Zuranolone and its role in treating major depressive disorder: a narrative review
-
Muneeza Ali
, Mufaddal Najmuddin Diwan
and Domenico De Berardis
Abstract
Major Depressive Disorder (MDD) is a mood disorder classified as a persistent depressive mood and loss of interest lasting for more than two weeks and accompanied by a list of symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria. MDD affects approximately 264 million people worldwide and is the most prevailing form of neuropsychiatric disorder. Owing to the probable hypothesized pathophysiology of MDD being an outcome of abnormalities in the amino acid neurotransmitter system, including glutamate (the primary excitatory neurotransmitter) and γ-aminobutyric acid (GABA), SAGE-217 (Zuranolone) is being evaluated as a possible therapeutic treatment for MDD. Zuranolone is a synthetic, neuroactive steroid (NAS) and positive allosteric modulator (PMA) of GABAA receptors, regulating both synaptic and extra-synaptic release of GABA. It is administered as a once-daily oral dose for 2 weeks due to its low-moderate clearance. A change in total HAM-D score from baseline was the primary end-point of all the trials. A phase II trial conducted to evaluate the efficacy and safety of Zuranolone (30 mg, once-daily dose), described a significant reduction in total HAM-D score at day 14 and reported the drug to be well tolerated with headache, dizziness, nausea, and somnolence as the most common adverse events (AE). Additional phase III trials were also conducted to evaluate similar outcomes, the interim topline results of which have been released. Consequently, this article attempts to briefly analyze the pharmacology of Zuranolone, review the available clinical data and outcomes regarding its use, and evaluate its place as a prospective novel therapy in the effective management of MDD.
References
1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 [published correction appears in Lancet. 2019;393(10190):e44]. Lancet. 2018;392:1789–858. https://doi.org/10.1016/S0140-6736(18)32279-7.Search in Google Scholar PubMed PubMed Central
2. Hecking, J, Davoudian, PA, Emerging therapeutics based on the amino acid neurotransmitter system: an update on the pharmaceutical pipeline for mood disorders. Chronic Stress 2021;5. https://doi.org/10.1177/24705470211020446.Search in Google Scholar PubMed PubMed Central
3. Rahman, S, Alzarea, S. Glial mechanisms underlying major depressive disorder: potential therapeutic opportunities. Prog Mol Biol Transl Sci 2019;167:159–78. https://doi.org/10.1016/bs.pmbts.2019.06.010.Search in Google Scholar PubMed
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013.10.1176/appi.books.9780890425596Search in Google Scholar
5. Hasin, DS, Sarvet, AL, Meyers, JL, Saha, TD, Ruan, WJ, Stohl, M, et al.. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatr 2018;75:336–46. https://doi.org/10.1001/jamapsychiatry.2017.4602.Search in Google Scholar PubMed PubMed Central
6. Kennedy, SH, Ceniti, AK. Unpacking major depressive disorder: from classification to treatment selection. Can J Psychiatry 2018;63:308–13. https://doi.org/10.1177/0706743717748883.Search in Google Scholar PubMed PubMed Central
7. Caspi, A, Sugden, K, Moffitt, TE, Taylor, A, Craig, IW, Harrington, H, et al.. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386–9. https://doi.org/10.1126/science.1083968.Search in Google Scholar PubMed
8. Kupferberg, A, Bicks, L, Hasler, G. Social functioning in major depressive disorder. Neurosci Biobehav Rev 2016;69:313–32. https://doi.org/10.1016/j.neubiorev.2016.07.002.Search in Google Scholar PubMed
9. Corfield, EC, Yang, Y, Martin, NG, Nyholt, DR. A continuum of genetic liability for minor and major depression. Transl Psychiatry 2017;7:e1131. https://doi.org/10.1038/tp.2017.99.Search in Google Scholar PubMed PubMed Central
