Evaluating the safety and efficacy of zuranolone in the management of major depressive disorder and postpartum depression, with or without concurrent insomnia: a rigorous systematic review and meta-analysis.

Introduction: Major depressive disorder (MDD), postpartum depression (PPD), and insomnia are neuropsychological conditions in which zuranolone is used to improve symptoms and prognosis of the disorder. This meta-analysis aimed to determine the efficacy of zuranolone in comparison to other drugs used for treating these conditions. Methods: This meta-analysis included patients aged between 18 and 75 years who were diagnosed with major depressive disorder and postpartum depression with or without insomnia and were administered zuranolone for treatment. Only randomized controlled trials (RCTs) were included, and animal studies were excluded. The databases used were PubMed, Scopus, Cochrane, and Clinicaltrials.gov, with MeSH terms and relevant keywords for (Zuranolone) and (Depression). The Cochrane risk of bias tool was used for quality assessment. Results: The meta-analysis included eight RCTs that analyzed data from 2031 patients. The meta-analysis revealed statistically significant changes in the Hamilton Depression Rating Scale (HAM-D), Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and treatment-emergent adverse effects (TEAE) scores in the PPD subgroup. HAM-D and TEAEs scores were also significant in the MDD subgroup, but the changes in the MADRS, HAM-A, and Bech-6 scores were insignificant. Serious adverse events were insignificant in all subgroups. Conclusion: Meta-analysis found a significant improvement in depressive symptoms with zuranolone treatment, especially on day 15. This suggests that zuranolone is a promising therapeutic option for patients with MDD and PPD with or without insomnia. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=459554, identifier CRD42023459554.

The efficacy and safety of Zuranolone for treatment of depression: A systematic review and meta-analysis.

RATIONALE: Zuranolone, a newly FDA-approved synthetic neurosteroid, shows promise in treating depression. OBJECTIVES: Our aim is to evaluate Zuranolone's efficacy and safety in treating depression. METHODS: Five databases were searched until September 2023 for relevant randomized clinical trials evaluating the efficacy and safety of zuranolone. The potential risk of bias in the included trials was evaluated by the Cochrane Risk of Bias II guideline Data were extracted and pooled using Review Manager Software (RevMan 5.3). RESULTS: An analysis of eight studies highlights Zuranolone's efficacy in treating depression compared to placebo across most of the outcomes. Notably, the 30mg and 50mg doses demonstrated significant improvements in reducing HAM-D scores by over 50% within a 15-day follow-up (RR) of 1.46 (95% CI [1.27, 1.68], p < 0.0001) and 1.14 (95% CI [1.01, 1.3], p = 0.04). Additionally, the HAM-D ≤ 7% score analysis revealed significant enhancements with the 30mg dose over both 15-day (RR = 1.82, 95% CI [1.44, 2.31], p < 0.0001) and 45-day (RR = 1.43, 95% CI [1.16, 1.77], p = 0.0008) durations. Adverse Events Drug Discontinuation demonstrated no overall significant difference (OR = 1.33, 95% CI: [0.79, 2.23], p = 0.282). Further, specific adverse events, such as headache, showed no significant overall difference between Zuranolone and placebo (OR = 1.11, 95% CI: [0.84, 1.47], p = 0.47), with dose-dependent analysis revealing less headache in the 30 mg group. CONCLUSION: Zuranolone demonstrates favorable tolerability and safety, particularly at 30mg and 50mg doses after 15 days, suggesting its potential and effective treatment for depression.

First Oral Treatment Specific for Postpartum Depression.

Postpartum depression is one of the most common perinatal mood disorders. The U.S. Food and Drug Administration approved the first oral medication developed specifically for the treatment of postpartum depression in August 2023. Zuranolone, marketed under the brand name Zurzuvae (Sage Therapeutics, Inc. and Biogen), is thought to work similarly to other positive allosteric modulators of gamma-aminobutyric acid A receptors such as benzodiazepines. It can be used alone or as an adjunct to other oral antidepressant medication. Its 2-week regimen of once-daily oral administration provides women with postpartum depression the opportunity to maintain their daily routines in an outpatient setting. This article provides an overview of zuranolone, including indications, mechanism of action, potential adverse reactions, and implications for nursing practice.

