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Psychopharmacology Sep 2023This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a... (Review)
Review
Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.
This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a first-in-class neurosteroid antidepressant with significant advantages over traditional antidepressants. PPD is a neuroendocrine disorder that affects about 20% of mothers after childbirth and is characterized by symptoms including persistent sadness, fatigue, dysphoria, as well as disturbances in cognition, emotion, appetite, and sleep. The main pathology behind PPD is the postpartum reduction of neurosteroids, referred to as neurosteroid withdrawal, a concept pioneered by our preclinical studies. We developed neurosteroid replacement therapy (NRT) as a rational approach for treating PPD and other conditions related to neurosteroid deficiency, unveiling the power of neurosteroids as novel anxiolytic-antidepressants. The neurosteroid, brexanolone (BX), is a progesterone-derived allopregnanolone that rapidly relieves anxiety and mood deficits by activating GABA-A receptors, making it a transformational treatment for PPD. In 2019, the FDA approved BX, an intravenous formulation of allopregnanolone, as an NRT to treat PPD. In clinical studies, BX significantly improved PPD symptoms within hours of administration, with tolerable side effects including headache, dizziness, and somnolence. We identified the molecular mechanism of BX in a neuronal PPD-like milieu. The mechanism of BX involves activation of both synaptic and extrasynaptic GABA-A receptors, which promote tonic inhibition and serve as a key target for PPD and related conditions. Neurosteroids offer several advantages over traditional antidepressants, including rapid onset, unique mechanism, and lack of tolerance upon repeated use. Some limitations of BX therapy include lack of aqueous solubility, limited accessibility, hospitalization for treatment, lack of oral product, and serious adverse events at high doses. However, the unmet need for synthetic neurosteroids to address this critical condition supersedes these limitations. Recently, we developed novel hydrophilic neurosteroids with a superior profile and improved drug delivery. Overall, approval of BX is a major milestone in the field of neurotherapeutics, paving the way for the development of novel synthetic neurosteroids to treat depression, epilepsy, and status epilepticus.
Topics: Female; Humans; Neurosteroids; Depression, Postpartum; Pregnanolone; Receptors, GABA-A; Antidepressive Agents
PubMed: 37566239
DOI: 10.1007/s00213-023-06427-2 -
Archives of Women's Mental Health Apr 2022Recent research has implicated allopregnanolone (ALLO), a neuroactive steroid and metabolite of progesterone, in perinatal mood and anxiety symptoms. We sought to add to...
Recent research has implicated allopregnanolone (ALLO), a neuroactive steroid and metabolite of progesterone, in perinatal mood and anxiety symptoms. We sought to add to the limited literature examining ALLO and mood and anxiety at multiple time points across the peripartum. We measured mood and anxiety symptoms and ALLO levels by ELISA at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in N = 73 women with prior histories of mood and/or anxiety disorders and N = 38 healthy controls. Analytic methods included multivariate and logistic regressions with linear mixed effect models. Among all participants (N = 111), higher ALLO levels at W6 were associated with higher depression and anxiety scores: each one unit increase in log ALLO at W6 was associated with a 2.54 point increase on the Edinburgh Postnatal Depression Scale (EPDS) (95% CI: 0.73 to 4.33) and an 8.0 point increase on the Perinatal Anxiety Screening Scale (PASS) (95% CI: 3.82 to 12.6). In addition, the nature of the relationship between log ALLO level and psychological measures changed across time; from T2 to W6 for EPDS, β = 3.73 (95% CI:1.16, 6.30), p = 0.0045; for PASS β = 9.78 (95% CI:3.77, 15.79), p = 0.0014); from T3 to W6, for (EPDS, β = 2.52 (95% CI:0.08, 4.96), p = 0.043; for PASS β = 7.33 (95% CI:1.63, 13.02), p = 0.018). The relationship of log ALLO to mood and anxiety symptoms was the same among women with and without psychiatric histories. Our exploratory findings indicate that the relationship between ALLO and mood and anxiety symptoms may change across the peripartum.
Topics: Anxiety; Depression; Depression, Postpartum; Female; Humans; Peripartum Period; Pregnancy; Pregnanolone; Psychiatric Status Rating Scales
PubMed: 34714413
DOI: 10.1007/s00737-021-01186-5 -
Drug Design, Development and Therapy 2021This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy. (Review)
Review
OBJECTIVE
This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy.
LITERATURE SEARCH
A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website.
DATA SYNTHESIS
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.
PLACE IN THERAPY
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.
