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Pediatric Neurology Apr 2020PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome characterized by brief clusters of febrile and afebrile seizures with onset primarily before the... (Review)
Review
PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome characterized by brief clusters of febrile and afebrile seizures with onset primarily before the age of three years, cognitive impairment, autistic traits, and behavioral abnormalities. PCDH19 gene is located in Xq22 and produces nonclustered delta protocadherin. This disorder primarily manifests in heterozygote females due to random X chromosome inactivation leading to somatic mosaicism and abnormal cellular interference between cells with and without delta-protocadherin. This article reviews the clinical features based on a comprehensive literature review (MEDLINE using PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence), personal practice, and experience. Significant progress has been made in the past 10 years, including identification of the gene responsible for the condition, characterization of clinical phenotypes, and development of animal models. More rigorous studies involving quality-of-life measures as well as standardized neuropsychiatric testing are necessary to understand the full spectrum of the disease. The recent discovery of allopregnanolone deficiency in patients with PCDH19-related epilepsy leads to opportunities in precision therapy. A phase 3 clinical study is currently active to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone (an allopregnanolone analog) therapy.
Topics: Animals; Behavioral Symptoms; Cadherins; Epileptic Syndromes; Humans; Intellectual Disability; Pregnanolone; Protocadherins
PubMed: 32057594
DOI: 10.1016/j.pediatrneurol.2019.10.009 -
Obstetrics and Gynecology Clinics of... Sep 2020Perinatal care, including the management of mental health issues, often falls under the auspices of primary care providers. Postpartum depression (PPD) is a common... (Review)
Review
Perinatal care, including the management of mental health issues, often falls under the auspices of primary care providers. Postpartum depression (PPD) is a common problem that affects up to 15% of women. Most women at risk can be identified before delivery based on psychiatric history, symptoms during pregnancy, and recent psychosocial stressors. Fortunately, there have been a variety of treatment studies using antidepressants, nonpharmacologic interactions, and most recently, allopregnanolone (Brexanolone) infusion that have shown benefits. The most commonly used screening scale, Edinburgh Postnatal Depression Scale, a 10-item self-rated scale, has been translated into a variety of languages.
Topics: Adult; Antidepressive Agents; Depression, Postpartum; Drug Combinations; Female; Humans; Infant; Mass Screening; Neurosteroids; Perinatal Care; Postpartum Period; Pregnancy; Pregnanolone; Prevalence; Psychiatric Status Rating Scales; Psychotherapy; Risk Factors; Selective Serotonin Reuptake Inhibitors; Surveys and Questionnaires; beta-Cyclodextrins
PubMed: 32762926
DOI: 10.1016/j.ogc.2020.05.001 -
Frontiers in Neuroendocrinology Oct 2020Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide... (Review)
Review
Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, emphasizing three key areas: biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be dealing with a two-edged sword: while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
Topics: Emotions; Female; Humans; Pregnanolone; Premenstrual Dysphoric Disorder; Progesterone
PubMed: 32730861
DOI: 10.1016/j.yfrne.2020.100856 -
The Journal of Clinical Psychiatry Feb 2020
Review
Topics: Adult; Contraceptives, Oral, Hormonal; Evidence-Based Medicine; Female; Gonadotropin-Releasing Hormone; Humans; Pregnanolone; Premenstrual Dysphoric Disorder; Selective Serotonin Reuptake Inhibitors
PubMed: 32023366
DOI: 10.4088/JCP.19ac13071 -
CNS Spectrums Feb 2015Despite decades of research aimed at identifying the causes of postpartum depression (PPD), PPD remains common, and the causes are poorly understood. Many have... (Review)
Review
Despite decades of research aimed at identifying the causes of postpartum depression (PPD), PPD remains common, and the causes are poorly understood. Many have attributed the onset of PPD to the rapid perinatal change in reproductive hormones. Although a number of human and nonhuman animal studies support the role of reproductive hormones in PPD, several studies have failed to detect an association between hormone concentrations and PPD. The purpose of this review is to examine the hypothesis that fluctuations in reproductive hormone levels during pregnancy and the postpartum period trigger PPD in susceptible women. We discuss and integrate the literature on animal models of PPD and human studies of reproductive hormones and PPD. We also discuss alternative biological models of PPD to demonstrate the potential for multiple PPD phenotypes and to describe the complex interplay of changing reproductive hormones and alterations in thyroid function, immune function, hypothalamic-pituitary-adrenal (HPA) axis function, lactogenic hormones, and genetic expression that may contribute to affective dysfunction. There are 3 primary lines of inquiry that have addressed the role of reproductive hormones in PPD: nonhuman animal studies, correlational studies of postpartum hormone levels and mood symptoms, and hormone manipulation studies. Reproductive hormones influence virtually every biological system implicated in PPD, and a subgroup of women seem to be particularly sensitive to the effects of perinatal changes in hormone levels. We propose that these women constitute a "hormone-sensitive" PPD phenotype, which should be studied independent of other PPD phenotypes to identify underlying pathophysiology and develop novel treatment targets.
