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Background: Zuranolone, an oral version of allopregnanolone and neurosteroid, is a novel drug for the treatment of major depressive disorder (MDD) and postpartum depression (PPD). Aim: The purpose of this systematic review and meta-analysis was to assess the efficacy of zuranolone in the treatment of MDD and PPD. Method: A systematic search was conducted using EBSCOhost to simultaneously search Academic Search Premier, APA PsycArticles, APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL Ultimate, and MEDLINE with Full Text. Two independent reviewers screened the articles and completed a full-text review using Covidence. The quality of each study was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2). A meta-analysis was then conducted using Review Manager (RevMan v5.4) software. Results: The initial search yielded 127 results, with 6 articles fitting our inclusion and exclusion criteria. All 6 studies, comprising 1707 participants, had an overall low risk of bias. There was a significant decrease in HAM-D scores for MDD at 15 days versus placebo (MD − 2.40, 95% CI − 3.07 to − 1.63; p <.001). When pooling data for PDD, there was an overall significant decrease in HAM-D scores at 15 days versus placebo (MD − 4.06, 95% CI − 4.25 to − 3.87; p <.001). Conclusion: The results suggest that zuranolone can improve symptoms of PPD at 15 days; however, results were not clinically significant for MDD. Future research is needed to evaluate the long-term efficacy of zuranolone in PPD and the treatment efficacy in MDD. [ABSTRACT FROM AUTHOR]

Introduction and purpose: The joyous occasion of childbirth is often overshadowed by the prevalence of postpartum depression (PPD), a complex mental health condition affecting mothers globally. This paper reviews the current state of knowledge on PPD, exploring its frequency, risk factors, pathogenesis, symptoms, and impact on maternal and child health. Description of the State of Knowledge: Recent studies indicate an alarming increase in PPD rates, with notable racial and socioeconomic disparities. Symptoms of PPD, ranging from mild to severe include mood disturbances, cognitive impairments, and self-harm ideation. The repercussions extend beyond the postpartum period, affecting long-term child development, breastfeeding practices, and the mother-infant bond. Advancements in screening tools, particularly the Edinburgh Postnatal Depression Scale (EPDS), have facilitated early detection. However, creating an environment conducive to open communication about mental health remains a significant challenge. Interventions for PPD include psychotherapeutic approaches, pharmacological interventions, and complementary therapies. Brexanolone, the first FDA-approved drug for PPD, represents a significant breakthrough. Community-based and peer support programs, alongside a multidisciplinary approach involving healthcare professionals and support networks, have shown promise in alleviating PPD symptoms. Summary: In conclusion, PPD remains a substantial public health concern. Increased awareness of its multifaceted nature has led to improved screening, diagnosis, and intervention strategies. Ongoing dialogue, supportive environments, and refined treatments are essential for enhancing the well-being of both mothers and their infants in the postpartum period. [ABSTRACT FROM AUTHOR]

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABAAR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABAARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABAARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed. [ABSTRACT FROM AUTHOR]

Objective: Brexanolone (Zulresso®) that was approved for the USA in March 2019 is indicated for the treatment of postpartum depression (PPD), but information on adverse drug reactions (ADRs) associated with its use is limited. The main aim of this study was to explore the postmarketing safety profile of brexanolone. Methods: In our case/non-case pharmacovigilance study based on the FDA Adverse Event Reporting System (FAERS), the reporting odds ratio and information component with 95% confidence intervals were estimated as measures of disproportionate reporting. Primary disproportionality analyses were performed by comparing brexanolone with all other drugs or selective serotonin reuptake inhibitors (SSRIs). Sensitivity analyses were performed on a subset of perinatal depression. Results: We identified 267 cases using brexanolone. Brexanolone was reported as a primary or secondary suspect drug in most cases (n = 260, 97.38%). Of the total brexanolone cases, positive dechallenge and discontinuation accounted for 12.36% (n = 33) and 26.22% (n = 70), respectively. Serious outcomes were reported in 11.61% (n = 31) patients. Compared to all the other drugs or SSRIs within the same time window, the reporting risks of brexanolone were mainly from psychiatric and nervous systems. Sensitivity analyses indicated that these significant disproportionalities were mostly retained. Conclusion: Our pharmacovigilance analysis showed a high reporting frequency of psychiatric and nervous system ADRs associated with the use of brexanolone. In additional prospective research, these signals urgently need to be clarified. [ABSTRACT FROM AUTHOR]