CONCLUSION
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; Bipolar Disorder; Depression, Postpartum; Depressive Disorder; Drug Combinations; Female; Humans; Pregnancy; Pregnanes; Pregnanolone; Psychiatric Status Rating Scales; Pyrazoles; beta-Cyclodextrins
PubMed: 34267503
DOI: 10.2147/DDDT.S240856 -
Frontiers in Neuroendocrinology Oct 2019Hormonal contraceptives are frequently prescribed drugs among women, mainly for their reversible contraceptive purposes but also for beneficial effects in some... (Review)
Review
Hormonal contraceptives are frequently prescribed drugs among women, mainly for their reversible contraceptive purposes but also for beneficial effects in some gynecological pathologies. Despite extensive studies aimed at elucidating the physical effects of hormonal contraceptives and ameliorating some unwanted outcomes, little is known yet about the effects of these drugs on brain function and related behavior, which are known to be modulated by endogenous steroid hormones. We describe the current literature on preclinical studies in animals undertaken to investigate effects of hormonal contraceptives on brain function and behavior. These studies suggest that hormonal contraceptives influence neurohormones, neurotransmitters, neuropeptides, and emotional, cognitive, social and sexual behaviors. Animals allow examination of the basic biological mechanisms of these drugs, devoid of the psychological aspect often associated to hormonal contraceptives' use in women. Understanding the neurobiological effects of these drugs may improve women's health and may help women making informed choices on hormonal contraception.
Topics: Animals; Anxiety; Behavior, Animal; Brain; Contraceptive Agents, Hormonal; Depression; Female; Humans; Learning; Neuropeptides; Neurosteroids; Pregnanolone; Sexual Behavior; Social Behavior; Stress, Psychological; Synaptic Transmission
PubMed: 31614151
DOI: 10.1016/j.yfrne.2019.100799 -
Current Psychiatry Reports Apr 2021To provide an overview of existing studies on alterations in gonadal and neuroactive steroids (NASs) and mood symptoms among women with polycystic ovary syndrome (PCOS). (Review)
Review
PURPOSE OF REVIEW
To provide an overview of existing studies on alterations in gonadal and neuroactive steroids (NASs) and mood symptoms among women with polycystic ovary syndrome (PCOS).
RECENT FINDINGS
Recent studies have demonstrated a previously underappreciated association between PCOS and comorbid depression and anxiety. However, most studies on affective symptoms among women with PCOS have been cross-sectional, limiting our knowledge about fluctuations in symptoms over the menstrual cycle and reproductive lifespan for women with PCOS, as well as the potential interplay between NAS alterations and mood symptoms. Changes in the NAS allopregnanolone (ALLO) have been implicated in several reproductive-related psychiatric disorders (e.g., premenstrual dysphoric disorder (PMDD) and postpartum depression (PPD)) as well as in normal reproductive functioning, warranting further investigation for its potential role in the psychiatric symptoms observed in women with PCOS. Prospective studies evaluating associations between psychiatric symptoms and NAS are needed to elucidate the biological causes of the increased rates of psychiatric symptoms among women with PCOS and inform clinical treatment. ALLO, with its role in normal reproductive function, menstrual dysregulation among women with PCOS, and reproductive-related psychiatric conditions, makes it a particularly intriguing candidate for future investigation.
Topics: Affective Symptoms; Cross-Sectional Studies; Female; Humans; Neurosteroids; Polycystic Ovary Syndrome; Pregnanolone; Prospective Studies
PubMed: 33881645
DOI: 10.1007/s11920-021-01244-w -
Journal of Neuroendocrinology Feb 2022GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake.... (Review)
Review
GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti-depressant. However, it is well established that, in certain individuals, GABA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β-OH sibling of Allo, functions as a GABA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA receptors. The antagonistic effect is noted in most GABA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo-induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABA system.
Topics: Animals; Anti-Anxiety Agents; Clinical Trials, Phase II as Topic; Female; GABA-A Receptor Antagonists; Hepatic Encephalopathy; Humans; Pregnanolone; Premenstrual Dysphoric Disorder; Rats; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 34337790
DOI: 10.1111/jne.13013 -
Psychiatry Research Jan 2024Major depressive disorder (MDD) and postpartum depression (PPD) are common and burdensome conditions. This study aims to evaluate the efficacy and safety of zuranolone,... (Meta-Analysis)
Meta-Analysis Review
Major depressive disorder (MDD) and postpartum depression (PPD) are common and burdensome conditions. This study aims to evaluate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid type A receptors-positive allosteric modulator, in treating MDD and PPD. A comprehensive literature search was conducted until September 2023, identifying seven randomized controlled trials (RCTs). The results demonstrated that zuranolone significantly decreased Hamilton Rating Scale for Depression (HAM-D) scores in patients with PPD or MDD at day 15 (concluding the 14-day course) and day 42-45 (4 weeks after treatment cessation) compared with the placebo, albeit exhibiting a diminishing trend. Moreover, a higher percentage of patients with PPD or MDD achieved HAM-D response and remission with zuranolone treatment compared with placebo at day 15. However, zuranolone did not significantly increase the proportion of MDD patients achieving HAM-D remission at 42/43 days. Adverse events (AEs) such as somnolence, dizziness, and sedation were linked to zuranolone, with a higher but not statistically significant rate of discontinuation due to AEs in the zuranolone group. Overall, our findings support the rapid antidepressant effects of zuranolone in MDD and PPD, along with a relatively favorable safety and tolerability. Large-scale longitudinal RCTs are needed to evaluate the long-term efficacy of zuranolone.
