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Zuranolone
View on Wikipediafrom Wikipedia
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| Clinical data | |
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| Pronunciation | /zʊˈrænəloʊn/ zuu-RAN-ə-lohn |
| Trade names | Zurzuvae |
| Other names | SAGE-217; S-812217; SGE-797; BIIB-125 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a623048 |
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| Routes of administration | By mouth |
| Drug class | Neurosteroid; GABAA receptor positive allosteric modulator |
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| Pharmacokinetic data | |
| Protein binding | 99.5%[5][unreliable medical source?] |
| Metabolism | CYP3A4[5][unreliable medical source?] |
| Elimination half-life | 16–23 hours[6][7] |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.271.331 |
| Chemical and physical data | |
| Formula | C25H35N3O2 |
| Molar mass | 409.574 g·mol−1 |
| 3D model (JSmol) | |
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Zuranolone, sold under the brand name Zurzuvae, is a medication used for the treatment of postpartum depression.[1] It is taken by mouth.[1] Zuranolone is a neuroactive steroid which enhances the activity of the neurotransmitter gamma-aminobutyric acid (GABA) and is thought to exert antidepressant effects by enhancing GABAergic inhibition.[3][8][9]
The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.[1][10]
Zuranolone was approved for medical use in the United States for the treatment of postpartum depression in August 2023.[10] It was developed by Sage Therapeutics and Biogen.[11]
Medical uses
[edit]Zuranolone is indicated for the treatment of postpartum depression.[1][10]
Adverse effects
[edit]The most common side effects include drowsiness, dizziness, diarrhea, fatigue, and urinary tract infection.[10]
The US prescribing information contains a boxed warning noting that zuranolone can impact a person's ability to drive and perform other potentially hazardous activities.[10] The use of zuranolone may cause suicidal thoughts and behavior.[10] Zuranolone may also cause fetal harm.[10]
History
[edit]Zuranolone was developed as an improvement on the intravenously administered neurosteroid brexanolone, with high oral bioavailability and a biological half-life suitable for once-daily administration.[8][12] Its half-life is around 16 to 23 hours, compared to approximately 9 hours for brexanolone.[6][7]
The efficacy of zuranolone for the treatment of postpartum depression in adults was demonstrated in two randomized, double-blind, placebo-controlled, multicenter studies.[10] The trial participants were women with postpartum depression who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode and whose symptoms began in the third trimester or within four weeks of delivery.[10] In study 1, participants received 50 mg of zuranolone or placebo once daily in the evening for 14 days.[10] In study 2, participants received another zuranolone product that was approximately equal to 40 mg of zuranolone or placebo, also for 14 days.[10] Participants in both studies were monitored for at least four weeks after the 14-day treatment.[10] The primary endpoint of both studies was the change in depressive symptoms using the total score from the 17-item Hamilton depression rating scale (HAMD-17), measured at day 15.[10] Participants in the zuranolone groups showed significantly more improvement in their symptoms compared to those in the placebo groups.[10] The treatment effect was maintained at day 42—four weeks after the last dose of zuranolone.[10]
Society and culture
[edit]Legal status
[edit]Zuranolone was approved by the US Food and Drug Administration (FDA) for the treatment of postpartum depression in August 2023.[10][13] The FDA granted the application for zuranolone priority review and fast track designations.[10] Approval of Zurzuvae was granted to Sage Therapeutics, Inc.[10] Zuranolone has also been under development for the treatment of major depressive disorder, but the application for this use was given a Complete Response Letter by the FDA due to insufficient evidence of effectiveness.[14]
In the United States, zuranolone is a Schedule IV controlled substance.[1]
In July 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zurzuvae, intended for the treatment of adults with postpartum depression.[3] The applicant for this medicinal product is Biogen Netherlands B.V.[3] Zuranolone was authorized for medical use in the European Union in September 2025.[3][4]
Names
[edit]Zuranolone is the international nonproprietary name.[15]
Zuranolone is sold under the brand name Zurzuvae.[1]
Research
[edit]In a randomized, placebo-controlled phase III trial to assess its efficacy and safety for the treatment of major depressive disorder, subjects in the zuranolone group (50 mg oral zuranolone once daily for 14 days) experienced statistically significant and sustained improvements in depressive symptoms (as measured by HAM-D score) throughout the treatment and follow-up periods of the study.[16]
Other investigational applications include insomnia, bipolar depression, essential tremor, and Parkinson's disease.[17][18]
References
[edit]- ^ a b c d e f g "Zurzuvae- zuranolone capsule". DailyMed. 5 November 2024. Retrieved 27 July 2025.
