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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 -
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 -
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 -
Drugs Nov 2023Zuranolone (ZURZUVAE) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABA) receptor being developed by Sage... (Review)
Review
Zuranolone (ZURZUVAE) is an oral neuroactive steroid and a positive allosteric modulator of the gamma aminobutyric acid A (GABA) receptor being developed by Sage Therapeutics and Biogen for the treatment of mood disorders. In August 2023, zuranolone received its first approval in the USA for the treatment of adults with postpartum depression [pending scheduling by the US Drug Enforcement Administration (DEA)]. This article summarizes the milestones in the development of zuranolone leading to this first approval.
Topics: Adult; Female; Humans; Pregnanes; Pyrazoles; Depression, Postpartum; Pregnanolone
PubMed: 37882942
DOI: 10.1007/s40265-023-01953-x -
Neuroscience and Biobehavioral Reviews Jun 2023Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These steroids... (Review)
Review
Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These steroids modulate major signaling systems in the brain and intracellular processes including inflammation, cellular stress and autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which are physiochemically identical to their natural counterparts except for rotation of polarized light. These studies led to insights in how NAS interact with receptors, ion channels and intracellular sites of action. Certain effects of NAS show high enantioselectivity, consistent with actions in chiral environments and likely direct interactions with signaling proteins. Other effects show no enantioselectivity and even reverse enantioselectivity. The spectrum of effects of NAS enantiomers raises the possibility that these agents, once considered only as tools for preclinical studies, have therapeutic potential that complements and in some cases may exceed their natural counterparts. Here we review studies of NAS enantiomers from the perspective of their potential development as novel neurotherapeutics.
Topics: Humans; Neurosteroids; Brain; Receptors, GABA-A
PubMed: 37085023
DOI: 10.1016/j.neubiorev.2023.105191