Zuranolone for treatment of major depressive disorder: a systematic review and meta-analysis.

Background: Current treatment modalities for Major Depressive Disorder have variable efficacies and a variety of side effects. To amend this, many trials for short term, well tolerated monotherapies are underway. One such option is Zuranolone (SAGE-217), which is a recent FDA approved antidepressant for Post Partum depression (PPD) and is undergoing clinical trials for PPD, major depressive disorder (MDD) and essential tremors (ET). Objectives: Pool currently available data that compare Zuranolone to Placebo for the treatment of Major Depressive Disorder and evaluate its efficacy and safety profile. Methods: We retrieved data from PUBMED and SCOPUS from inception to July 2023. We included articles comparing Zuranolone or SAGE 217 with placebo in patients suffering from Major Depressive Disorder. Review Manager 5.4 was used to analyze the outcomes including changes in the Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline as well as any treatment emergent adverse events (TEAEs) and severe adverse events. Results: Our review analyzed 4 trials and the data of 1,357 patients. Patients treated with Zuranolone indicated a statistically significant effect in the change from baseline in HAM-D score (p = 0.0009; MD [95% CI]: -2.03 [-3.23, -0.84]) as well as in MADRS score (p = 0.02; MD [95% CI]: -2.30[-4.31, -0.30]) and HAM-A score (p = 0.03; MD [95% CI]: -1.41[-2.70, -0.11]) on 15th day when compared to the Placebo group. Zuranolone was also significantly associated with a higher response rate (p = 0.0008; OR [95% CI]: 1.63[1.14, 2.35]) and higher remission rate (p = 0.03; OR [95% CI]: 1.65[1.05, 2.59]) when compared with the placebo. As for safety, Zuranolone was significantly associated with 1 or more TEAE (p = 0.006; RR [95% CI]: 1.14[1.04, 1.24]) but an insignificant association with side effects that lead to drug discontinuation (p = 0.70; RR [95% CI]: 1.18[0.51, 2.76]) and serious adverse events (p = 0.48; RR [95% CI]: 1.46 [0.52, 4.10]) when compared with placebo. Conclusion: Zuranolone is an effective and safe drug for short course major depressive disorder monotherapy. It shows results in 14 days (compared to 2-4 weeks that SSRI's take) and has anti-anxiolytic effects as well. However, only 4 trials have been used for the analysis and the sample size was small. The trials reviewed also cannot determine the long-term effects of the drug. More trials are needed to determine long term effects.

Zuranolone: A Narrative Review of a New Oral Treatment for Postpartum Depression.

PURPOSE: Postpartum depression is a prevalent and overlooked mental disorder. Pathophysiology is thought to originate from a combination of biological and social factors, including hormones, and genetics. The consequences of untreated postpartum depression can be severe and negatively impact maternal and infant health. Zuranolone was approved as an oral agent in August 2023 for the treatment of postpartum depression in adults. The purpose of this article is evaluating the clinical aspects of zuranolone, including safety and efficacy pertaining to the drug and the clinical data that led to its approval. METHODS: A literature search was conducted using PubMed, Web of Science, and EMBASE with the terms postpartum depression, postpartum depression management, and zuranolone to locate relevant data for this narrative review. The prescribing information of zuranolone and clinicaltrials.gov were also utilized. FINDINGS: Two Phase III trials (Study 1-NCT04442503 and Study 2-NCT02978326) led to the approval of zuranolone by the Food and Drug Administration (FDA) based on clinically meaningful improvement in depressive symptoms. The trials met their primary endpoint, a change from baseline in HAM-D total score at day 15 (Study 1; 95% CI -6.3 to -1.7, P = 0.001: Study 2; 95% CI (-6.9 to -1.5, P = 0.003). IMPLICATIONS: Zuranolone, an oral and rapidly acting antidepressant, represents a promising new oral treatment option for individuals with postpartum depression.

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens.

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 (α1/2ßγ2) and extrasynaptic (α4ßδ) 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.