- ^ "Schedules of Controlled Substances: Placement of Zuranolone in Schedule IV". Federal Register. 31 October 2023. Retrieved 5 March 2024.
- ^ a b c d e "Zurzuvae EPAR". European Medicines Agency (EMA). 25 July 2025. Retrieved 27 July 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ a b "Zurzuvae PI". Union Register of medicinal products. 18 September 2025. Retrieved 30 September 2025.
- ^ a b "Zuranolone". DrugBank Online.
- ^ a b Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. (2022). "GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors". Pharmacology & Therapeutics. 234 108035. doi:10.1016/j.pharmthera.2021.108035. PMC 9787737. PMID 34793859. S2CID 244280839.
- ^ a b Faden J, Citrome L (2020). "Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used?". Therapeutic Advances in Psychopharmacology. 10 2045125320968658. doi:10.1177/2045125320968658. PMC 7656877. PMID 33224470.
- ^ a b Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, et al. (2018). "Breakthroughs in neuroactive steroid drug discovery". Bioorganic & Medicinal Chemistry Letters. 28 (2): 61–70. doi:10.1016/j.bmcl.2017.11.043. PMID 29223589.
- ^ Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, et al. (2017). "Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor". Journal of Medicinal Chemistry. 60 (18): 7810–7819. doi:10.1021/acs.jmedchem.7b00846. PMID 28753313.
- ^ a b c d e f g h i j k l m n o p q r "FDA Approves First Oral Treatment for Postpartum Depression". U.S. Food and Drug Administration (FDA) (Press release). 4 August 2023. Retrieved 4 August 2023.
This article incorporates text from this source, which is in the public domain.
- ^ Saltzman J (4 August 2023). "FDA approves postpartum depression pill from two Cambridge drug firms". The Boston Globe. Archived from the original on 6 August 2023. Retrieved 5 August 2023.
- ^ Althaus AL, Ackley MA, Belfort GM, Gee SM, Dai J, Nguyen DP, et al. (2020). "Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator". Neuropharmacology. 181 108333. doi:10.1016/j.neuropharm.2020.108333. PMC 8265595. PMID 32976892.
- ^ "FDA Approves Zurzuvae (zuranolone), the First and Only Oral Treatment Approved for Women with Postpartum Depression, and Issues a Complete Response Letter for Major Depressive Disorder" (Press release). Biogen Inc. 4 August 2023. Retrieved 4 August 2023 – via GlobeNewswire.
- ^ McKenzie H. "Sage Hints at Difficult Decisions After Zuranolone's Rejection in MDD".
- ^ World Health Organization (2019). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82". WHO Drug Information. 33 (3). hdl:10665/330879.
- ^ Clayton AH, Lasser R, Parikh SV, Iosifescu DV, Jung J, Kotecha M, et al. (May 2023). "Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial". The American Journal of Psychiatry. 180 (9): 676–684. doi:10.1176/appi.ajp.20220459. PMID 37132201. S2CID 258461851.
- ^ Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, et al. (2021). "Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial". JAMA Psychiatry. 78 (9): 951–959. doi:10.1001/jamapsychiatry.2021.1559. PMC 8246337. PMID 34190962.
- ^ Bullock A, Kaul I, Li S, Silber C, Doherty J, Kanes SJ (2021). "Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study". Journal of the Neurological Sciences. 421 117277. doi:10.1016/j.jns.2020.117277. PMID 33387701. S2CID 229333842.
