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Cited by 232Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

Trial of SAGE-217 in Patients with Major Depressive Disorder

Gunduz-Bruce, Handan, Silber, Christopher, Kaul, Inder, Rothschild, Anthony J., Riesenberg, Robert, Sankoh, Abdul J., Li, Haihong, Lasser, Robert +6 more·2019·New England Journal of Medicine
DOI 10.1056/nejmoa1815981
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Abstract

BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).

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Crossref · 10.1056/nejmoa1815981

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  • Zuranolone (SAGE-217) has been approved by FDA for post-partum depression, has increased oral bioavailability and limited side effects.

    “The analogous compound zuranolone (SAGE-217), also approved by FDA for the same disorder [152], has an increased oral bioavailability and limited side effects [153,154].”

    From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [153]

  • Given the average placebo response rate of 40%, the SMD of 0·3 or 0·2 would translate into NNTs of approximately 9 and 13, respectively.

    “Given the average placebo response rate of 40%, 509 the SMD of 0·3 or 0·2 would translate into NNTs of approximately 9 and 13, respectively. 510-512”

    From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [512]

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Authors
Gunduz-Bruce, H., Silber, C., Kaul, I., Rothschild, A. J., Riesenberg, R., Sankoh, A. J., Li, H., Lasser, R., Zorumski, C. F., Rubinow, D. R., Paul, S. M., Jonas, J., Doherty, J. J., & Kanes, S. J.
Affiliations
  • From Sage Therapeutics, Cambridge (H.G.-B., C.S., A.J.S., H.L., R.L., S.M.P., J.J., J.J.D., S.J.K.), Kaul Consulting, Concord (I.K.), and the University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester (A.J.R.) — all in Massachusetts; the Atlanta Center for Medical Research, Atlanta (R.R.); Washington University School of Medicine, St. Louis (C.F.Z., S.M.P.); and the University of North Carolina School of Medicine, Chapel Hill (D.R.R.).
  • University of Massachusetts Chan Medical School (US)
  • UMass Memorial Health Care (US)
  • University of North Carolina at Chapel Hill (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2019-09-05
Volume
381
Issue
10
Pages
903-911
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1815981
OpenAlex
W2972149772
Cited by
232
References
34
Citations by year
2026: 15 · 2025: 28 · 2024: 35 · 2023: 45 · 2022: 31 · 2021: 42 · 2020: 28 · 2019: 8
FWCI
16.89
Type
journal article
Language
en
Open access
closed
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders
Sage Therapeutics, Inc. (N/A)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords
major depressive disorder, positive allosteric modulators, antidepressant efficacy, depression treatment, anxiety, adverse events, Hamilton Depression Rating Scale, drug safety, depression pathogenesis, neurotransmission, oral administration, headache, dizziness
MeSH terms
Administration, Oral, Adult, Allosteric Regulation, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Dizziness, Double-Blind Method, Female, Humans, Male, Middle Aged, Nausea, Pregnanes, Pregnanolone, Psychiatric Status Rating Scales, Pyrazoles, Receptors, GABA-A, Least-Squares Analysis, GABA Modulators

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