Different dosage regimens of zuranolone in the treatment of major depressive disorder: A meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate the efficacy and safety of different dosage regimens of zuranolone in the treatment of patients with major depressive disorder (MDD). METHODS: PubMed, Embase, The Cochrane Library and other databases were searched from inception until July 2019. Randomized controlled trials (RCTs) related to the efficacy and safety of zuranolone in the treatment of MDD were included. The data were extracted independently by 2 investigators and assessed the study quality by the Cochrane risk-of-bias tool. The primary outcome includes the 17-item HAMILTON total score (HAMD-17) and the incidence of adverse events (AEs). RESULTS: Six high-quality RCTs with 1593 patients were finally included in our analysis. Zuranolone group achieve a notable treatment effect at day15 in HAMD-17 compared with placebo group (MD = -2.69, 95 % CI: -4.45 to -0.94, P < 0.05). For safety, no significant differences existed in the proportion of patients with AEs between zuranolone with placebo (RR = 1.25, 95 % CI: 0.99 to 1.58, P = 0.06). CONCLUSION: Zuranolone has a significant efficacy in improving depressive symptoms in the short term and is positively correlated with the dosage administered. However, the efficacy of zuranolone decreased significantly when the time of administration was extended. Zuranolone demonstrated a controllable safety issue. But adverse effects increased as the dose of zuranolone was gradually increased to 50 mg.

Indirect comparisons of relative efficacy estimates of zuranolone and selective serotonin reuptake inhibitors for postpartum depression.

AIMS: Estimate relative efficacy of zuranolone, a novel oral, Food and Drug Administration-approved treatment for postpartum depression (PPD) in adults vs. selective serotonin reuptake inhibitors (SSRIs) and combination therapies used for PPD in the United States. MATERIALS AND METHODS: Randomized controlled trials (RCTs) for zuranolone and SSRIs, identified from systematic review, were used to construct evidence networks, linking via common comparator arms. Due to heterogeneity in placebo responses, matching-adjusted indirect comparison (MAIC) was applied, statistically weighting the zuranolone treatment arm of Phase 3 SKYLARK Study (NCT04442503) to the placebo arm of RCTs investigating SSRIs for PPD. MAIC outputs were applied in Bucher indirect treatment comparisons (ITCs) and network meta-analysis (NMA), using Edinburgh Postnatal Depression Scale (EPDS) and 17-item Hamilton Rating Scale for Depression (HAMD-17) change from baseline (CFB) on Days 3, 15, 28 (Month 1), 45, and last observation (Day 45, Week 12/18). RESULTS: Larger EPDS CFB was observed among zuranolone-treated vs. SSRI-treated patients from Day 15 onward. Zuranolone-treated (vs. SSRI-treated) patients exhibited 4.22-point larger reduction in EPDS by Day 15 (95% confidence interval: -6.16, -2.28) and 7.43-point larger reduction at Day 45 (-9.84, -5.02) with Bucher ITC. NMA showed EPDS reduction for zuranolone was 4.52 (-6.40, -2.65) points larger than SSRIs by Day 15 and 7.16 (-9.47, -4.85) larger at Day 45. Lack of overlap between study populations substantially reduced effective sample size post-matching, making HAMD-17 CFB analysis infeasible. LIMITATIONS: Limited population overlap between SKYLARK Study and RCTs reduced feasibility of undertaking HAMD-17 CFB ITCs and may introduce uncertainty to EPDS CFB ITC results. CONCLUSIONS: Analysis showed zuranolone-treated patients with PPD experienced greater symptom improvement than SSRI-treated patients from Day 15 onward, with largest mean difference at Day 45. Adjusting for differences between placebo arms, zuranolone may be associated with greater PPD symptom improvement (measured by EPDS) vs. SSRIs.

The efficacy of zuranolone versus placebo in postpartum depression and major depressive disorder: a systematic review and meta-analysis.

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.

The cost-effectiveness of zuranolone versus selective serotonin reuptake inhibitors for the treatment of postpartum depression in the United States.