External links
[edit]- Clinical trial number NCT04442503 for "A Study to Evaluate the Efficacy and Safety of SAGE-217 in Participants With Severe Postpartum Depression (PPD)" at ClinicalTrials.gov
- Clinical trial number NCT02978326 for "A Study to Evaluate SAGE-217 in Participants With Severe Postpartum Depression" at ClinicalTrials.gov
Zuranolone
View on Grokipediafrom Grokipedia
Pharmacology
Mechanism of action
Zuranolone is a synthetic neuroactive steroid that functions as a positive allosteric modulator of the gamma-aminobutyric acid type A (GABA_A) receptor, enhancing inhibitory neurotransmission in the central nervous system.[7] As a structural analog of the endogenous neurosteroid allopregnanolone, it binds to a distinct neurosteroid site on the GABA_A receptor, increasing the receptor's affinity for GABA and potentiating chloride ion influx, which hyperpolarizes neurons and reduces excitability.[8] This non-genomic mechanism allows for rapid modulation of GABAergic signaling, contributing to its antidepressant and anxiolytic effects, though the precise pathways linking this to mood regulation remain under investigation.[9] Zuranolone exhibits activity at both synaptic and extrasynaptic GABA_A receptors. Synaptic receptors, typically containing γ subunits, mediate phasic inhibition in response to high GABA concentrations, while extrasynaptic receptors, often incorporating δ subunits, sustain tonic inhibition at lower ambient GABA levels; zuranolone potentiates currents through both, with particular sensitivity at δ-containing extrasynaptic sites.[10] This dual modulation enhances overall GABA_A receptor function, including increased receptor expression and chloride conductance, which is thought to restore balance in dysregulated inhibitory circuits implicated in conditions like postpartum depression.[9] Unlike benzodiazepines, which primarily target synaptic α/γ subunit interfaces, zuranolone's broader action profile avoids some tolerance issues while synergizing with other GABAergic agents non-competitively.[11] The drug's neurosteroid properties derive from its synthesis mimicking endogenous production from progesterone via 5α-reductase enzymes in neurons and glia, enabling oral bioavailability and brain penetration to achieve therapeutic levels.[12] Preclinical studies confirm its selectivity across multiple GABA_A receptor subtypes, underscoring its role in augmenting tonic inhibition to alleviate depressive symptoms without directly agonizing the receptor.[7]Pharmacokinetics
Zuranolone is rapidly absorbed following oral administration, with median peak plasma concentrations (T_max) achieved at 5–6 hours post-dose when taken with a fat-containing meal.[5] Food significantly enhances bioavailability; a high-fat meal increases C_max by approximately 4.3-fold and AUC by 2-fold compared to the fasted state, while a low-fat meal results in a 3.5-fold increase in C_max and 1.8-fold in AUC.[13] The pharmacokinetics are dose-proportional over the therapeutic range (30–60 mg), with steady-state concentrations reached within 3–5 days of once-daily dosing and an accumulation ratio of about 1.5-fold.[5] The apparent volume of distribution exceeds 500 L, indicating extensive tissue distribution, and plasma protein binding is high at greater than 99.5%, independent of concentration.[13] Zuranolone crosses the blood-brain barrier, consistent with its neuroactive steroid profile.[5] Metabolism is extensive and primarily mediated by cytochrome P450 3A4 (CYP3A4), with minor contributions from CYP2C8, CYP2C9, and CYP2B6; no circulating metabolites exceed 10% of total drug-related material.[13] Strong CYP3A4 inhibitors increase exposure (e.g., 63% higher AUC with itraconazole), while inducers decrease it (e.g., 85% lower AUC with rifampin).[13] Elimination occurs mainly via hepatic metabolism, with the terminal half-life ranging from 19.7 to 24.6 hours and apparent oral clearance of approximately 33 L/h.[5] Following a radiolabeled dose, about 45% is recovered in urine and 41% in feces as metabolites, with negligible unchanged drug (<2%) excreted.[13] Pharmacokinetic parameters show no clinically significant differences between Japanese and White healthy adults or Japanese elderly subjects.[14] In special populations, exposure increases in moderate-to-severe renal impairment (up to 47% higher AUC) and severe hepatic impairment (38% higher AUC), necessitating dose reductions.[13]Medical uses
Indications
