Trial of SAGE-217 in patients with major depressive disorder

New England Journal of Medicine

Volumn 381, Issue 10, 2019, Pages 903-911

  Gunduz Bruce, Handan ^a   Silber, Christopher ^a   Kaul, Inder ^b   Rothschild, Anthony J ^c   Riesenberg, Robert ^d   Sankoh, Abdul J ^a   Li, Haihong ^a   Lasser, Robert ^a   Zorumski, Charles F ^e   Rubinow, David R ^f   Paul, Steven M ^a,e   Jonas, Jeffrey ^a   Doherty, James J ^a   Kanes, Stephen J ^a  

^a Sage Therapeutics Inc   (United States)

^b Kaul Consulting   (United States)

^c UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^d Atlanta Center for Medical Research   (United States)

^e WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; ANTIDEPRESSANT AGENT; BENZODIAZEPINE RECEPTOR AFFECTING AGENT;

ADULT; ALLOSTERISM; CLASSIFICATION; CLINICAL TRIAL; CONTROLLED STUDY; DIZZINESS; DOUBLE BLIND PROCEDURE; FEMALE; HUMAN; LEAST SQUARE ANALYSIS; MAJOR DEPRESSION; MALE; METABOLISM; MIDDLE AGED; MULTICENTER STUDY; NAUSEA; ORAL DRUG ADMINISTRATION; PHASE 2 CLINICAL TRIAL; PSYCHOLOGICAL RATING SCALE; RANDOMIZED CONTROLLED TRIAL;

ADMINISTRATION, ORAL; ADULT; ALLOSTERIC REGULATION; ANTIDEPRESSIVE AGENTS; DEPRESSIVE DISORDER, MAJOR; DIZZINESS; DOUBLE-BLIND METHOD; FEMALE; GABA MODULATORS; HUMANS; LEAST-SQUARES ANALYSIS; MALE; MIDDLE AGED; NAUSEA; PSYCHIATRIC STATUS RATING SCALES; RECEPTORS, GABA-A;

EID: 85071773185     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMoa1815981     Document Type: Article

References (38)

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-42.
2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28-40.
3. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. October 2010 (https://psychiatryonline.org/ pb/assets/raw/sitewide/practice_guidelines/ guidelines/mdd.pdf).
4. Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2011;16: 383-406.
5. Gerner RH, Hare TA. CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa. Am J Psychiatry 1981;138:1098-101.
6. Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary investigation. J Psychiatr Res 1988;22:159-64.
7. Mann JJ, Oquendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid. Depress Anxiety 2014;31: 814-21.
8. Gabbay V, Mao X, Klein RG, et al. Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry 2012;69: 139-49.
9. Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004;61:705-13.
10. Schür RR, Draisma LW, Wijnen JP, et al. Brain GABA levels across psychiatric disorders: a systematic literature review and meta-analysis of (1) H-MRS studies. Hum Brain Mapp 2016;37:3337-52.
11. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2007;64:193-200.
12. Guilloux JP, Douillard-Guilloux G, Kota R, et al. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol Psychiatry 2012;17: 1130-42.
13. Karolewicz B, Maciag D, O’Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G. Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 2010;13:411-20.
14. Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 2007;32:471-82.
15. Merali Z, Du L, Hrdina P, et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004;24:1478-85.
16. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6:2311-22.
17. Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 1999;22:410-6.
18. Rupprecht R, Reul JM, Trapp T, et al. Progesterone receptor-mediated effects of neuroactive steroids. Neuron 1993;11:523-30.
19. Zorumski CF, Paul SM, Izumi Y, Covey DF, Mennerick S. Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev 2013; 37:109-22.
20. Uzunov DP, Cooper TB, Costa E, Guidotti A. Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci U S A 1996;93:12599-604.
21. Vallée M, Rivera JD, Koob GF, Purdy RH, Fitzgerald RL. Quantification of neurosteroids in rat plasma and brain following swim stress and allopregnanolone administration using negative chemical ionization gas chromatography/mass spectrometry. Anal Biochem 2000;287:153-66.
22. Dong E, Matsumoto K, Uzunova V, et al. Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci U S A 2001;98:2849-54.
23. Pibiri F, Nelson M, Guidotti A, Costa E, Pinna G. Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: a model relevant for posttraumatic stress disorder. Proc Natl Acad Sci U S A 2008;105:5567-72.
24. Uzunova V, Sheline Y, Davis JM, et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A 1998;95:3239-44.
25. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet 2017;390:480-9.
26. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018;392: 1058-70.
27. Althaus AL, Belfort GM, Lewis MC, et al. SAGE-217, a next generation neuroactive steroid positive allosteric modulator of synaptic and extra-synaptic GABAA receptors, is active against a rat model of reserpine-induced oral dyskinesia. Presented at the 69th Annual Meeting of the American Academy of Neurology, Boston, April 22-28, 2017. abstract.
28. Robichaud AJ, Doherty JJ, Salituro FG, et al. SAGE-217: a 2nd generation neuroactive steroid. Presented at the 68th Annual Meeting of the American Epilepsy Society, Seattle, December 5-9, 2014. abstract.
29. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII). Epilepsy Res 2015;111:85-141.
30. A receptor. J Med Chem 2017;60:7810-9.
31. Kanes S, Nomikos G, Quirk M, et al. A multiple-ascending dose study of the neuroactive steroid SAGE-217. Biol Psychiatry 2017;81:Suppl:S347. abstract.
32. Kanes S, Nomikos G, Quirk M, et al. A single-ascending dose study of the neuroactive steroid SAGE-217. Biol Psychiatry 2017;81:Suppl:S31. abstract.
33. Gunduz-Bruce H, Riesenberg R, Sankoh A, et al. SAGE-217 in subjects with major depressive disorder: efficacy and safety results from open-label Part A of a phase 2A study. Eur Neuropsychopharmacol 2017; 27:S856-S857.
34. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
35. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association, 2013.
36. Bech P, Allerup P, Gram LF, et al. The Hamilton Depression Scale: evaluation of objectivity using logistic models. Acta Psychiatr Scand 1981;63:290-9.
37. Busner J, Targum SD. The Clinical Global Impressions Scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007;4:28-37.
38. Luscher B, Fuchs T. GABAergic control of depression-related brain states. Adv Pharmacol 2015;73:97-144.