Neurosteroids, such as allopregnanolone, are primarily synthesized substances in the central nervous system which influence processes occurring in the brain. Fluctuations in the levels of neurosteroids can result in an increased anxiety and heightened sensitivity. Significant reduction in neurosteroid synthesis usually occurs during the perimenstrual and postpartum periods when very low levels of progesterone are observed. It is believed that a lack of neurosteroids in the body is one of the main causes of postpartum depression. Postpartum depression (PPD) is a form of depression which develops in women during the postnatal period. Clinical studies have been conducted, and the results indicate that Brexanolone (a water-soluble formulation of allopregnanolone) is effective in treating postpartum depression. Based on the evaluation of the HAMD-17 depression scale, women with PGD who received injectable neurosteroid doses achieved remission from postpartum depression more effectively and quickly than those in the placebo group. Subsequent studies were also conducted with the tablet form of neurosteroids (Zuranolone), and the results similarly showed favorable outcomes for postpartum depression. Additionally, during treatment with both injectable and tablet forms of neurosteroids, there were relatively few and non-threatening side effects for patients. This suggests that the benefits of neurosteroids in treating PPD may outweigh the potential harm and should possibly be considered and incorporated into the European psychiatric practice.

Introduction and purpose: The joyous occasion of childbirth is often overshadowed by the prevalence of postpartum depression (PPD), a complex mental health condition affecting mothers globally. This paper reviews the current state of knowledge on PPD, exploring its frequency, risk factors, pathogenesis, symptoms, and impact on maternal and child health. Description of the State of Knowledge: Recent studies indicate an alarming increase in PPD rates, with notable racial and socioeconomic disparities. Symptoms of PPD, ranging from mild to severe include mood disturbances, cognitive impairments, and self-harm ideation. The repercussions extend beyond the postpartum period, affecting long-term child development, breastfeeding practices, and the mother-infant bond. Advancements in screening tools, particularly the Edinburgh Postnatal Depression Scale (EPDS), have facilitated early detection. However, creating an environment conducive to open communication about mental health remains a significant challenge. Interventions for PPD include psychotherapeutic approaches, pharmacological interventions, and complementary therapies. Brexanolone, the first FDA-approved drug for PPD, represents a significant breakthrough. Community-based and peer support programs, alongside a multidisciplinary approach involving healthcare professionals and support networks, have shown promise in alleviating PPD symptoms. Summary: In conclusion, PPD remains a substantial public health concern. Increased awareness of its multifaceted nature has led to improved screening, diagnosis, and intervention strategies. Ongoing dialogue, supportive environments, and refined treatments are essential for enhancing the well-being of both mothers and their infants in the postpartum period.

With each passing year, the number of people suffering from mental disorders grows at a disturbing speed. Neuroactive steroids are a new promising group of drugs with the potential for use in many diseases like postpartum depression, postnatal psychosis, major depression, insomnia, bipolar disorder, and Parkinson's tremor, due to their ability to modulate the activity of GABAA receptor. Neurosteroids are progesterone metabolites that are synthesized from cholesterol or steroid hormones in various brain regions. They regulate neuronal development, regeneration, and neurotransmission. They are implicated in mood disorders, anxiety disorders, schizophrenia, PTSD, and impulsive aggression. Neurosteroids have been studied for their potential to prevent or treat neurodegenerative diseases such as Alzheimer's disease and HIV-associated dementia. They can promote neurogenesis, neuronal survival, myelination, and memory function. They can also affect the growth and sensitivity of hormone-dependent brain tumors such as gliomas. Zuranolone, a newly registered neurosteroid drug has shown huge flexibility in both clinical and ambulatory treatment thanks to its pharmacokinetic traits, especially the possibility for oral administration, unlike its predecessor Brexanolone. Zuranolone is a synthetic positive allosteric modulator of the GABAA receptor that can be taken orally. The review aims to summarize the current knowledge on zuranolone as a novel neurosteroid drug for various mental disorders, especially for postpartum mental disorders for which this drug was meant originally. It covers studies indexed in the PubMed, Scopus, and Web of Science databases published since 2017. Keywords used in the search, as well as inclusion and exclusion criteria, are given in the aims and methodology section. The review explains the evidence for the role of neurosteroids, especially allopregnanolone, in the pathophysiology and treatment of postpartum depression. It discusses the mechanisms of neurosteroid action, the changes in neurosteroid levels during pregnancy and postpartum, and the clinical trials of brexanolone and zuranolone, two synthetic analogs of allopregnanolone, for postpartum depression. It provides an overview of the biosynthesis and metabolism of neurosteroids in the central and peripheral nervous system. Furthermore, it explains the different sources and pathways of neurosteroid production and the factors that influence their synthesis and regulation, such as stress, hormones, drugs, and genetic variations. The review also explores the potential relevance of neurosteroids for other psychiatric disorders, such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD), schizophrenia, and premenstrual dysphoric disorder. Finally, it highlights the associations between neurosteroid levels and symptom severity and the effects of neurosteroid modulation on mood, cognition, and neuroplasticity. [ABSTRACT FROM AUTHOR]

