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Journal of Women's Health (2002) Mar 2021Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on... (Meta-Analysis)
Meta-Analysis
Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clinical trials. Data from the three trials were combined. PPD-specific 17-item Hamilton Rating Scale for Depression (HAMD-17) group-level minimal important difference (MID) and patient-level meaningful change (meaningful change threshold [MCT]) were estimated and applied to differences in BRX versus placebo (PBO) at hour 60 (primary endpoint) and day 30 (end of trial follow-up). Likelihood of HAMD-17 response and remission and Clinical Global Impression of Improvement (CGI-I) response for BRX versus PBO were assessed at hour 60 and as sustained through day 30 using relative risk. Associated number needed to treat (NNT) and number needed to harm (NNH) values were also estimated. Two-hundred nine patients were included. The average HAMD-17 MID estimate was -2.1; the least-squared mean difference between BRX and PBO exceeded this at hour 60 and day 30. Minimal, moderate, and large MCTs were estimated to be -9, -15, and -20 points, respectively. Significantly more BRX-treated than PBO-treated patients achieved minimal, moderate, and large change (all s < 0.05) at hour 60 and large meaningful response at day 30 ( < 0.05). BRX-treated patients were more likely to sustain HAMD-17 remission and CGI-I response through day 30 versus PBO. NNTs ranged from 4 to 8, with NNH of 97. BRX provided meaningful changes relative to PBO, rapid (hour 60), and sustained improvements (day 30) in PPD symptoms, low NNT, and large NNH. These results may help inform treatment decision-making. Clinicaltrials.gov registration numbers: NCT02614547, NCT02942004, and NCT02942017.
Topics: Adult; Clinical Decision-Making; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone; Treatment Outcome; beta-Cyclodextrins
PubMed: 33181049
DOI: 10.1089/jwh.2020.8483 -
Alcohol (Fayetteville, N.Y.) Mar 2015The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug... (Comparative Study)
Comparative Study
The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under a FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the interval of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the interval for food reinforcement was low and maintained under a variable-interval schedule.
Topics: Acamprosate; Alcohol Drinking; Alcoholism; Animals; Dehydroepiandrosterone; Dose-Response Relationship, Drug; Eating; Ethanol; Male; Naltrexone; Pregnanolone; Rats; Rats, Long-Evans; Self Administration; Taurine
PubMed: 25620274
DOI: 10.1016/j.alcohol.2014.07.024 -
Neurotherapeutics : the Journal of the... Oct 2017
Topics: Ataxia; Fragile X Syndrome; Humans; Male; Neurotransmitter Agents; Pregnanolone; Tremor
PubMed: 28884425
DOI: 10.1007/s13311-017-0569-0 -
International Journal of Molecular... Feb 2021Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world,... (Review)
Review
Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a for the diagnosis of both MDD and PTSD.
Topics: Animals; Biomarkers; Brain; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Humans; Nerve Growth Factors; Neurosteroids; Pregnanolone; Stress Disorders, Post-Traumatic
PubMed: 33578758
DOI: 10.3390/ijms22041758 -
Journal of Neuroendocrinology Feb 2022The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and... (Review)
Review
The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti-inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate-to-severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post-traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic-like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse-control problems and manic symptoms.
Topics: Animals; Female; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A; Tic Disorders; Tics
PubMed: 34423500
DOI: 10.1111/jne.13022 -
Cell Reports Oct 2022The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps....
The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identifies etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step 2 activators. High concentrations of these metabolites fully and rapidly activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the "steroid fever" described in the late 1950s upon steroid injection in humans.
Topics: Etiocholanolone; Familial Mediterranean Fever; Humans; Inflammasomes; Mutation; Pregnanolone; Progesterone; Pyrin; Testosterone
PubMed: 36223753
DOI: 10.1016/j.celrep.2022.111472 -
Neuropharmacology Apr 2021Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative... (Review)
Review
Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'
Topics: Affect; Alcohol-Related Disorders; Androgens; Dehydroepiandrosterone; Estradiol; Female; Humans; Male; Neurosteroids; Pregnanolone; Progesterone; Progestins; Sex Factors; Stress Disorders, Traumatic; Testosterone
PubMed: 33600842
DOI: 10.1016/j.neuropharm.2021.108499 -
Biomolecules Feb 2023The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABA receptors. Interestingly, the PAM...
