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CNS Drugs Aug 2023Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal... (Review)
Review
Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.
Topics: Female; Humans; Premenstrual Dysphoric Disorder; Pregnanolone; Quality of Life; Menstrual Cycle; Luteal Phase; GABA Modulators; gamma-Aminobutyric Acid; Premenstrual Syndrome
PubMed: 37542704
DOI: 10.1007/s40263-023-01030-7 -
The Annals of Pharmacotherapy Jul 2024The objective of this study was to review the characteristics, efficacy, and safety of zuranolone in the management of postpartum depression (PPD). (Review)
Review
OBJECTIVE
The objective of this study was to review the characteristics, efficacy, and safety of zuranolone in the management of postpartum depression (PPD).
DATA SOURCES
Literature was identified using PubMed (1966-August 2023) and EMBASE (1973-August 2023) and clinicaltrials.gov. Search terms included zuranolone, SAGE-217, and PPD with further limitation of those published in English.
STUDY SELECTION AND DATA EXTRACTION
Articles selected for inclusion included trials evaluating zuranolone for the treatment of PPD.
DATA SYNTHESIS
Zuranolone was evaluated for the treatment of moderate to severe PPD in 2 phase III trials. Both studies resulted in statistically significant improvement in depressive symptoms at day 15 ( = 0.003 and < 0.001). Sustained differences in remission rates favoring zuranolone were found in both studies at day 45 compared with placebo ( = 0.01 and < 0.05). Zuranolone was well tolerated, with somnolence, dizziness, headache, and sedation reported as the most common side effects.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS
Zuranolone is only the second medication approved by the Food and Drug Administration (FDA) for PPD and offers an advantage over brexanolone in that it can administered orally in the outpatient setting. The rapid onset of effect of zuranolone is advantageous to traditional antidepressant therapy which can be weeks to months; however, limited information is available on safety during lactation.
CONCLUSIONS
The recent FDA approval of oral zuranolone for PPD offers a second rapid-acting treatment for PPD, extending the opportunity for treatment to patients in the outpatient setting.
Topics: Humans; Depression, Postpartum; Female; Administration, Oral; Drug Approval; United States Food and Drug Administration; United States; Antidepressive Agents; Treatment Outcome; Pregnanolone; Pyrazoles
PubMed: 37876133
DOI: 10.1177/10600280231204953 -
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 -
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 -
Neuroscience and Biobehavioral Reviews May 2024Tics are sudden, repetitive movements or vocalizations. Tic disorders, such as Tourette syndrome (TS), are contributed by the interplay of genetic risk factors and... (Review)
Review
Tics are sudden, repetitive movements or vocalizations. Tic disorders, such as Tourette syndrome (TS), are contributed by the interplay of genetic risk factors and environmental variables, leading to abnormalities in the functioning of the cortico-striatal-thalamo-cortical (CSTC) circuitry. Various neurotransmitter systems, such as gamma-aminobutyric acid (GABA) and dopamine, are implicated in the pathophysiology of these disorders. Building on the evidence that tic disorders are predominant in males and exacerbated by stress, emerging research is focusing on the involvement of neuroactive steroids, including dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone, in the ontogeny of tics and other phenotypes associated with TS. Emerging evidence indicates that DHEAS levels are significantly elevated in the plasma of TS-affected boys, and the clinical onset of this disorder coincides with the period of adrenarche, the developmental stage characterized by a surge in DHEAS synthesis. On the other hand, allopregnanolone has garnered particular attention for its potential to mediate the adverse effects of acute stress on the exacerbation of tic severity and frequency. Notably, both neurosteroids act as key modulators of GABA-A receptors, suggesting a pivotal role of these targets in the pathophysiology of various clinical manifestations of tic disorders. This review explores the potential mechanisms by which these and other neuroactive steroids may influence tic disorders and discusses the emerging therapeutic strategies that target neuroactive steroids for the management of tic disorders.
Topics: Male; Humans; Tics; Neurosteroids; Pregnanolone; Tic Disorders; Tourette Syndrome
PubMed: 38519023
DOI: 10.1016/j.neubiorev.2024.105637 -
Nature Communications Feb 2024Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health...
Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis. The discovery analysis includes 3299 individuals, with validation in a separate dataset of 1522 individuals. Five metabolite associations with SDB PCs are discovered and replicated. SDB PC1, characterized by frequent respiratory events common in older and male adults, is associated with pregnanolone and progesterone-related sulfated metabolites. SDB PC2, characterized by short respiratory event length and self-reported restless sleep, enriched in young adults, is associated with sphingomyelins. Metabolite risk scores (MRSs), representing metabolite signatures associated with the two SDB PCs, are associated with 6-year incident hypertension and diabetes. These MRSs have the potential to serve as biomarkers for SDB, guiding risk stratification and treatment decisions.