Postpartum depression (PPD) is associated with a decline in progesterone-derived anxiolytic–antidepressant neurosteroids after delivery. Neurosteroid replacement therapy (NRT) with GABA-A receptor-modulating allopregnanolone (brexanolone) shows promise as the first drug treatment for PPD. Here we describe the molecular insights of the neurosteroid approach for rapid relief of PPD symptoms compared with traditional antidepressants. [ABSTRACT FROM AUTHOR]

The evolution of research in the field of antidepressant pharmacology registered a period of apparent stagnation after the appearance of multimodal agents (vilazodone, approved by FDA in 2011, and vortioxetine, approved in 2013) in the clinical use, which raised concern among mental health specialists, mainly due to the high rates of partial response or nonresponse in patients with major depressive disorder (MDD). Also, the reduced tolerability of some antidepressants, with an important incidence of adverse effects such as weight gain, sexual dysfunctions or sedation, supported the need for further pharmacological explorations in order to find new therapeutic solutions in MDD. The “new wave” of antidepressants includes agents with different mechanisms of action, namely partial agonism of type 1A serotoninergic receptors, glutamatergic modulation, simultaneous inhibition of the three monoamine transporters, allosteric modulation of GABA-A receptors, or the combination of distinct mechanisms of several pharmacological agents in a single tablet. Gepirone, esketamine, toludesvenlafaxine, zuranolone, brexanolone and the combination dextromethorphan+bupropion are the representatives of the new generation of antidepressants, all of which have been approved in the last five years by various national or regional agencies with responsibilities in the field of medicines authorization, for depressive disorders (MDD, postpartum depression, or treatment-resistant depression). These new agents came not only with the promise of better efficacy (esketamine, dextromethorphan+bupropion) or indications for which there were no specific treatments until now (brexanolone), but also of a superior tolerability profile (gepirone and toludesvenlafaxine). Given that the number of studies supporting the approval of these drugs is currently limited, pharmacovigilance activity and new independent studies will determine whether we can talk about a therapeutic paradigm shift in depression. [ABSTRACT FROM AUTHOR]

This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a first-in-class neurosteroid antidepressant with significant advantages over traditional antidepressants. PPD is a neuroendocrine disorder that affects about 20% of mothers after childbirth and is characterized by symptoms including persistent sadness, fatigue, dysphoria, as well as disturbances in cognition, emotion, appetite, and sleep. The main pathology behind PPD is the postpartum reduction of neurosteroids, referred to as neurosteroid withdrawal, a concept pioneered by our preclinical studies. We developed neurosteroid replacement therapy (NRT) as a rational approach for treating PPD and other conditions related to neurosteroid deficiency, unveiling the power of neurosteroids as novel anxiolytic-antidepressants. The neurosteroid, brexanolone (BX), is a progesterone-derived allopregnanolone that rapidly relieves anxiety and mood deficits by activating GABA-A receptors, making it a transformational treatment for PPD. In 2019, the FDA approved BX, an intravenous formulation of allopregnanolone, as an NRT to treat PPD. In clinical studies, BX significantly improved PPD symptoms within hours of administration, with tolerable side effects including headache, dizziness, and somnolence. We identified the molecular mechanism of BX in a neuronal PPD-like milieu. The mechanism of BX involves activation of both synaptic and extrasynaptic GABA-A receptors, which promote tonic inhibition and serve as a key target for PPD and related conditions. Neurosteroids offer several advantages over traditional antidepressants, including rapid onset, unique mechanism, and lack of tolerance upon repeated use. Some limitations of BX therapy include lack of aqueous solubility, limited accessibility, hospitalization for treatment, lack of oral product, and serious adverse events at high doses. However, the unmet need for synthetic neurosteroids to address this critical condition supersedes these limitations. Recently, we developed novel hydrophilic neurosteroids with a superior profile and improved drug delivery. Overall, approval of BX is a major milestone in the field of neurotherapeutics, paving the way for the development of novel synthetic neurosteroids to treat depression, epilepsy, and status epilepticus. [ABSTRACT FROM AUTHOR]

