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

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.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

“…140 Other promising compounds include GluN2B antagonists (e.g., CERC-301) 141 ; GLYX-13, which targets the glycine coagonist site on the NMDA receptor 142 ; and basimglurant, which targets the metabotropic glutamate (mGlu) receptors. 143 Other potential candidates for antidepressant actions include drugs that target the endocannabinoid system and drugs with neuroplasticity mechanisms, which are thought to play a role in sustained antidepressant effects.…”

A Systematic Review of the Clinimetric Properties of the 6-Item Version of the Hamilton Depression Rating Scale (HAM-D₆)

“…However, HAM-D 6 was also used in the study by Preskorn et al [51] to allow assessment of the potentially rapid onset of an N-methyl- D -aspartate (NMDA) agonist in a placebo-controlled paradigm. This study included the assessment of antidepressant effect at 2, 4, 8, and 12 h after the drug/placebo administration.…”

“…This review clearly demonstrates that the HAM-D 6 , consisting of item 1 (depressed mood), item 2 (guilt feelings), item 7 (work and interests), item 8 (psychomotor retardation), item 10 (psychic anxiety), and item 13 (somatic symptoms, general) from HAM-D 17 , displays clinical validity (the total score is strongly associated with the global perception of severity evaluated by clinical experts), scalability (each item contains unique information regarding depressive severity), and responsiveness (the scale is highly sensitive in detecting differences in antidepressant efficacy in drug vs. placebo and drug vs. drug trials). Furthermore, due to its brevity and item composition (without items covering sleep and weight loss), HAM-D 6 can be used to detect acute changes (within hours) in the severity of depression [51]. This is not possible with HAM-D 17 and MADRS.…”

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

“…Whether rapastinel, like D-cycloserine, possesses pharmacodynamic specificity that varies by the NMDA receptor subunit on which the glycine binding site resides is unknown. The literature search identified one randomized clinical trial of rapastinel (116,117) (see Table S2 in the data supplement), evaluating the antidepressant efficacy of a single intravenous infusion at four doses (1, 5, 10, and 30 mg/kg) with treatment effects assessed at 2, 4, 8, and 12 hours and 1, 3, 7, and 14 days postinfusion.…”