Zuranolone, marketed as Zurzuvae, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of postpartum depression (PPD) in adults.[1][15] This approval, granted on August 4, 2023, marks it as the first oral medication specifically indicated for this condition, offering a rapid-acting alternative to existing treatments like intravenous brexanolone.[1][16] The indication targets adults, typically women aged 18–44 years, experiencing PPD as defined by DSM-5 or DSM-IV criteria, with symptoms onset in the third trimester of pregnancy or within 4 weeks postpartum.[15] PPD is characterized by persistent sadness, anxiety, and mood changes that can impair daily functioning and bonding with the infant, affecting approximately 10–15% of postpartum individuals.[15][17] Zuranolone may be used as monotherapy or adjunctively with other antidepressants, provided those treatments are stable.[15] Efficacy for this indication was established in two multicenter, double-blind, randomized, placebo-controlled trials involving women with moderate to severe PPD.[15] In these studies, patients received zuranolone once daily for 14 days, with the primary measure being the change in Hamilton Depression Rating Scale (HAM-D) total score from baseline to day 15, showing statistically significant improvements over placebo (placebo-subtracted mean differences of -4.0 and -4.2 points, respectively).[15] Sustained benefits were observed at follow-up assessments up to 45 days post-treatment, supporting its role in addressing acute PPD symptoms.[15] As of 2025, zuranolone remains approved solely for PPD and is not indicated for major depressive disorder (MDD), despite prior submission of a New Drug Application for that use, which received a Complete Response Letter from the FDA in 2023 citing insufficient data.[18][15] Ongoing research explores its potential in MDD and other depressive disorders, but no additional indications have been authorized.[18] In July 2025, the European Medicines Agency's Committee for Medicinal Products for Human Use issued a positive opinion for zuranolone in treating PPD in adults. The European Commission granted marketing authorization on September 17, 2025.[19][2]Administration and dosage
Zuranolone (ZURZUVAE) is administered orally as capsules taken once daily in the evening for a 14-day treatment course. The recommended dosage for adults with postpartum depression is 50 mg (two 25 mg capsules), which must be taken with a fat-containing meal providing 400–1,000 calories and 25%–50% fat to ensure adequate absorption.[3] Dose adjustments are required in certain populations to mitigate risks of excessive central nervous system (CNS) depression. For patients experiencing somnolence, dizziness, or other CNS effects, the dose may be reduced to 40 mg once daily. In cases of severe hepatic impairment (Child-Pugh Class C), moderate or severe renal impairment (eGFR <60 mL/min/1.73 m²), or concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole), the recommended dose is 30 mg once daily. The safety and efficacy of doses beyond 14 days or repeated courses have not been established.[3] If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose to make up for the missed one. Due to potential CNS depressant effects, patients are advised to avoid operating machinery or driving for at least 12 hours after each dose, and dose reduction or discontinuation should be considered if severe CNS symptoms or suicidal ideation emerge.[3]Safety and tolerability
Adverse effects
Zuranolone is generally well-tolerated in clinical trials for postpartum depression, with most adverse effects being mild to moderate and transient. In two pivotal randomized, double-blind, placebo-controlled studies (ROBIN and SKYLARK), the incidence of any adverse event was approximately 59% in the zuranolone group compared to 46% in the placebo group across pooled data.[13] Discontinuation due to adverse events occurred in approximately 3% of zuranolone-treated patients versus 1% in placebo-treated patients.[13] The most common adverse reactions (occurring in ≥5% of patients and at a rate greater than placebo) include somnolence, dizziness, fatigue, diarrhea, and nasopharyngitis. These effects are primarily attributed to zuranolone's positive allosteric modulation of GABA_A receptors, leading to central nervous system (CNS) depression. Somnolence was the most frequent, reported in up to 36% of patients at higher doses (50 mg) in Study 1 (ROBIN), compared to 6% with placebo.[3] In Study 2 (SKYLARK) at 30 mg, somnolence occurred in 19% versus 11% with placebo.[3]| Adverse Reaction | Study 1 (50 mg zuranolone, n=98) | Placebo (n=97-98) | Study 2 (30 mg zuranolone, n=78) | Placebo (n=73) |
|---|---|---|---|---|
| Somnolence | 36% | 6% | 19% | 11% |
| Dizziness | 13% | 2% | 8% | 6% |
| Diarrhea | 6% | 2% | 5% | 3% |
| Fatigue | 5% | 3% | 5% | 1% |
| Nasopharyngitis | Not reported as ≥5% | Not reported | 9% | 2% |
| Urinary Tract Infection | 5% | 4% | Not reported as ≥5% | Not reported |
Contraindications and warnings
