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Journal of Neuroendocrinology Apr 2024Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and...
Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α-reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma-aminobutyric acid-A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.
Topics: Animals; Mice; Neurosteroids; Pregnanolone; Receptors, GABA-A; Fear; Emotions; Cholestenone 5 alpha-Reductase
PubMed: 38482748
DOI: 10.1111/jne.13378 -
Journal of Medical Economics 2024The objective of this research is to evaluate the cost-effectiveness of zuranolone, the first oral treatment indicated for postpartum depression (PPD) in adults approved...
AIMS
The objective of this research is to evaluate the cost-effectiveness of zuranolone, the first oral treatment indicated for postpartum depression (PPD) in adults approved by the United States Food and Drug Administration.
METHODS
Zuranolone and selective serotonin reuptake inhibitor (SSRI) trial-based efficacy was derived from an indirect treatment comparison. Long-term efficacy outcomes were based on a large longitudinal cohort study. Maternal health utility values were derived from trial-based, short-form 6-D responses. Other inputs were derived from literature and economic data from the US Bureau of Labor Statistics. We estimated costs (2023 US dollars) and quality-adjusted life-years (QALYs) for patients with PPD treated with zuranolone (14-day dosing) or SSRIs (chronic dosing). The indirect costs and QALYs of the children and partners were also estimated.
RESULTS
The incremental cost-effectiveness ratio for zuranolone versus SSRIs was $94,741 per QALY gained over an 11-year time horizon. Maternal total direct medical costs averaged $84,318 in the zuranolone arm, compared to $86,365 in the SSRI arm. Zuranolone-treated adults averaged 6.178 QALYs compared to 6.116 QALYs for the SSRI arm. Costs and utilities for the child and partner were also included in the base case. Drug and administration costs for zuranolone averaged $15,902, compared to $30 for SSRIs over the studied time horizon. Results were sensitive to the model time horizon.
LIMITATIONS
As head-to-head trials were not available to permit direct comparison, efficacy inputs were derived from an indirect treatment comparison which can be confounded by cross-trial differences. The data used are reflective of a general PPD population rather than marginalized individuals who may be at a greater risk for adverse PPD outcomes. The model likely excludes unmeasured effects for patient, child, and partner.
CONCLUSIONS
This economic model's results suggest that zuranolone is a more cost-effective therapy compared to SSRIs for treating adults with PPD.
Topics: Adult; Female; Child; Humans; United States; Selective Serotonin Reuptake Inhibitors; Cost-Benefit Analysis; Depression, Postpartum; Longitudinal Studies; Quality-Adjusted Life Years; Pregnanolone; Pyrazoles
PubMed: 38465615
DOI: 10.1080/13696998.2024.2327946 -
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 -
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 -
Progress in Neuro-psychopharmacology &... Jun 2024Postpartum depression (PPD) poses a major threat to maternal mental health and wellbeing while also adversely affecting the mother's relationship with her baby, leading... (Review)
Review
Postpartum depression (PPD) poses a major threat to maternal mental health and wellbeing while also adversely affecting the mother's relationship with her baby, leading to significant repercussions that may hinder the growth and cognitive development of the child. For decades, antidepressants have been the mainstay of treating PPD; however, recent evidence suggests that antidepressants are not as effective as they are believed to be and there is a dire need to explore new treatment options. In 2023, a breakthrough in treating PPD emerged with the recent FDA approval of zuranolone, a gamma-aminobutyric acid (GABA) receptor selective positive allosteric modulator. The implementation of zuranolone in treating PPD can prove to be revolutionary, considering it is the first oral medication available for PPD. Our review aims to discuss the various clinical trials that have been conducted to validate the efficacy of zuranolone in mitigating the symptoms of PPD, hence, leading to better outcomes for mothers.
Topics: Humans; Female; Child; Depression, Postpartum; Pregnanolone; Pyrazoles; Antidepressive Agents
PubMed: 38412941
DOI: 10.1016/j.pnpbp.2024.110983 -
Journal of Affective Disorders Apr 2024Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact... (Randomized Controlled Trial)
Randomized Controlled Trial
The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.
BACKGROUND
Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36).
METHODS
Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed.
RESULTS
Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001).
LIMITATIONS
Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal.
CONCLUSIONS
Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.
Topics: Adult; Female; Humans; Depressive Disorder, Major; Double-Blind Method; Pregnanolone; Pyrazoles; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 38325605
DOI: 10.1016/j.jad.2024.01.268 -
Archives of Toxicology Apr 2024Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by...
Cardiovascular responses of adult male Sprague-Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone.
Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.