The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABA receptors. Interestingly, the PAM effects of ALLO are strongly enantioselective, whereas those of PREG are not. This study was aimed at determining the basis for this difference in enantioselectivity. The oocyte electrophysiology studies showed that -ALLO potentiates GABA-elicited currents in αβ GABA receptors with lower potency and efficacy than ALLO, PREG or -PREG. The small PAM effect of -ALLO was prevented by the α(Q242L) mutation in the intersubunit neurosteroid binding site between the β and α subunits. Consistent with this result, neurosteroid analogue photolabeling with mass spectrometric readout, showed that -ALLO binds weakly to the β-α intersubunit binding site in comparison to ALLO, PREG and -PREG. Rigid body docking predicted that -ALLO binds in the intersubunit site with a preferred orientation 180° different than ALLO, PREG or -PREG, potentially explaining its weak binding and effect. Photolabeling studies did not identify differences between ALLO and -ALLO binding to the α or β intrasubunit binding sites that also mediate neurosteroid modulation of GABA receptors. The results demonstrate that differential binding of -ALLO and -PREG to the β-α intersubunit site accounts for the difference in enantioselectivity between ALLO and PREG.
Topics: Receptors, GABA-A; Neurosteroids; Stereoisomerism; Pregnanolone; gamma-Aminobutyric Acid
PubMed: 36830708
DOI: 10.3390/biom13020341 -
The Journal of Clinical Endocrinology... Jun 2021Postpartum depression (PPD) is a serious psychiatric disorder. While causes remain poorly understood, perinatal sex hormone fluctuations are an important factor, and...
CONTEXT
Postpartum depression (PPD) is a serious psychiatric disorder. While causes remain poorly understood, perinatal sex hormone fluctuations are an important factor, and allopregnanolone in particular has emerged as a key determinant. Although synthetic environmental chemicals such as bisphenols and phthalates are known to affect sex hormones, no studies have measured allopregnanolone and the consequences of these hormonal changes on PPD have not been interrogated.
OBJECTIVE
To investigate associations of repeated measures of urinary bisphenols and phthalates in early and midpregnancy with serum pregnenolone, progesterone, allopregnanolone, and pregnanolone concentrations in midpregnancy and PPD symptoms at 4 months postpartum.
METHODS
Prospective cohort study of 139 pregnant women recruited between 2016 and 2018. Bisphenols and phthalates were measured in early and midpregnancy urine samples. Serum sex steroid hormone concentrations were measured in midpregnancy. PPD was assessed at 4 months postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multiple informant models were fit using generalized estimating equations. Serum levels of allopregnanolone, progesterone, pregnanolone, and pregnenolone were examined as log-transformed continuous variables. PPD symptoms were examined as continuous EPDS scores and dichotomously with scores ≥10 defined as PPD.
RESULTS
Di-n-octyl phthalate (DnOP) and diisononyl phthalate (DiNP) metabolites were associated with reduced progesterone concentrations. Log-unit increases in ∑DnOP and ∑DiNP predicted 8.1% (95% CI -15.2%, -0.4%) and 7.7% (95% CI -13.3%, -1.7%) lower progesterone, respectively. ∑DnOP was associated with increased odds of PPD (odds ratio 1.48; 95% CI 1.04, 2.11).
CONCLUSION
Endocrine disrupting chemicals may influence hormonal shifts during pregnancy as well as contribute to PPD.