Zuranolone has no known contraindications.[3] A boxed warning highlights the risk of central nervous system (CNS) depression leading to impaired ability to drive or engage in other potentially hazardous activities. Zuranolone causes driving impairment due to its CNS depressant effects, and patients are advised not to drive or perform such activities until at least 12 hours after administration.[3] CNS depressant effects, including somnolence and confusion, are common with zuranolone treatment. In clinical trials, somnolence occurred in 36% of patients receiving 50 mg doses and 19% receiving 40 mg equivalent doses, compared to 6% and 11% on placebo, respectively. If significant CNS depression develops, dosage reduction or discontinuation of zuranolone should be considered.[3] Patients treated with zuranolone should be monitored for worsening postpartum depression or emergent suicidal thoughts and behaviors, as these may occur. In such cases, the therapeutic regimen, including potential discontinuation of zuranolone, should be reevaluated.[3] Zuranolone may cause embryo-fetal toxicity based on animal studies. Pregnant women should be advised of the potential risk to the fetus from in utero exposure. Females of reproductive potential are recommended to use effective contraception during treatment and for one week after the final dose.[3]History
Development
Zuranolone, known during development as SAGE-217, was developed by Sage Therapeutics as an investigational oral neuroactive steroid designed to modulate GABA_A receptors for the treatment of mood disorders, building on the company's earlier work with intravenous brexanolone (SAGE-547).[23] Preclinical studies demonstrated its potential as a positive allosteric modulator with rapid antidepressant effects and improved oral bioavailability compared to brexanolone.[23] Development began with Phase 1 clinical trials initiated in October 2015, evaluating single ascending doses in healthy volunteers to assess safety, tolerability, and pharmacokinetics.[24] Positive topline results from these trials were reported in June 2016, showing no serious adverse events and supporting advancement to further studies.[25] In June 2018, Sage entered a collaboration with Shionogi & Co., granting Shionogi rights to develop and commercialize zuranolone in Japan, Taiwan, South Korea, and Hong Kong.[26] The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for zuranolone in major depressive disorder (MDD) in February 2018, recognizing its potential to address unmet needs in depression treatment.[18] Phase 2 trials followed, including the ROBIN study in postpartum depression (PPD), which reported positive results in 2019, and the MDD-201 study in MDD, published in 2019, demonstrating significant reductions in depressive symptoms after 14 days of dosing.[20][27] However, a Phase 3 trial (MOUNTAIN) missed its primary endpoint in late 2019, leading Sage to refine its development strategy after FDA guidance in March 2020.[18] In November 2020, Sage partnered with Biogen in a global collaboration to co-develop and commercialize zuranolone, with Biogen handling commercialization outside the U.S. and sharing development costs.[28] The pivotal Phase 3 program included the NEST trials for PPD (ROBIN and SKYLARK) and LANDSCAPE trials for MDD (MOUNTAIN, WATERFALL, and CORAL). The SKYLARK study met primary and secondary endpoints in June 2022, showing rapid symptom improvement in PPD.[29] Similarly, the CORAL study for MDD succeeded in February 2022.[18] Long-term data from the open-label SHORELINE study in December 2021 confirmed safety and tolerability over one year in MDD patients.[30] Sage and Biogen initiated a rolling New Drug Application (NDA) submission to the FDA in May 2022 for both MDD and PPD indications, completing it in December 2022.[18] The FDA accepted the NDA in February 2023 with Priority Review, setting a PDUFA date of August 5, 2023.[31] On August 4, 2023, the FDA approved zuranolone (branded Zurzuvae) for PPD in adults, marking it as the first oral therapy for this indication, based primarily on the NEST program data.[16] However, the FDA issued a Complete Response Letter (CRL) for the MDD indication, citing insufficient evidence of durability of effect, prompting further data analysis.[18] Post-approval, development continued internationally; Shionogi submitted an NDA in Japan for MDD in September 2024. On October 30, 2025, an expert panel under Japan's Ministry of Health, Labour and Welfare recommended approval for zuranolone in major depressive disorder.[32][33] In July 2025, the European Medicines Agency's Committee for Medicinal Products for Human Use issued a positive opinion for PPD, recommending approval.[19] In September 2024, Biogen terminated its collaboration with Sage Therapeutics on the SAGE-324 program for essential tremor, effective February 2025. The collaboration on zuranolone continued, with Supernus Pharmaceuticals becoming Sage's successor and Biogen's partner for ex-US rights following Supernus's acquisition of Sage in July 2025.[34] In July 2025, Supernus Pharmaceuticals acquired Sage Therapeutics, integrating zuranolone into its portfolio.[35]Regulatory approvals