Topics: Humans; Rats; Male; Animals; Rats, Sprague-Dawley; Midazolam; Pregnanolone; Isoflurophate; Organophosphates; Brain; Organophosphate Poisoning
PubMed: 38305864
DOI: 10.1007/s00204-023-03679-x -
Journal of Anesthesia Apr 2024Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and... (Review)
Review
Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABA) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.
Topics: Anesthetics, General; Neurosteroids; Anesthetics; Pregnanolone; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 38252143
DOI: 10.1007/s00540-023-03291-4 -
Frontiers in Endocrinology 2023Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration,...
OBJECTIVE
Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer's disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways.
METHODS
Mechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses.
RESULTS
In hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABA and L-type Ca channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABA and L-type Ca channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics.
CONCLUSION
Collectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain.
Topics: Humans; Calcium Signaling; Astrocytes; Pregnanolone; Neurons; gamma-Aminobutyric Acid
PubMed: 38189047
DOI: 10.3389/fendo.2023.1286931 -
Frontiers in Endocrinology 2023Previous studies demonstrated the inhibitory effect of allopregnanolone (3α,5α-THP) on the activation of inflammatory toll-like receptor 4 (TLR4) signals in RAW264.7...
BACKGROUND
Previous studies demonstrated the inhibitory effect of allopregnanolone (3α,5α-THP) on the activation of inflammatory toll-like receptor 4 (TLR4) signals in RAW264.7 macrophages and the brains of selectively bred alcohol-preferring (P) rats. In the current study, we investigated the impact of 3α,5α-THP on the levels of IL-10 and activation of the TRIF-dependent endosomal TLR4 pathway.
METHODS
The amygdala and nucleus accumbens (NAc) of P rats, which exhibit innately activated TLR4 pathways as well as RAW264.7 cells, were used. Enzyme-linked immunosorbent assays (ELISA) and immunoblotting assays were used to ascertain the effects of 3α,5α-THP on the TRIF-dependent endosomal TLR4 pathway and endosomes were isolated to examine translocation of TLR4 and TRIF. Additionally, we investigated the effects of 3α,5α-THP and 3α,5α-THDOC (0.1, 0.3, and 1.0 µM) on the levels of IL-10 in RAW264.7 macrophages. Finally, we examined whether inhibiting TRIF (using TRIF siRNA) in RAW264.7 cells altered the levels of IL-10.
RESULTS
3α,5α-THP administration facilitated activation of the endosomal TRIF-dependent TLR4 pathway in males, but not female P rats. 3α,5α-THP increased IL-10 levels (+13.2 ± 6.5%) and BDNF levels (+21.1 ± 11.5%) in the male amygdala. These effects were associated with increases in pTRAM (+86.4 ± 28.4%), SP1 (+122.2 ± 74.9%), and PI(3)K-p110δ (+61.6 ± 21.6%), and a reduction of TIRAP (-13.7 ± 6.0%), indicating the activation of the endosomal TRIF-dependent TLR4 signaling pathway. Comparable effects were observed in NAc of these animals. Furthermore, 3α,5α-THP enhanced the accumulation of TLR4 (+43.9 ± 11.3%) and TRIF (+64.8 ± 32.8%) in endosomes, with no significant effect on TLR3 accumulation. Additionally, 3α,5α-THP facilitated the transition from early endosomes to late endosomes (increasing Rab7 levels: +35.8 ± 18.4%). In RAW264.7 cells, imiquimod (30 µg/mL) reduced IL-10 while 3α,5α-THP and 3α,5α-THDOC (0.1, 0.3, and 1.0 µM) restored IL-10 levels. To determine the role of the TRIF-dependent TLR4 signaling pathway in IL-10 production, the downregulation of TRIF (-62.9 ± 28.2%) in RAW264.7 cells led to a reduction in IL-10 levels (-42.3 ± 8.4%). TRIF (-62.9 ± 28.2%) in RAW264.7 cells led to a reduction in IL-10 levels (-42.3 ± 8.4%) and 3α,5α-THP (1.0 µM) no longer restored the reduced IL-10 levels.
CONCLUSION
The results demonstrate 3α,5α-THP enhancement of the endosomal TLR4-TRIF anti-inflammatory signals and elevations of IL-10 in male P rat brain that were not detected in female P rat brain. These effects hold significant implications for controlling inflammatory responses in both the brain and peripheral immune cells.
Topics: Animals; Female; Male; Rats; Adaptor Proteins, Vesicular Transport; Endosomes; Interleukin-10; Neurosteroids; Pregnanolone; Signal Transduction; Toll-Like Receptor 4; RAW 264.7 Cells; Mice
PubMed: 38179300
DOI: 10.3389/fendo.2023.1299420