10. Sullivan, PF, Neale, MC, Kendler, KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000;157:1552–62. https://doi.org/10.1176/appi.ajp.157.10.1552.Search in Google Scholar PubMed
11. Chiriţă, AL, Gheorman, V, Bondari, D, Rogoveanu, I. Current understanding of the neurobiology of major depressive disorder. Rom J Morphol Embryol 2015;56:651–8.Search in Google Scholar
12. American College of Physicians. ACP finds that cognitive behavioral therapy and second-generation antidepressants are similarly effective treatments for adults with major depressive disorder. American College of Physicians; 2021. https://www.acponline.org/acp-newsroom/acp-finds-that-cognitive-behavioral-therapy-and-second-generation-antidepressants-are-similarly [Accessed 24 Aug 2021].Search in Google Scholar
13. Qaseem, A, Snow, V, Denberg, TD, Forciea, MA, Owens, DK. Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians [published correction appears in Ann Intern Med. 2009 Jan 20;150(2):148]. Ann Intern Med 2008;149:725–33. https://doi.org/10.7326/0003-4819-149-10-200811180-00007.Search in Google Scholar PubMed
14. Gartlehner, G, Gaynes, BN, Hansen, RA, Thieda, P, DeVeaugh-Geiss, A, Krebs, EE, et al.. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008;149:734–50. https://doi.org/10.7326/0003-4819-149-10-200811180-00008.Search in Google Scholar PubMed
15. Qaseem, A, Barry, MJ, Kansagara, D. Clinical Guidelines Committee of the American College of Physicians. Nonpharmacologic versus pharmacologic treatment of adult patients with major depressive disorder: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2016;164:350–9. https://doi.org/10.7326/M15-2570.Search in Google Scholar PubMed
16. Arnaud, A, Suthoff, E, Stenson, K, Werneburg, B, Hodgkins, P, Bonthapally, V, et al.. Number needed to treat and number needed to harm analysis of the Zuranolone Phase II clinical trial results in major depressive disorder. J Affect Disord 2021;285:112–9. https://doi.org/10.1016/j.jad.2021.02.027.Search in Google Scholar PubMed
17. Althaus, AL, Ackley, MA, Belfort, GM, Gee, SM, Dai, J, Nguyen, DP, et al.. Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology 2020;181:108333. https://doi.org/10.1016/j.neuropharm.2020.108333.Search in Google Scholar PubMed PubMed Central
18. Hoffmann, E, Nomikos, GG, Kaul, I, Raines, S, Wald, J, Bullock, A, et al.. SAGE-217, A novel GABAA receptor positive allosteric modulator: clinical pharmacology and tolerability in randomized phase I dose-finding studies. Clin Pharmacokinet 2020;59:111–20. https://doi.org/10.1007/s40262-019-00801-0.Search in Google Scholar PubMed PubMed Central
19. Möhler, H. GABA(A) receptor diversity and pharmacology. Cell Tissue Res 2006;326:505–16. https://doi.org/10.1007/s00441-006-0284-3.Search in Google Scholar PubMed
20. Gunduz-Bruce, H, Silber, C, Kaul, I, Rothschild, AJ, Riesenberg, R, Sankoh, AJ, et al.. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med 2019;381:903–11. https://doi.org/10.1056/NEJMoa1815981.Search in Google Scholar PubMed
21. Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. https://doi.org/10.1136/jnnp.23.1.56.Search in Google Scholar PubMed PubMed Central
22. Montgomery, SA, Asberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–9. https://doi.org/10.1192/bjp.134.4.382.Search in Google Scholar PubMed
23. Busner, J, Targum, SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry 2007;4:28–37.Search in Google Scholar
24. Hoddes, E, Zarcone, V, Smythe, H, Phillips, R, Dement, WC. Quantification of sleepiness: a new approach. Psychophysiology 1973;10:431–6. https://doi.org/10.1111/j.1469-8986.1973.tb00801.x.Search in Google Scholar PubMed
25. Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, et al.. The columbia–suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatr 2011;168:1266–77. https://doi.org/10.1176/appi.ajp.2011.10111704.Search in Google Scholar PubMed PubMed Central
26. Sage, B. Therapeutics reports topline results from Pivotal Phase 3 MOUNTAIN Study of SAGE-217 in major depressive disorder [Internet]. Cambridge: Businesswire; 2019. https://www.businesswire.com/news/home/20191205005375/en/Sage-TherapeuticsReports-Topline-Results-Pivotal-Phase [Accessed 26 Aug 2021].Search in Google Scholar
27. Clayton, A, Lasser, R, Nandy, I, Sankoh, AJ, Campbell, A, Werneburg, B, et al.. A phase 3, multicenter, double-blind, randomized, placebo-controlled study evaluating the efficacy of SAGE-217 in the treatment of adult patients with major depressive disorder. Biol Psychiatr 2020;87:S86. https://doi.org/10.1016/J.BIOPSYCH.2020.02.242.Search in Google Scholar
28. National Institute of Health. A study to evaluate the efficacy of SAGE-217 in the treatment of adult subjects with major depressive disorder. NIH, U.S. National Library of Medicine; 2021. https://clinicaltrials.gov/ct2/show/NCT03672175 [Accessed 26 Aug 2021].Search in Google Scholar
29. Walkery, A, Leader, LD, Cooke, E, VandenBerg, A. Review of allopregnanolone agonist therapy for the treatment of depressive disorders. Drug Des Dev Ther 2021;15:3017–26. https://doi.org/10.2147/DDDT.S240856.Search in Google Scholar PubMed PubMed Central
30. National Institute of Health. A study to evaluate SAGE-217 in adult participants with Major Depressive Disorder (MDD). NIH, U.S. National Library of Medicine; 2021. https://clinicaltrials.gov/ct2/show/NCT03864614 [Accessed 27 Aug 2021].Search in Google Scholar
31. Cutler, A, Aaronson, ST, Mattingly, GW, Wilkinson, ST, Lasser, R, Nandy, I, et al.. Zuranolone in major depressive disorder: interim safety results from a phase 3, open-label, longitudinal study. Biol Psychiatr 2021;89:S161. https://doi.org/10.1016/J.BIOPSYCH.2021.02.413.Search in Google Scholar
32. Sage, B. Therapeutics announces positive interim, Topline Zuranolone Safety and Tolerability Data from open-label SHORELINE Study in patients with MDD [Internet]. Cambridge: Businesswire; 2020. https://www.businesswire.com/news/home/20201015005330/en/Sage-Therapeutics-Announces-Positive-Interim-Topline-Zuranolone-Safety-and-Tolerability-Data-from-Open-Label-SHORELINE-Study-in-Patients-with-MDD [Accessed 27 Aug 2021].Search in Google Scholar
33. National Institute of Health. A study to evaluate the efficacy of Sage-217 in the treatment of adult participants with Major Depressive Disorder (MDD). NIH, U.S. National Library of Medicine; 2021. https://clinicaltrials.gov/ct2/show/NCT04442490 [Accessed 27 Aug 2021].Search in Google Scholar
34. National Institute of Health. A comparative study of Sage-217 plus an Antidepressant (ADT) versus placebo plus an ADT in adults with major depressive disorder. NIH, U.S. National Library of Medicine; 2021. https://clinicaltrials.gov/ct2/show/NCT04476030 [Accessed 27 Aug 2021].Search in Google Scholar
35. Wilkinson, ST, Sanacora, G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today 2019;24:606–15. https://doi.org/10.1016/j.drudis.2018.11.007.Search in Google Scholar PubMed PubMed Central
36. Sanacora, G, Zarate, CA, Krystal, JH, Manji, HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 2008;7:426–37. https://doi.org/10.1038/nrd2462.Search in Google Scholar PubMed PubMed Central
37. FDA News Release. FDA approves first treatment for postpartum depression. Food and Drug Administration, United States of America; 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-post-partum-depression [Accessed 27 Aug 2021].Search in Google Scholar