The neurosteroid 3α,5α-THP is a potent GABAA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum β-endorphin (β-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation. [ABSTRACT FROM AUTHOR]

Introduction: Brexanolone demonstrates short-term efficacy for the treatment of postpartum depression (PPD). Postpartum depression is linked to infanticide and maternal suicide, and current treatment often fails to adequately control depressive symptoms. The purpose of this analysis is to further understand the experience(s) of women who have received brexanolone for the treatment of PPD. Methods: Semistructured interviews modeled after the theory of planned behavior (TPB) were conducted to assess women's perceptions of treatment for PPD with brexanolone. Women who received treatment with brexanolone at this inpatient facility were eligible to participate in this study. The TPB is often used to predict intention to perform health-related behaviors. Semistructured interviews were recorded and transcribed, and thematic analysis was conducted to identify common ideas across all interviews. Follow-up assessment of depressive and anxious symptoms was also conducted using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Results: Five of the 10 women who received treatment with brexanolone at this facility were interviewed, and common themes related to the TPB were analyzed. Attitudes toward brexanolone were favorable, and having a strong support system was a motivating factor in receiving treatment for PPD. Insurance approval, need for childcare, and poor understanding of symptoms of PPD were barriers to receiving treatment with brexanolone. Symptoms of depression and anxiety were rated as low at the time of the follow-up interview as measured by the PHQ-9 (mean 1.6, range 1 to 3) and GAD-7 (mean 2.8, range 2 to 4), respectively. Discussion: Brexanolone rapidly and sustainably reduced symptoms of PPD and was well-received by patients. Despite significant barriers to use, women who received treatment with brexanolone advocated for its availability as well as increased awareness of PPD.

Neurosteroids, such as allopregnanolone, are primarily synthesized substances in the central nervous system which influence processes occurring in the brain. Fluctuations in the levels of neurosteroids can result in an increased anxiety and heightened sensitivity. Significant reduction in neurosteroid synthesis usually occurs during the perimenstrual and postpartum periods when very low levels of progesterone are observed. It is believed that a lack of neurosteroids in the body is one of the main causes of postpartum depression. Postpartum depression (PPD) is a form of depression which develops in women during the postnatal period. Clinical studies have been conducted, and the results indicate that Brexanolone (a water-soluble formulation of allopregnanolone) is effective in treating postpartum depression. Based on the evaluation of the HAMD17 depression scale, women with PGD who received injectable neurosteroid doses achieved remission from postpartum depression more effectively and quickly than those in the placebo group. Subsequent studies were also conducted with the tablet form of neurosteroids (Zuranolone), and the results similarly showed favorable outcomes for postpartum depression. Additionally, during treatment with both injectable and tablet forms of neurosteroids, there were relatively few and non-threatening side effects for patients. This suggests that the benefits of neurosteroids in treating PPD may outweigh the potential harm and should possibly be considered and incorporated into the European psychiatric practice. [ABSTRACT FROM AUTHOR]

Background: Brexanolone is currently the only treatment specifically approved for postpartum depression (PPD) in the United States, based on the results from one Phase 2 and two Phase 3 double-blind, randomized, controlled trials in the HUMMINGBIRD program.Methods: Adults with PPD randomized to a 60-h infusion of brexanolone 90 μg/kg/h (BRX90) or placebo from the 3 trials were included in these post hoc analyses. Data on change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score, HAMD-17 Anxiety/Somatization and Insomnia subscales, and Clinical Global Impression of Improvement (CGI-I) scale were pooled. Response rates for HAMD-17 (≥50 % reduction from baseline) and CGI-I (score of 1 or 2) scales and time to response were analyzed.Results: Patients receiving BRX90 (n = 102) versus placebo (n = 107) achieved a more rapid HAMD-17 response (median, 24 vs 36 h; p = 0.0265), with an Hour-60 cumulative response rate of 81.4 % versus 67.3 %; results were similar for time to CGI-I response (median, 24 vs 36 h; p = 0.0058), with an Hour-60 cumulative response rate of 81.4 % versus 61.7 %. CFB in HAMD-17 Anxiety/Somatization and Insomnia subscales also favored BRX90 versus placebo, starting at Hour 24 through Day 30 (all p < 0.05), and response rates for both subscales were higher with BRX90.Limitations: The study was not powered to assess exploratory outcomes.Conclusions: Brexanolone was associated with rapid improvement in depressive symptoms and symptoms of anxiety and insomnia compared with placebo in women with PPD. These data continue to support the use of brexanolone to treat adults with PPD. [ABSTRACT FROM AUTHOR]

