title: Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent.
abstract: BACKGROUND
  Approximately 45% of patients with major depressive disorder (MDD) do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents with different mechanisms of action. Early proof of concept (POC) studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate (NMDA) receptor blockers (eg, ketamine) can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist.
  
  
  METHODS
  In this double-blind, randomized, placebo-controlled study, a single intravenous (IV) dose of GLYX-13 (1, 5, 10, or 30 mg/kg) or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 (Ham-D17), which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration.
  
  
  RESULTS
  GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects.
  
  
  CONCLUSIONS
  In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.
authors.affiliation: PRESKORN and MACALUSO: University of Kansas School of Medicine, Wichita, KS; MEHRA: Artemis Institute for Clinical Research, San Diego, CA; ZAMMIT: CliniLabs, New York, NY; MOSKAL: Dept Biomedical Engineering, Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University, and Naurex Inc, Evanston, IL; BURCH: Naurex Inc, Evanston, IL.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Preskorn
authors.forename: Matthew
authors.initials: M
authors.lastname: Macaluso
authors.forename: D O Vishaal
authors.initials: DO
authors.lastname: Mehra
authors.forename: Gary
authors.initials: G
authors.lastname: Zammit
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Moskal
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Burch
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D055808:Drug Discovery; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D005998:Glycine / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D018690:Excitatory Amino Acid Agonists; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; C507283:GLYX-13 peptide; D005998:Glycine