Zuranolone, marketed as Zurzuvae, received its first regulatory approval from the U.S. Food and Drug Administration (FDA) on August 4, 2023, for the treatment of postpartum depression (PPD) in adults.[1] This marked it as the first and only oral medication specifically indicated for PPD, based on positive results from the phase 3 SKYLARK study demonstrating rapid symptom reduction.[36] However, the FDA rejected its application for major depressive disorder (MDD) in the same year, citing insufficient evidence of efficacy from the phase 3 WATERFALL trial.[37] In October 2023, the U.S. Drug Enforcement Administration (DEA) classified zuranolone as a Schedule IV controlled substance under the Controlled Substances Act, recognizing its accepted medical use while acknowledging potential for abuse due to its neuroactive steroid properties.[38] The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom granted approval on August 27, 2025, via the International Recognition Procedure, authorizing zuranolone for PPD in adults following childbirth.[39] This made it the first targeted oral treatment for postnatal depression in the UK, supported by the same clinical data as the FDA approval.[40] On September 17, 2025, the European Commission approved zuranolone for PPD in adults, following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in July 2025.[41] This authorization, granted to Biogen, established it as the first EU-approved therapy for PPD, with marketing rights held by Biogen outside the U.S. (excluding Japan, Taiwan, and South Korea).[41] As of November 2025, no approvals have been reported in other major markets such as Canada or Australia.Society and culture
Legal status
Zuranolone, marketed as Zurzuvae, received approval from the U.S. Food and Drug Administration (FDA) on August 4, 2023, as the first oral treatment specifically indicated for postpartum depression in adults.[1] In the United States, it is classified as a Schedule IV controlled substance under the Controlled Substances Act by the Drug Enforcement Administration (DEA), effective October 31, 2023, due to its potential for abuse relative to substances in Schedule III, though it has a low potential for abuse overall.[38] This scheduling requires prescriptions to be handled with specific regulatory controls, including limitations on refills and record-keeping for dispensing.[38] In the European Union, the European Commission granted marketing authorization for Zurzuvae on September 17, 2025, making it available throughout the EU for the treatment of postpartum depression in adult women.[41] This followed a positive opinion from the European Medicines Agency (EMA) on July 25, 2025.[2] The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) approved zuranolone on August 27, 2025, via the International Recognition Procedure, for treating postnatal depression in adults following childbirth.[39] As of November 2025, zuranolone has not received regulatory approval in other major markets such as Japan for postpartum depression, although a new drug application for major depressive disorder was submitted by Shionogi in September 2024 and remains under review following a positive recommendation from an expert panel on October 30, 2025.[32][33] In approved regions, it is available only by prescription and subject to standard pharmaceutical regulations for dispensing and monitoring.Names and availability
Zuranolone is the international nonproprietary name (INN) for this neuroactive steroid medication. It is marketed under the brand name Zurzuvae in regions where it has been approved. During its development, it was known by several investigational codes, including SAGE-217, BIIB-125, S-81217, and SGE-797.[42][43] In the United States, Zurzuvae became available following its approval by the Food and Drug Administration (FDA) on August 4, 2023, as an oral capsule formulation in strengths of 20 mg, 25 mg, and 30 mg, taken once daily for 14 days. It is supplied by Sage Therapeutics and Biogen, with no generic version currently available.[1][44][45] In the European Union, the European Commission granted marketing authorization for Zurzuvae on September 17, 2025, authorizing its use as capsules taken once daily for 14 days; it is under additional monitoring and available only by prescription, held by Biogen Netherlands B.V.[2][41]Research
Ongoing clinical investigations