Autumn Walkery,1 Lauren D Leader,1 Emily Cooke,2 Amy VandenBerg1 1Department of Pharmacy Services, Michigan Medicine, Ann Arbor, MI, USA; 2Department of Pharmacy, Barnes-Jewish Hospital, St. Louis, MO, USACorrespondence: Lauren D LeaderMichigan Medicine, Department of Pharmacy Services, 1540 E. Medical Center Dr., Ann Arbor, MI, 48109 Tel +1 734 647-5938Email leaderla@med.umich.eduObjective: This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy.Literature Search: A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer’s website.Data Synthesis: One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache.Place in Therapy: Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed.Conclusion: Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.Keywords: postpartum, bipolar, brexanolone, zuranolone

Many investigational drugs with antidepressant activity are currently explored in different phases of clinical research, with indications such as major depressive disorder, treatment-resistant major depression, bipolar depression, post-partum depression, and late-life depression. Although the vast majority of the antidepressants in clinical use are based on the monoaminergic hypothesis of depression, recent data supported the launching on the market of two new, non-monoamine-modulating drugs. Esketamine for treatment-resistant major depression and brexanolone for post-partum depression are two exceptions from the monoaminergic model, although their use is still limited by high costs, unique way of administration (only intravenously for brexanolone), physicians' reluctance to prescribe new drugs, and patients' reticence to use them. Glutamatergic neurotransmission is explored based on the positive results obtained by intranasal esketamine, with subanesthetic intravenous doses of ketamine, and D-cycloserine, traxoprodil, MK-0657, AXS-05, AVP-786, combinations of cycloserine and lurasidone, or dextromethorphan and quinidine, explored as therapeutic options for mono- or bipolar depression. Sestrin modulators, cholinergic receptor modulators, or onabotulinumtoxinA have also been investigated for potential antidepressant activity. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost 7 decades of monoamine-modulating antidepressants, that new pathogenetic pathways should be targeted to increase the response rate in this population. [ABSTRACT FROM AUTHOR]

Therapeutic management of depression has currently important limitations, and its low efficacy is reflected in high rates of non-response even after multiple trials of antidepressants. Almost two-thirds of the patients diagnosed with major depression who received a 4–6 weeks trial of antidepressant could not reach remission, and more than 30% of these patients are considered treatment-resistant. In bipolar depression, the situation is also discouraging if we analyze the high suicide rate, the risk for the treatment-emergent affective switch when antidepressants are added, the high rate of treatment resistance (up to 25%), and the severe functional impairments associated with these episodes. Therefore, new therapeutic agents are needed, as well as new pathogenetic models for depression. The vast majority of the currently approved antidepressants are based on the monoamine hypothesis, although new drugs exploiting different neurotransmitter pathways have been recently approved by FDA. Brexanolone, an allopregnanolone analog, is an example of such new antidepressants, and its approval for post-partum depression inspired the search for a new generation of neurosteroids and GABA-ergic modulators, with an easier way of administration and superior tolerability profile. Orexin receptors antagonists are also extensively studied for different psychiatric disorders, depression included, in phase II trials. Antiinflammatory drugs, both cyclo-oxygenase 2 inhibitors and biological therapy, are investigated in patients with depressive disorders based on the proven correlation between inflammation and mood disorders in preclinical and clinical studies. Also, a new generation of monoamine-based investigational drugs is explored, ranging from triple reuptake inhibitors to atypical antipsychotics, in patients with major depression. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost seven decades, that new pathogenetic pathways should be targeted to increase these patients' response rate. [ABSTRACT FROM AUTHOR]