AIMS: The objective of this research is to evaluate the cost-effectiveness of zuranolone, the first oral treatment indicated for postpartum depression (PPD) in adults approved by the United States Food and Drug Administration. METHODS: Zuranolone and selective serotonin reuptake inhibitor (SSRI) trial-based efficacy was derived from an indirect treatment comparison. Long-term efficacy outcomes were based on a large longitudinal cohort study. Maternal health utility values were derived from trial-based, short-form 6-D responses. Other inputs were derived from literature and economic data from the US Bureau of Labor Statistics. We estimated costs (2023 US dollars) and quality-adjusted life-years (QALYs) for patients with PPD treated with zuranolone (14-day dosing) or SSRIs (chronic dosing). The indirect costs and QALYs of the children and partners were also estimated. RESULTS: The incremental cost-effectiveness ratio for zuranolone versus SSRIs was $94,741 per QALY gained over an 11-year time horizon. Maternal total direct medical costs averaged $84,318 in the zuranolone arm, compared to $86,365 in the SSRI arm. Zuranolone-treated adults averaged 6.178 QALYs compared to 6.116 QALYs for the SSRI arm. Costs and utilities for the child and partner were also included in the base case. Drug and administration costs for zuranolone averaged $15,902, compared to $30 for SSRIs over the studied time horizon. Results were sensitive to the model time horizon. LIMITATIONS: As head-to-head trials were not available to permit direct comparison, efficacy inputs were derived from an indirect treatment comparison which can be confounded by cross-trial differences. The data used are reflective of a general PPD population rather than marginalized individuals who may be at a greater risk for adverse PPD outcomes. The model likely excludes unmeasured effects for patient, child, and partner. CONCLUSIONS: This economic model's results suggest that zuranolone is a more cost-effective therapy compared to SSRIs for treating adults with PPD.

QUESTION: Is zuranolone cost-effective compared to selective serotonin-reuptake inhibitors for the treatment of postpartum depression (PPD) in adults in a United States (US) health care setting? FINDINGS: The model, which incorporated clinical trial data, long-term longitudinal cohort data, US Bureau of Labor Statistics data on compensation, and other peer-reviewed literature, projects that zuranolone is cost-effective compared to selective serotonin-reuptake inhibitors for the treatment of PPD at a willingness-to-pay threshold of $150,000 (USD).Meaning: For adults with PPD requiring pharmacological intervention, zuranolone may be a cost-effective treatment option with the potential to confer quality-of-life benefits for these patients and their families as well as economic benefits for society.

The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

Zuranolone, a neuroactive drug, used in the treatment of postpartum depression by modulation of GABAA receptors.

BACKGROUND: Postpartum depression [PPD] is a prevalent and debilitating mood disorder that affects mothers in the weeks to months after childbirth. Zuranolone (Zurzuvae) is a novel pharmaceutical agent that was approved by the US FDA on 4 August 2023 for the management of PPD. This review article provides a comprehensive overview of zuranolone, focusing on its dosing, chemistry, mechanism of action, clinical trials, adverse drug reaction, and overall conclusion regarding its utility in the management of PPD. It also discusses the recommended dosing strategies to achieve optimal efficacy while minimizing adverse effects as the dosage regimen of zuranolone is critical for its therapeutic application. Moreover, it gives insights into neurobiological pathways involved in PPD. METHODOLOGY: Data from randomized controlled trials and observational studies was collected to provide a comprehensive understanding of zuranolone in the management and treatment of PPD. CONCLUSION: Zuranolone represents a promising therapeutic option for women suffering from postpartum depression. However, ongoing research and post-marketing surveillance are essential to further elucidate its long-term safety and efficacy. The integration of zuranolone into clinical practice may significantly improve the quality of life for mothers facing the challenges of postpartum depression.

Exploring the clinical potentials of zuranolone in managing postpartum depression: A new therapeutic horizon.

Postpartum depression (PPD) poses a major threat to maternal mental health and wellbeing while also adversely affecting the mother's relationship with her baby, leading to significant repercussions that may hinder the growth and cognitive development of the child. For decades, antidepressants have been the mainstay of treating PPD; however, recent evidence suggests that antidepressants are not as effective as they are believed to be and there is a dire need to explore new treatment options. In 2023, a breakthrough in treating PPD emerged with the recent FDA approval of zuranolone, a gamma-aminobutyric acid (GABAA) receptor selective positive allosteric modulator. The implementation of zuranolone in treating PPD can prove to be revolutionary, considering it is the first oral medication available for PPD. Our review aims to discuss the various clinical trials that have been conducted to validate the efficacy of zuranolone in mitigating the symptoms of PPD, hence, leading to better outcomes for mothers.