Topics: Young Adult; Humans; Male; Aged; Sleep Apnea Syndromes; Diabetes Mellitus; Hypertension; Risk Factors; Regression Analysis
PubMed: 38418471
DOI: 10.1038/s41467-024-46019-y -
Neuroscience and Biobehavioral Reviews Jun 2024Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis.... (Review)
Review
Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
Topics: Pregnanolone; Humans; Animals; Neuroinflammatory Diseases; Microglia; Astrocytes; GABA-A Receptor Antagonists
PubMed: 38608826
DOI: 10.1016/j.neubiorev.2024.105668 -
Drug Design, Development and Therapy 2023Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABA receptor positive modulator. However,... (Review)
Review
BACKGROUND
Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABA receptor positive modulator. However, at present, no comprehensive bibliometric analysis regarding allopregnanolone research is available. In our study, we intend to analyze the research trends and hot spots related to allopregnanolone in the past 20 years.
METHODS
We searched for allopregnanolone related articles and reviews between 2004 and 2023 from the Web of Science Core Collection database. Then, the bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel 2019, as well as the online bibliometric analysis platform (http://bibliometric.com/).
RESULTS
A total of 1841 eligible publications were identified. The number of annual publications and citations was generally on the rise. Among countries, the United States ranked first in overall publications, citations, international cooperation, and the number of research institutions. The University of North Carolina was the most active institution, conducting numerous preclinical and clinical work that focusing on allopregnanolone treatment for diverse psychiatric or neurologic disorders. As for authors, Dr. Frye CA, Morrow AL, and Pinna G were identified as the top three prolific scholars due to their great publications and citations. Based on the publication clusters and citation bursts analysis, the keyword co-occurrence network, the strongest citation bursts, and co-cited references analysis, the hot spots in recent years included "depression", "postpartum depression", "GABA receptor", and so on.
CONCLUSION
Allopregnanolone is still a popular area of research, and the United States leads the way in this area. Dr. Frye CA, Morrow AL, Pinna G, and their teams contributed greatly to the mechanism study and translation study of allopregnanolone. The use of allopregnanolone for the treatment of psychiatric or neurologic disorders, especially postpartum depression, is the current hot spot. However, the underlying mechanisms of anti-depression are still not clear, deserving more in-depth research.
Topics: Female; Humans; Pregnanolone; Bibliometrics; Central Nervous System; Databases, Factual; Depression, Postpartum; Nervous System Diseases
PubMed: 38024537
DOI: 10.2147/DDDT.S434364 -
Psychoneuroendocrinology Feb 2024Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual...
RATIONALE
Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD.
AIMS
The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms.
METHODS
Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5β-THP; pregnenolone; 3α,5α-androsterone; 3α,5β-androsterone; 3α,5α-A-diol; 3α5β-A-diol; 3α,5α-THDOC; 3α5β-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment.
RESULTS
Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone.
CONCLUSIONS
This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.
Topics: Humans; Female; Premenstrual Dysphoric Disorder; Neurosteroids; Sertraline; Progesterone; Pregnanolone; Androsterone; gamma-Aminobutyric Acid; Premenstrual Syndrome
PubMed: 38091917
DOI: 10.1016/j.psyneuen.2023.106684 -
Psychoneuroendocrinology Nov 2023The neuroactive metabolite of progesterone, allopregnanolone (ALLO), has been implicated in premenstrual syndrome (PMS) physiopathology and preclinical studies suggested... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The neuroactive metabolite of progesterone, allopregnanolone (ALLO), has been implicated in premenstrual syndrome (PMS) physiopathology and preclinical studies suggested that low doses of fluoxetine increase the ALLO brain concentration.
OBJECTIVES
To assess which low dose of fluoxetine (2 mg/d, 5 mg/d or 10 mg/d), administered exclusively during the luteal phase of menstrual cycle, has a potential effect for preventing or mitigating emotional PMS symptoms.
METHODS
In this randomized, double-blind, placebo-controlled pilot study, we followed 40 women (mean age = 29.7 +/- 7.4 years) with emotional PMS, during two menstrual cycles: cycle 1, without pharmacological intervention; and cycle 2, with pharmacological intervention. Participants took capsules, on average, seven days preceding the likely date of menses. We assessed the severity of PMS symptoms in both cycles using the Daily Record of Severity of Problems scale (DRSP).
RESULTS
There was an increase in the DRSP scores during the late luteal phase of cycle 1, confirming the diagnosis of emotional PMS. Low doses of fluoxetine (5 mg/d: 33.5%; 10 mg/d: 48.4%) reduced DRSP total score in the day before menses (day-1) at cycle 2 compared with day-1 at cycle 1. Fluoxetine 10 mg/d had the most consistent decline in emotional PMS symptoms; 70% of the participants reported a reduction greater than 40% in the DRSP score.
CONCLUSIONS
Low doses of fluoxetine, which may have no or few effect on the serotonergic system, but may interfere in the progesterone metabolization, seem to have some potential to mitigate emotional PMS symptoms. While the 10 mg/d of fluoxetine had the best performance on reducing emotional PMS symptoms, the 5 mg/d dose also seems to have some effect on emotional PMS symptoms. Further larger studies will help establish the lowest effective dose of flouxetine for PMS treatment.
Topics: Female; Humans; Young Adult; Adult; Fluoxetine; Pilot Projects; Progesterone; Premenstrual Syndrome; Menstrual Cycle; Pregnanolone; Double-Blind Method
PubMed: 37572412
DOI: 10.1016/j.psyneuen.2023.106360