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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 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 -
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 -
Neurochemistry International May 2024Picrotoxin (PTX), a convulsant of plant origin, has been used in many studies as research tool. PTX is the open channel blocker of the GABA receptor (GABAR). Being in...
Picrotoxin (PTX), a convulsant of plant origin, has been used in many studies as research tool. PTX is the open channel blocker of the GABA receptor (GABAR). Being in the pore, PTX initiates transfer of the channel to the closed state and thus it falls into the "trap". The consequence of this PTX trapping is so-called aftereffect, i.e. continuation of the blockade of the GABA-induced chloride current (I) after removal of PTX from the external solution. The present work shows that the positive allosteric modulators (PAMs) of the GABA receptor, allopregnanolone (Allo) and zolpidem (Zolp) as well as a high concentration of GABA shortened the PTX aftereffect. Experiments were carried out on isolated Purkinje neurons of the rat cerebellum using the whole-cell patch-clamp method. I was induced by applications of 5 μM GABA (EC) for 1 s with 30 s intervals. 50 μM PTX completely blocked I, and recovery upon PTX washout occurred with a time constant (τ) of 20.2 min. 1 μM Allo reduced the blocking effect of PTX by 30% and accelerated the recovery of I by almost 10 times (τ = 2.4 min). 0.5 μM Zolp did not change the I block in the presence of PTX but accelerated the recovery of I by more than 3 times (τ = 5.6 min). Increasing the GABA concentration to 20 μM did not change the blocking effect of PTX, but accelerated recovery by 6 times (τ = 3.3 min). The mechanism of the shortening of the PTX aftereffect is presumably the expansion of the GABAR pore in the presence of PAMs and a high concentration of the agonist and, as a consequence, the escape of PTX from the "trap". The work describes new pharmacological properties of Allo and Zolp.
Topics: Rats; Animals; Receptors, GABA-A; Picrotoxin; Convulsants; Pregnanolone; gamma-Aminobutyric Acid
PubMed: 38395151
DOI: 10.1016/j.neuint.2024.105703 -
Pharmacology, Biochemistry, and Behavior May 2024Postpartum depression [PPD] is a prevalent and debilitating mood disorder that affects mothers in the weeks to months after childbirth. Zuranolone (Zurzuvae) is a novel... (Review)
Review
BACKGROUND
Postpartum depression [PPD] is a prevalent and debilitating mood disorder that affects mothers in the weeks to months after childbirth. Zuranolone (Zurzuvae) is a novel pharmaceutical agent that was approved by the US FDA on 4 August 2023 for the management of PPD. This review article provides a comprehensive overview of zuranolone, focusing on its dosing, chemistry, mechanism of action, clinical trials, adverse drug reaction, and overall conclusion regarding its utility in the management of PPD. It also discusses the recommended dosing strategies to achieve optimal efficacy while minimizing adverse effects as the dosage regimen of zuranolone is critical for its therapeutic application. Moreover, it gives insights into neurobiological pathways involved in PPD.
METHODOLOGY
Data from randomized controlled trials and observational studies was collected to provide a comprehensive understanding of zuranolone in the management and treatment of PPD.
CONCLUSION
Zuranolone represents a promising therapeutic option for women suffering from postpartum depression. However, ongoing research and post-marketing surveillance are essential to further elucidate its long-term safety and efficacy. The integration of zuranolone into clinical practice may significantly improve the quality of life for mothers facing the challenges of postpartum depression.
Topics: Female; Humans; Depression, Postpartum; Receptors, GABA-A; Quality of Life; gamma-Aminobutyric Acid; Pregnanolone; Pyrazoles
PubMed: 38387651
DOI: 10.1016/j.pbb.2024.173734 -
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 -
Journal of Women's Health (2002) Apr 2024
Topics: Humans; Female; Depression, Postpartum; Antidepressive Agents; Pregnanolone; Pregnancy; Treatment Outcome
PubMed: 38306166
DOI: 10.1089/jwh.2023.0991