The efficacy of zuranolone in postpartum depression and major depressive disorder: a review & number needed to treat (NNT) analysis.

INTRODUCTION: Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABAA receptors, is an attractive alternative as a rapid-acting antidepressant treatment. AREAS COVERED: This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants. EXPERT OPINION: Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).

Efficacy and safety of zuranolone for the treatment of depression: A systematic review and meta-analysis.

Major depressive disorder (MDD) and postpartum depression (PPD) are common and burdensome conditions. This study aims to evaluate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid type A receptors-positive allosteric modulator, in treating MDD and PPD. A comprehensive literature search was conducted until September 2023, identifying seven randomized controlled trials (RCTs). The results demonstrated that zuranolone significantly decreased Hamilton Rating Scale for Depression (HAM-D) scores in patients with PPD or MDD at day 15 (concluding the 14-day course) and day 42-45 (4 weeks after treatment cessation) compared with the placebo, albeit exhibiting a diminishing trend. Moreover, a higher percentage of patients with PPD or MDD achieved HAM-D response and remission with zuranolone treatment compared with placebo at day 15. However, zuranolone did not significantly increase the proportion of MDD patients achieving HAM-D remission at 42/43 days. Adverse events (AEs) such as somnolence, dizziness, and sedation were linked to zuranolone, with a higher but not statistically significant rate of discontinuation due to AEs in the zuranolone group. Overall, our findings support the rapid antidepressant effects of zuranolone in MDD and PPD, along with a relatively favorable safety and tolerability. Large-scale longitudinal RCTs are needed to evaluate the long-term efficacy of zuranolone.

Efficacy and safety of zuranolone in major depressive disorder: a meta-analysis of factor effect and dose-response analyses.

Background: Zuranolone is recognised as a promising antidepressant agent. Our study aimed to investigate the efficacy and safety of zuranolone in treating major depressive disorder (MDD). Methods: A systematic review was conducted by searching major databases from inception to August 20, 2023 (INPLASY: 202360087). A meta-analysis was performed by using a random-effects model to calculate effect sizes, expressed as standardised mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome was improvement in depressive symptoms, while secondary outcomes included response and remission rates of depression, improvement in anxiety symptoms, incidence of dropouts, and any side effects. We conducted subgroup analyses for general MDD and postpartum-onset MDD and a dose-response meta-analysis to estimate the relationship between zuranolone dose and outcomes. Findings: The study included seven randomised control trials involving 1789 patients. Zuranolone reduced depressive symptoms (SMD = -0.37, 95% CIs = -0.51 to -0.23), increased response rate (OR = 2.06, 95% CIs = 1.48-2.85) and remission rate (OR = 2.04, 95% CIs = 1.38-3.02), and reduced anxiety symptoms (SMD = -0.26, 95% CIs = -0.39 to -0.14). Furthermore, zuranolone-treated patients experienced more side effects than those in the control group (OR = 1.40, 95% CIs = 1.10-1.78), although dropout rate did not significantly differ between the two groups (OR = 1.13, 95% CIs = 0.85-1.49). According to the dose-response meta-analysis, zuranolone could effectively improve depression and anxiety at increasing doses up to a maximum daily dose of 30 mg; however, side effects increased with doses exceeding 30 mg. Based on subgroup analyses, zuranolone showed greater efficacy in treatment of postpartum-onset MDD than general MDD, but the difference did not reach statistical significance. Interpretation: Our findings suggested that zuranolone is effective in alleviating depression and anxiety. Nevertheless, there is a potential risk of adverse effects. Given its therapeutic efficacy and risk of side effects, a daily dose of 30 mg appears to be the optimal choice. Funding: Chang Gung Medical Foundation.

Zuranolone - synthetic neurosteroid in treatment of mental disorders: narrative review.

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.