Objectives: To review the pharmacology, efficacy, and safety of Brexanolone and define its role in the treatment of postpartum depression. Date Sources: A MEDLINE/PubMed search was conducted (1980-May 2020) using the following keywords: postpartum depression, antidepressants, pharmacologic therapy, drug therapy, and brexanolone to identify relevant articles. Study Selection/Data Extraction: Literature search was limited to human studies published in the English language. Phase I, II, and III studies evaluating the pharmacology, efficacy, safety of brexanolone for postpartum depression were included. Bibliographies of relevant articles evaluating postpartum depression and treatment were reviewed for additional citations and background information. Data Synthesis: Brexanolone is a soluble, proprietary, injectable formulation of allopregnanolone, a neuroactive steroid that modulates neuronal excitability. Allopregnanolone levels increase during pregnancy and decrease substantially after birth. These fluctuations have profound effects on anxiety and depression. Three clinical trials established the efficacy and safety of brexanolone in the treatment of postpartum depression. In all 3 trials, brexanolone had an acceptable safety profile and was well tolerated. The most common adverse effects were loss of consciousness, sedation, dry mouth, headache, dizziness, and flushing. Due to sudden loss of consciousness and excessive sedation, continuous pulse oximetry is recommended. Conclusion: Brexanolone has a novel mechanism of action and appears to be safe and effective for the treatment of moderate to severe postpartum depression. At present, high cost, serious adverse effects, and restricted access may limit its use in clinical practice. [ABSTRACT FROM AUTHOR]

Therapeutic management of depression has currently important limitations, and its low efficacy is reflected in high rates of non-response even after multiple trials of antidepressants. Almost two-thirds of the patients diagnosed with major depression who received a 4–6 weeks trial of antidepressant could not reach remission, and more than 30% of these patients are considered treatment-resistant. In bipolar depression, the situation is also discouraging if we analyze the high suicide rate, the risk for the treatment-emergent affective switch when antidepressants are added, the high rate of treatment resistance (up to 25%), and the severe functional impairments associated with these episodes. Therefore, new therapeutic agents are needed, as well as new pathogenetic models for depression. The vast majority of the currently approved antidepressants are based on the monoamine hypothesis, although new drugs exploiting different neurotransmitter pathways have been recently approved by FDA. Brexanolone, an allopregnanolone analog, is an example of such new antidepressants, and its approval for post-partum depression inspired the search for a new generation of neurosteroids and GABA-ergic modulators, with an easier way of administration and superior tolerability profile. Orexin receptors antagonists are also extensively studied for different psychiatric disorders, depression included, in phase II trials. Antiinflammatory drugs, both cyclo-oxygenase 2 inhibitors and biological therapy, are investigated in patients with depressive disorders based on the proven correlation between inflammation and mood disorders in preclinical and clinical studies. Also, a new generation of monoamine-based investigational drugs is explored, ranging from triple reuptake inhibitors to atypical antipsychotics, in patients with major depression. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost seven decades, that new pathogenetic pathways should be targeted to increase these patients’ response rate.

Many investigational drugs with antidepressant activity are currently explored in different phases of clinical research, with indications such as major depressive disorder, treatment-resistant major depression, bipolar depression, post-partum depression, and late-life depression. Although the vast majority of the antidepressants in clinical use are based on the monoaminergic hypothesis of depression, recent data supported the launching on the market of two new, non-monoamine-modulating drugs. Esketamine for treatment-resistant major depression and brexanolone for post-partum depression are two exceptions from the monoaminergic model, although their use is still limited by high costs, unique way of administration (only intravenously for brexanolone), physicians’ reluctance to prescribe new drugs, and patients’ reticence to use them. Glutamatergic neurotransmission is explored based on the positive results obtained by intranasal esketamine, with subanesthetic intravenous doses of ketamine, and D-cycloserine, traxoprodil, MK-0657, AXS-05, AVP-786, combinations of cycloserine and lurasidone, or dextromethorphan and quinidine, explored as therapeutic options for mono- or bipolar depression. Sestrin modulators, cholinergic receptor modulators, or onabotulinumtoxinA have also been investigated for potential antidepressant activity. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost 7 decades of monoamine-modulating antidepressants, that new pathogenetic pathways should be targeted to increase the response rate in this population.

