPX), atomoxetine (ATX) and propranolol (PRL) also possess the AOPA pharmacophore and are used to treat some psychiatric disorders, the capabilities of these drugs to increase the brain AP and the possible involvement of AP in their CNS effects remain to be fully elucidated. To clarify these points, we first developed a method for quantifying AP in the rat brain by liquid chromatography/electrospray ionization-tandem mass spectrometry. Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP (DLX: < 0.40-2.74 ng/g tissue, DPX: 1.48-3.83 ng/g tissue and PRL: < 0.40-2.09 ng/g tissue) compared to the saline administration (<0.40 ng/g tissue). These results suggested the possible involvement of the GABAergic neurosteroid, AP, in the central actions of DLX, DPX and PRL. In contrast, ATX (10 mg/kg) did not affect the AP levels in the brain. In addition, the brain and serum AP levels had a remarkably high positive correlation after the administration of DLX, DPX and PRL. Thus, this study proposed the AP-related novel mechanism of actions of DLX, DPX and PRL in the CNS.
Topics: Animals; Rats; Brain; Duloxetine Hydrochloride; Neurosteroids; Pharmaceutical Preparations; Pharmacophore; Pregnanolone; Propranolol; Propylamines
PubMed: 37468115
DOI: 10.1016/j.steroids.2023.109272