As of November 2025, ongoing clinical investigations of zuranolone primarily focus on post-approval evaluation for postpartum depression (PPD) and exploratory applications in other depressive conditions. A key study is an observational, multicenter trial (NCT07047820) sponsored by Biogen, which is actively recruiting participants to assess the real-world effectiveness of zuranolone in reducing PPD symptoms among women who received the drug within 12 months following the end of their pregnancy.[46] This study, which began enrollment in June 2025, targets adults prescribed zuranolone for PPD treatment between June 2025 and May 2026, using validated scales such as the Edinburgh Postnatal Depression Scale to measure symptom improvement and long-term outcomes.[46] The primary objective is to evaluate sustained symptom relief beyond the initial 14-day treatment course, with secondary aims including safety monitoring in diverse real-world settings.[47] In addition, a phase II trial (NCT06759558) is planned to investigate zuranolone's safety and tolerability in patients with post-stroke depression, though it has not yet begun recruiting as of late 2025.[48] Sponsored by an academic institution, this randomized, placebo-controlled study aims to enroll stroke survivors experiencing depressive symptoms, administering oral zuranolone over a short course to determine its potential as a rapid-acting intervention in this population, where traditional antidepressants often show delayed efficacy.[48] Preliminary design emphasizes monitoring for neurological adverse events and depressive symptom reduction via standard scales like the Hamilton Depression Rating Scale.[48] Broader research calls highlight the need for extended trials to explore zuranolone's role in relapse prevention for major depressive disorder (MDD) and PPD, particularly long-term maintenance dosing, though no such phase III studies are currently active.[49] These investigations build on zuranolone's established rapid-onset mechanism as a positive allosteric modulator of GABA_A receptors, aiming to expand its therapeutic scope while confirming safety in varied clinical contexts.[49]Comparative studies
Comparative studies of zuranolone have primarily focused on its efficacy and safety relative to standard treatments for postpartum depression (PPD) and major depressive disorder (MDD), including selective serotonin reuptake inhibitors (SSRIs), intravenous brexanolone, and antidepressants alone. These investigations often employ indirect comparison methods, such as network meta-analysis (NMA) and matching-adjusted indirect comparisons (MAIC), due to the lack of head-to-head trials. For instance, an indirect comparison using data from the phase 3 SKYLARK study (NCT04442503) and randomized controlled trials (RCTs) of SSRIs demonstrated that zuranolone (50 mg daily for 14 days) achieved greater reductions in Edinburgh Postnatal Depression Scale (EPDS) scores compared to SSRIs. Specifically, zuranolone resulted in a 4.22-point larger EPDS reduction by day 15 (95% CI: -6.16 to -2.28) and a 7.43-point larger reduction by day 45 (95% CI: -9.84 to -5.02) versus SSRIs, indicating more rapid and sustained symptom improvement in PPD.[50] In the context of MDD, the phase 3 CORAL study (NCT04442490) evaluated zuranolone (50 mg) co-initiated with an oral antidepressant (ADT) against placebo plus ADT in adults with moderate-to-severe symptoms. Zuranolone plus ADT showed faster onset of action, with a least-squares mean change from baseline (CFB) in Hamilton Depression Rating Scale-17 (HAM-D-17) total score of -8.9 points on day 3 compared to -7.0 points for placebo plus ADT (p=0.0004; Cohen's d=0.38). Over days 3 to 15, the difference was -11.7 versus -10.1 points (p=0.0054), highlighting zuranolone's additive benefit when combined with standard antidepressants for quicker relief without increasing suicidal ideation or withdrawal risks.[51] Comparisons with brexanolone, the first FDA-approved treatment for PPD, underscore zuranolone's advantages in administration and tolerability, though both target allosteric modulation of GABA_A receptors. Brexanolone requires a 60-hour intravenous infusion in a healthcare setting with a Risk Evaluation and Mitigation Strategy (REMS) due to sedation risks, achieving HAM-D-17 reductions as early as 24 hours but sustained only to day 30 in phase 3 trials. In contrast, oral zuranolone (30-50 mg daily for 14 days) demonstrates effects from day 3, sustained to day 45, with common adverse events like somnolence (15.3%) and dizziness (13.8%) that are generally mild and resolve post-treatment, avoiding the need for inpatient monitoring.[52][53] Both drugs permit continuation of stable antidepressants, but zuranolone's outpatient profile enhances accessibility for postpartum patients.[53]| Aspect | Zuranolone | Brexanolone | SSRIs (Indirect) |
|---|---|---|---|
| Administration | Oral, 14 days outpatient | IV infusion, 60 hours inpatient | Oral, ongoing |
| Onset of Effect | Day 3 | 24 hours | Slower (weeks) |
| Sustained Response | To day 45 | To day 30 | Variable, long-term |
| Key AEs | Somnolence, dizziness | Sedation, loss of consciousness | Nausea, sexual dysfunction |
| Efficacy Metric (vs. Placebo) | HAM-D-17 CFB: -17.8 (day 15) | HAM-D-17 CFB: -17.6 (range -14.6 to -19.5; 60 hours) | EPDS CFB: -7.8 (day 15)* |