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Zuranolone

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Zuranolone
Clinical data
Pronunciation/zʊˈrænəloʊn/
zuu-RAN-ə-lohn
Trade namesZurzuvae
Other namesSAGE-217; S-812217; SGE-797; BIIB-125
License data
Pregnancy
category
  • Contraindicated
Routes of
administration		By mouth
Drug classNeurosteroid;GABAAreceptor positive allosteric modulator
ATC code
  • None
Legal status
Legal status
Pharmacokineticdata
Protein binding99.5%[2][unreliable medical source?]
MetabolismCYP3A4[2][unreliable medical source?]
Eliminationhalf-life16–23 hours[3][4]
Identifiers
  • 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.271.331Edit this at Wikidata
Chemical and physical data
FormulaC25H35N3O2
Molar mass409.574g·mol−1
3D model (JSmol)
  • O=C(CN1N=CC(C#N)=C1)[C@H]2CC[C@@]3([H])[C@]4([H])CC[C@]5([H])C[C@](C)(O)CC[C@]5([H])[C@@]4([H])CC[C@@]32C
  • InChI=1S/C25H35N3O2/c1-24(30)9-7-18-17(11-24)3-4-20-19(18)8-10-25(2)21(20)5-6-22(25)23(29)15-28-14-16(12-26)13-27-28/h13-14,17-22,30H,3-11,15H2,1-2H3/t17-,18+,19-,20-,21+,22-,24-,25+/m1/s1
  • Key:HARRKNSQXBRBGZ-GVKWWOCJSA-N

Zuranolone,sold under the brand nameZurzuvae,is a medication used for the treatment ofpostpartum depression.[5][6]It is takenby mouth.[5]

The most commonside effectsincludedrowsiness,dizziness,diarrhea,fatigue,nasopharyngitis,andurinary tract infection.[5][6]Anorally activeinhibitorypregnaneneurosteroid,zuranolone acts as apositive allosteric modulatorof theGABAAreceptor.[7][8][9]

Zuranolone was approved for medical use in the United States for the treatment of postpartum depression in August 2023.[6]It was developed by Sage Therapeutics andBiogen.[10]

Medical uses[edit]

Zuranolone isindicatedfor the treatment ofpostpartum depression.[5][6]

Adverse effects[edit]

The most common side effects include drowsiness, dizziness, diarrhea, fatigue, and urinary tract infection.[6]

The US FDA label contains aboxed warningnoting that zuranolone can impact a person's ability to drive and perform other potentially hazardous activities.[6]The use of zuranolone may cause suicidal thoughts and behavior.[6]Zuranolone may also cause fetal harm.[6]

History[edit]

Zuranolone was developed as an improvement on the intravenously administered neurosteroidbrexanolone,with high oralbioavailabilityand abiological half-lifesuitable for once-daily administration.[8][11]Its half-life is around 16 to 23hours, compared to approximately 9hours for brexanolone.[3][4]

The efficacy of zuranolone for the treatment of postpartum depression in adults was demonstrated in two randomized, double-blind, placebo-controlled, multicenter studies.[6]The trial participants were women with postpartum depression who met theDiagnostic and Statistical Manual of Mental Disorderscriteria for a major depressive episode and whose symptoms began in the third trimester or within four weeks of delivery.[6]In study 1, participants received 50 mg of zuranolone or placebo once daily in the evening for 14 days.[6]In study 2, participants received another zuranolone product that was approximately equal to 40 mg of zuranolone or placebo, also for 14 days.[6]Participants in both studies were monitored for at least four weeks after the 14-day treatment.[6]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.[6]Participants in the zuranolone groups showed significantly more improvement in their symptoms compared to those in the placebo groups.[6]The treatment effect was maintained at day 42—four weeks after the last dose of zuranolone.[6]

Society and culture[edit]

Zuranolone is theinternational nonproprietary name.[12]

Legal status[edit]

Zuranolone was approved by the USFood and Drug Administration(FDA) for the treatment of postpartum depression in August 2023.[6][13]The FDA granted the application for zuranolonepriority reviewandfast trackdesignations.[6]Approval of Zurzuvae was granted to Sage Therapeutics, Inc.[6]

Zuranolone has also been under development for the treatment ofmajor depressive disorder,but the application for this use was given aComplete Response Letter(CRL) by the FDA due to insufficient evidence of effectiveness.[14]

In the United States, zuranolone is aSchedule IV controlled substance.

Research[edit]

In a randomized, placebo-controlledphase III trialto assess its efficacy and safety for the treatment ofmajor 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 byHAM-Dscore) throughout the treatment and follow-up periods of the study.[15]

Other investigational applications includeinsomnia,bipolar depression,essential tremor,andParkinson's disease.[16][7][17]

References[edit]

  1. ^"Schedules of Controlled Substances: Placement of Zuranolone in Schedule IV".Federal Register.31 October 2023.Retrieved5 March2024.
  2. ^ab"Zuranolone".DrugBank Online.
  3. ^abCerne 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 GABAAreceptors ".Pharmacology & Therapeutics.234:108035.doi:10.1016/j.pharmthera.2021.108035.PMC9787737.PMID34793859.S2CID244280839.
  4. ^abFaden 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.PMC7656877.PMID33224470.
  5. ^abcd"Zurzuvae (zuranolone) capsules, for oral use, [controlled substance schedule pending]"(PDF).Archived(PDF)from the original on 5 August 2023.Retrieved5 August2023.
  6. ^abcdefghijklmnopqrs"FDA Approves First Oral Treatment for Postpartum Depression".U.S.Food and Drug Administration(FDA)(Press release). 4 August 2023.Retrieved4 August2023.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  7. ^ab"SAGE 217".AdisInsight.Archivedfrom the original on 29 March 2019.Retrieved10 February2018.
  8. ^abBlanco 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.PMID29223589.
  9. ^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)AReceptor ".Journal of Medicinal Chemistry.60(18): 7810–7819.doi:10.1021/acs.jmedchem.7b00846.PMID28753313.
  10. ^Saltzman J (4 August 2023)."FDA approves postpartum depression pill from two Cambridge drug firms".The Boston Globe.Archivedfrom the original on 6 August 2023.Retrieved5 August2023.
  11. ^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 GABAAreceptor positive allosteric modulator ".Neuropharmacology.181:108333.doi:10.1016/j.neuropharm.2020.108333.PMC8265595.PMID32976892.
  12. ^World Health Organization(2019). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82".WHO Drug Information.33(3).hdl:10665/330879.
  13. ^"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.Retrieved4 August2023– via GlobeNewswire.
  14. ^McKenzie H."Sage Hints at Difficult Decisions After Zuranolone's Rejection in MDD".
  15. ^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.PMID37132201.S2CID258461851.
  16. ^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.PMC8246337.PMID34190962.
  17. ^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.PMID33387701.S2CID229333842.

External links[edit]

  • Clinical trial numberNCT04442503for "A Study to Evaluate the Efficacy and Safety of SAGE-217 in Participants With Severe Postpartum Depression (PPD)" atClinicalTrials.gov
  • Clinical trial numberNCT02978326for "A Study to Evaluate SAGE-217 in Participants With Severe Postpartum Depression" atClinicalTrials.gov
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