Topics: Female; Humans; Depression; Antidepressive Agents; Pregnanolone; Depressive Disorder, Major; Treatment Outcome; Double-Blind Method
PubMed: 38029628
DOI: 10.1016/j.psychres.2023.115640 -
Endocrinology, Diabetes & Metabolism Apr 2021The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABA receptor. Whether neurosteroid levels and...
INTRODUCTION
The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABA receptor. Whether neurosteroid levels and the function of the GABA receptor are involved in the risk of preterm labour in pregnant women is unknown.
METHODS
Pregnant women with ( = 16) or without ( = 20) threatened preterm labour (TPL) in gestational week 33 + 6 days to 37 + 0 days were studied prospectively with procedures including foetal heart rate monitoring, vaginal examination, ultrasound examination and blood tests to determine allopregnanolone, progesterone and oxytocin levels. The GABA receptor function in both groups was measured with a saccadic eye velocity test (SEVT).
RESULTS
Plasma oxytocin levels were higher in the TPL group than in the control group (41.5 vs. 37.0 pmol/L, respectively, = .021). Although the allopregnanolone and progesterone levels in both groups did not differ, there was a negative association between blood oxytocin and allopregnanolone (as predictor) levels in the TPL group (B: -3.2, 95% confidence interval (CI): -5.5 to -0.9, = .012). As a predictor of TPL, progesterone was associated with cervix maturity (odds ratio: 1.02, 95% CI: 1.00-1.04, = .038). SEVT showed that the women in both groups had similar GABA receptor functions. In both groups, body mass index correlated with peak saccadic eye velocity ( = .34, = .044) and negatively with allopregnanolone ( = -.41, = .013).
CONCLUSIONS
Neurosteroid levels were unchanged in the peripheral blood of women with TPL, despite the increase in available oxytocin. Although the function of the GABA receptor was unchanged in women with TPL, to ensure reliable results, saccadic eye velocity should be investigated during a challenge test with a GABA receptor agonist.
Topics: Adolescent; Adult; Biomarkers; Body Mass Index; Brain; Female; Humans; Male; Obstetric Labor, Premature; Oxytocin; Pregnancy; Pregnanolone; Progesterone; Receptors, GABA-A; Risk; Saccades; Young Adult
PubMed: 33855217
DOI: 10.1002/edm2.216 -
Annals of Neurology Dec 2022Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective...
OBJECTIVE
Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia.
METHODS
Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology.
RESULTS
Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus.
INTERPRETATION
Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.
Topics: Animals; Humans; Infant, Newborn; Anticonvulsants; Asphyxia Neonatorum; Epilepsy; Phenobarbital; Seizures; Sheep; Animals, Newborn; Pregnanolone; Disease Models, Animal
PubMed: 36054160
DOI: 10.1002/ana.26493 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2023Despite the proven importance of neurosteroids in many physiological processes, their role in the pathogenesis of the most of psychiatric disorders remains relatively... (Review)
Review
Despite the proven importance of neurosteroids in many physiological processes, their role in the pathogenesis of the most of psychiatric disorders remains relatively understudied. This article reviews the current clinical evidence on the effects of neurosteroids on the formation and treatment of anxiety disorder, depression, bipolar disorder, and schizophrenia. In particular, the article points out the ambivalent nature of the effects of neurosteroids on GABA- and other receptors. We are especially interested in the anxiolytic and anxiogenic effects of some neurosteroids, the antidepressant effect of allopregnanolone in treating postpartum and other forms of depression, and the nature of short- and long-term mechanisms of antidepressant effects of neurosteroids of different types. The currently unproven hypothesis about the effect of changes in the level of neurosteroids on the course of bipolar disorder is also discussed, with an analysis of the scientific evidence on the development of schizophrenic symptomatology in relation to changing neurosteroid levels in the context of positive and cognitive symptoms.
Topics: Female; Humans; Neurosteroids; Mental Disorders; Bipolar Disorder; Anxiety Disorders; Pregnanolone
PubMed: 37084362
DOI: 10.17116/jnevro202312304131