Topics: Adult; Benzhydryl Compounds; Depression, Postpartum; Endocrine Disruptors; Female; Humans; Maternal Exposure; Neurosteroids; Phenols; Phthalic Acids; Postpartum Period; Pregnancy; Pregnancy Trimesters; Pregnanolone; Pregnenolone; Progesterone; Prospective Studies; Psychiatric Status Rating Scales
PubMed: 33792735
DOI: 10.1210/clinem/dgab199 -
Psychoneuroendocrinology Nov 2020Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal...
Longitudinal proneuroactive and neuroactive steroid profiles in medication-free women with, without and at-risk for perinatal depression: A liquid chromatography-tandem mass spectrometry analysis.
BACKGROUND
Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal plasma proneuroactive and NAS in healthy perinatal comparison women (HPCW), women at-risk for perinatal depression (AR-PND), and women with PND with/without comorbid anxiety. We hypothesized that AR-PND women who either did or did not go on to develop PND would have elevated NAS concentrations as compared to HPCW and that NAS would be correlated to depressive and anxiety symptoms.
METHODS
A prospective cohort study evaluated 75 medication-free perinatal women (HPCW, n = 30; AR-PND, n = 19; PND, n = 26). Standardized depression and anxiety assessments and blood samples were completed across 5 visits. Structured Clinical Interviews for DSM-IV TR Disorders were administered at study entry and exit. Plasma pregnenolone, progesterone, 5α- and 5β-dihydroprogesterone, pregnanolone, allopregnanolone, deoxycorticosterone and tetrahydrodeoxycorticosterone were quantified by liquid chromatography-tandem mass spectrometry. Longitudinal relationships between risk-group, depression and anxiety symptoms, and NAS concentrations were analyzed using generalized estimating equations to control for repeated measures correlations.
RESULTS
Perinatal 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, deoxycorticosterone, and tetrahydrodeoxycorticosterone concentrations were higher in AR-PND and PND women compared to HPCW (β = 3.57 ± 1.40 and β = 2.11 ± 1.12, p = 0.03; β = 0.18 ± 0.06 and β = 0.03 ± 0.05, p = 0.02; β = 1.06 ± 0.42 and β = 1.19 ± 0.47, p = 0.01; β = 0.17 ± 0.07 and β = 0.11 ± 0.06, p = 0.05; β = 0.03 ± 0.01 and β = 0.03 ± 0.01, p = 0.05, respectively). Perinatal allopregnanolone, 5α-dihydroprogesterone and tetrahydrodeoxycorticosterone were positively associated with HAM-D (all p < 0.02). HAM-A was positively associated with 5α- and 5β-dihydroprogesterone, pregnanolone, allopregnanolone, deoxycorticosterone and tetrahydrodeoxycorticosterone (all p < 0.05). A history of depression was associated with increased 5α-dihydroprogesterone (2.20 ± 1.09, p = 0.05), deoxycorticosterone (0.13 ± 0.06, p = 0.03) and tetrahydrodeoxycorticosterone (0.03 ± 0.01, p = 0.02).
CONCLUSION
To our knowledge, this study represents the largest prospective study of 5-α and 5-β reductase products of progesterone and deoxycorticosterone in HPCW and women AR-PND. Data suggest that PND is associated with both a reduction of progesterone to 5β-dihydroprogesterone, 5α-dihydroprogesterone, and allopregnanolone, and the 21-hydroxylation to deoxycorticosterone and tetrahydrodeoxycorticosterone. The shift towards 5α-dihydroprogesterone, deoxycorticosterone and tetrahydrodeoxycorticosterone was associated with a history of depression, a significant risk factor for PND.
Topics: 20-alpha-Dihydroprogesterone; Adult; Anxiety; Chromatography, Liquid; Depression; Depression, Postpartum; Depressive Disorder; Desoxycorticosterone; Female; Humans; Longitudinal Studies; Neurosteroids; Parturition; Pregnancy; Pregnanolone; Pregnenolone; Prenatal Care; Progesterone; Prospective Studies; Risk Factors; Tandem Mass Spectrometry
PubMed: 32828068
DOI: 10.1016/j.psyneuen.2020.104827