Topics: Animals; Depression, Postpartum; Estrogens; Female; Humans; Pregnancy; Pregnanolone; Progesterone
PubMed: 25263255
DOI: 10.1017/S1092852914000480 -
CNS Drugs Mar 2019Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of... (Review)
Review
Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of the mother and child, negatively impacting child cognitive, behavioral, and emotional development with lasting consequences. There are a number of therapeutic interventions for postpartum depression including pharmacotherapy, psychotherapy, neuromodulation, and hormonal therapy among others, most of which have been adapted from the treatment of major depressive disorder outside of the peripartum period. Current evidence of antidepressant treatment for postpartum depression is limited by the small number of randomized clinical trials, underpowered samples, and the lack of long-term follow-up. The peripartum period is characterized by rapid and significant physiological change in plasma levels of endocrine hormones, peptides, and neuroactive steroids. Evidence supporting the role of neuroactive steroids and γ-aminobutyric acid (GABA) in the pathophysiology of postpartum depression led to the investigation of synthetic neuroactive steroids and their analogs as potential treatment for postpartum depression. Brexanolone, a soluble proprietary intravenous preparation of synthetic allopregnanolone, has been developed. A recent series of open-label and placebo-controlled randomized clinical trials of brexanolone in postpartum depression demonstrated a rapid reduction in depressive symptoms, and has led to the submission for regulatory approval to the US Food and Drug Administration (decision due in March 2019). SAGE-217, an allopregnanolone analog, with oral bioavailability, was recently tested in a randomized, double-blind, placebo-controlled phase III study in severe postpartum depression, with reportedly positive results. Finally, a 3β-methylated synthetic analog of allopregnanolone, ganaxolone, is being tested in both intravenous and oral forms, in randomized, double-blind, placebo-controlled phase II studies in severe postpartum depression.
Topics: Animals; Depression, Postpartum; Drug Combinations; Drug Development; Female; GABA Modulators; Humans; Neurosteroids; Pregnanes; Pregnanolone; Pyrazoles; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration; beta-Cyclodextrins
PubMed: 30790145
DOI: 10.1007/s40263-019-00605-7 -
Clinical Drug Investigation Dec 2020Hormonal contraceptives are used worldwide by more than 100 million women. Some studies have been published about the possible appearance of depressive symptoms when... (Review)
Review
Hormonal contraceptives are used worldwide by more than 100 million women. Some studies have been published about the possible appearance of depressive symptoms when using hormonal contraceptives, but this link is still a matter of debate. The purpose of this review is to provide an update of the literature on this issue, and to investigate the possible explanations of this problem based on animal and human studies. The main pathway responsible for menstrual cycle-related mood changes is the γ-aminobutyric acid pathway, which is sensitive to changes in the levels of progesterone and of its metabolites, the neurosteroids. In particular, allopregnanolone is a potentiating neurosteroid with anxiolytic and anti-convulsant effects whose levels change during a normal menstrual cycle together with progesterone levels. Progestins have different effects on allopregnanolone, mainly owing to their diverse androgenicity. Moreover, they might affect brain structure and function, even though the meaning of these changes has yet to be clarified. It is important to define the groups of women in which negative mood disorders are more likely to occur. Adolescence is a critical period and this age-specific vulnerability is complex and likely bidirectional. Moreover, women with a history of mood affective disorders or premenstrual dysphoric syndrome are at a higher risk when taking contraceptives. In this review, we aim to provide clinicians with advice on how to approach these difficult situations.
Topics: Adolescent; Animals; Depression; Female; Hormonal Contraception; Humans; Menstrual Cycle; Pregnanolone; Premenstrual Dysphoric Disorder; Premenstrual Syndrome; Progesterone; Young Adult
PubMed: 32980990
DOI: 10.1007/s40261-020-00966-8 -
Lancet (London, England) Sep 2018Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABA) receptors, for the treatment of moderate to severe post-partum depression.
METHODS
We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2).
FINDINGS
Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related.
INTERPRETATION
Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder.
FUNDING
Sage Therapeutics, Inc.
Topics: Adult; Depression, Postpartum; Double-Blind Method; Drug Combinations; Female; GABA Agonists; Humans; Injections, Intravenous; Pregnancy; Pregnancy Trimester, Third; Pregnanolone; Psychiatric Status Rating Scales; Receptors, GABA; Severity of Illness Index; Treatment Outcome; Young Adult; beta-Cyclodextrins
PubMed: 30177236
DOI: 10.1016/S0140-6736(18)31551-4 -
Biological Psychiatry Feb 2022Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting...
BACKGROUND
Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABA (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects.
METHODS
We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states.
RESULTS
We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABA receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6-12 Hz) through δ-containing GABA receptors, a mechanism distinct from other GABA positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress.
CONCLUSIONS
Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.
Topics: Animals; Antidepressive Agents; Basolateral Nuclear Complex; Female; GABA Modulators; Mice; Pregnanolone; Rats; Receptors, GABA-A
PubMed: 34561029
DOI: 10.1016/j.biopsych.2021.07.017 -
American Journal of Health-system... Oct 2022
Topics: Humans; Pregnanolone; Anticonvulsants
PubMed: 36099427
DOI: 10.1093/ajhp/zxac219