38. Ali, M, Aamir, A, Diwan, MN, Awan, HA, Ullah, I, Irfan, M, et al.. Treating postpartum depression: what do we know about brexanolone? Diseases 2021;9:52. https://doi.org/10.3390/diseases9030052.Search in Google Scholar PubMed PubMed Central
39. Psych Congress. Novel depression drug awarded FDA’s breakthrough therapy designation. Psych Congress Network; 2018. https://www.hmpgloballearningnetwork.com/site/pcn/article/novel-depression-drug-awarded-fdas-breakthrough-therapy-designation [Accessed 27 Aug 2021].Search in Google Scholar
40. Ogawa, Y, Takeshima, N, Hayasaka, Y, Tajika, A, Watanabe, N, Streiner, D, et al.. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst Rev 2019;6:CD001026. https://doi.org/10.1002/14651858.CD001026.pub2.Search in Google Scholar PubMed PubMed Central
41. Rosenblat, JD. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med 2019;381:2178–9. https://doi.org/10.1056/NEJMc1913170.Search in Google Scholar PubMed
42. Ten Doesschate, F, van Waarde, JA, van Wingen, GA. Non-superiority of zuranolone (SAGE-217) at the longer-term. J Affect Disord 2021;291:329–30. https://doi.org/10.1016/j.jad.2021.05.015.Search in Google Scholar PubMed
43. Deligiannidis, KM, Lasser, R, Gunduz-Bruce, H, Doherty, J, Jonas, J, Li, S, et al.. The ROBIN trial, a phase 3, double-blind, placebo-controlled trial of zuranolone in postpartum depression. In: Poster presented at: psych Congress 2020 Virtual Experience. Virtual 2020.Search in Google Scholar
44. Gunduz-Bruce, H, Lasser, R, Nandy, I, Sankoh, AJ, Jonas, J, Doherty, J, et al.. Open-label, Phase 2 trial of the oral neuroactive steroid GABAA receptor positive allosteric modulator zuranolone in bipolar disorder I and II. In: Poster presented at: psych Congress 2020 Virtual Experience. Virtual; 2020.Search in Google Scholar
45. World Health Organization. Depression – fact sheet. Geneva: World Health Organization; 2020. https://www.who.int/news-room/fact-sheets/detail/depression [Accessed 27 Aug 2021].Search in Google Scholar
© 2022 Walter de Gruyter GmbH, Berlin/Boston
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- Review Articles
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Articles in the same Issue
- Frontmatter
- Letter to the Editor
- The role of gut microbiota in etiopathogenesis of long COVID syndrome
- Original Articles
- Risk factors and inflammatory markers in acute coronary syndrome-ST elevation myocardial infarction (STEMI)
- Association of pro-inflammatory cytokines, inflammatory proteins with atherosclerosis index in obese male subjects
- Exploration of meteorin-like peptide (metrnl) predictors in type 2 diabetic patients: the potential role of irisin, and other biochemical parameters
- Distinct urinary progesterone metabolite profiles during the luteal phase
- Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients
- Population status of selenium in Colombia and associated factors: a cross-sectional study
- Bambusa vulgaris leaves reverse mitochondria dysfunction in diabetic rats through modulation of mitochondria biogenic genes
- Increased expression of androgen receptor and PSA genes in LNCaP (prostate cancer) cell line due to high concentrations of EGCG, an active ingredient in green tea
- The effects of endurance exercise and metformin on memory impairment caused by diabetes
- Exercise modulation in inflammation and metabolic hormonal disorders of COVID-19 to decrease risk factors in coronary heart disease
- The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice
- Case Report
- Unilateral ovarian agenesis with ipsilateral tubal presence – report of a case
- Review Articles
- Brown adipose tissue as an endocrine organ: updates on the emerging role of batokines
- Zuranolone and its role in treating major depressive disorder: a narrative review