Introduction Postpartum depression (PPD) is an important cause of discomfort and dysfunction that impair the quality of life and the daily functionality not only of the patient but also of her child and her family, in its entirety. New treatment options have been made available for this pathology, but their use is restricted by methodological aspects, like the difficulty of administration, lack of enough data regarding their long-term efficacy, and costs. Objectives To conduct a literature review in order to find the most evidence-based pharmacological interventions for PPD. Methods A literature review was performed through the main electronic databases (PubMed, CINAHL, SCOPUS, EMBASE) using the search paradigm “postpartum depression” AND “treatment” OR “pharmacological agents”. All papers published between January 2000 and August 2021 were included. Results Among the most evidence-based agents for PPD treatment are serotonin selective reuptake inhibitors (SSRIs). As individual agents, sertraline seems to be the most supported antidepressant by evidence from clinical trials, followed by escitalopram/citalopram, and fluoxetine. Other antidepressants supported by clinical data were venlafaxine, desvenlafaxine, nortriptyline, and bupropion. A 6-12 months maintenance treatment is considered optimal after remission, in women with a low risk of recurrence. Brexanolone, zuranolone, and ganaxolone are members of a new class of drugs studied for postpartum depression, but currently, only the first agent is FDA-approved for this indication. Conclusions SSRIs are the most supported by evidence treatments for PPD, and brexanolone is a drug with a new mechanism, dedicated to this pathology that provides new hope for recovery. Disclosure No significant relationships.

Neurosteroids are involved in the pathophysiology of many neuroendocrine disorders in women. This review describes recent advancements in pharmacology of neurosteroids and emphasizes the benefits of neurosteroid replacement therapy for the management of neuroendocrine disorders such as catamenial epilepsy (CE), postpartum depression (PPD) and premenstrual brain conditions. Neurosteroids are endogenous modulators of neuronal excitability. A variety of neurosteroids are present in the brain including allopregnanolone (AP), allotetrahydro‐deoxycorticosterone and androstanediol. Neurosteroids interact with synaptic and extrasynaptic GABAA receptors in the brain. AP and related neurosteroids, which are positive allosteric modulators of GABAA receptors, are powerful anticonvulsants, anxiolytic, antistress and neuroprotectant agents. In CE, seizures are most often clustered around a specific menstrual period in women. Neurosteroid withdrawal‐linked plasticity in extrasynaptic receptors has been shown to play a key role in catamenial seizures, anxiety and other mood disorders. Based on our extensive research spanning two decades, we have proposed and championed neurosteroid replacement therapy as a rational strategy for treating disorders marked by neurosteroid‐deficiency, such as CE and other related ovarian or menstrual disorders. In 2019, AP (renamed as brexanolone) was approved for treating PPD. A variety of synthetic neurosteroids are in clinical trials for epilepsy, depression and other brain disorders. Recent advancements in our understanding of neurosteroids have entered a new era of drug discovery and one that offers a high therapeutic potential for treating complex brain disorders. [ABSTRACT FROM AUTHOR]

Postpartum depression (PPD) is a debilitating psychiatric disorder characterized by a high worldwide prevalence and serious long-term negative outcomes for both mothers and children. The lack of a specific treatment and overreliance on pharmacotherapy with limited efficacy and delayed treatment response has constituted a complication in the management of PPD. Recently, the Food and Drug Administration (FDA) in the USA approved a synthetic formulation of the GABAergic neurosteroid allopregnanolone, administered intravenously (brexanolone) for the rapid, long-lasting and effective treatment of PPD. Hereinafter, we review findings on allopregnanolone biosynthesis and GABAA receptor plasticity in the pathophysiology of PPD. We also discuss evidence supporting the efficacy of brexanolone for the treatment of PPD, which opens a promising new horizon for neurosteroid-based therapeutics for mood disorders.

Background: Postpartum depression (PPD) is linked to hormonal changes. Brexanolone, the first FDA-approved drug for PPD, is a potential treatment. This study analyzes Brexanolone's safety using the FAERS database, highlighting its adverse effects and potential risk factors., Methods: We analyzed FAERS data from Q3 2019 to Q3 2023, evaluating adverse reactions to Brexanolone. The analysis includes demographics, reporting regions, reporter identities, and types of adverse reactions., Results: Most reports are from the United States, with consumers and physicians as primary reporters. Adverse reactions mainly involve severe systemic diseases, administration site reactions, injuries, intoxication, operational complications, and mental disorders. Specific adverse reactions include incorrect drug monitoring, PPD, intrusive thoughts, delayed treatment efficacy, sedation complications, product discontinuation, misuse, infusion site leakage and pain, and medication errors., Conclusion: The study confirms known safety information about Brexanolone and provides comprehensive data for medical practices and public health decisions. However, relying on spontaneous reports may introduce biases and incomplete information. Continued monitoring and reporting of adverse reactions to newer drugs like Brexanolone remain crucial.