NMDA Receptor Glycine Site Modulators as Therapeutics for Depression: Rapastinel has Antidepressant Activity without Causing Psychotomimetic Side Effects.
Abstract Major depressive disorder and related despressive disorders continue to be poorly treated with existing therapies. Most current therapies target biogenic amines, have low efficacy among the depressed population, failing to achieve clinical response >50% reduction in depression score) in many patients, and often exhibit delayed onset. Since 2000, much attention has focused on ionotropic N methyl D aspartate (NMDA) receptors, resulting from several reports that ketamine, a NMDA receptor noncompetitive antagonist which blocks channel opening, produces a rapid (hours) and large clinical response (effect size >1 in some studies) in a majority of subjects following a single dose, with prolonged duration of action (three days to one week or more) in subjects with treatment resistant depression. A major shortcoming of ketamine is that it causes psychotomimetic side effects. Other NMDA receptor full antagonists have also demonstrated efficacy in depressed subjects without psychotomimetic side effects at relatively low doses, but like ketamine induce psychotomimetic side effects at high receptor occupancy. It has been suggested that NMDA receptor partial agonists may produce efficacy in affective and neurological disorders without producing psychotomimetic effects. D cycloserine, a glycine site partial agonist at some classes of NMDA receptors, has been extensively studied in subjects with affective disorders and has demonstrated efficacy in schizophrenic subjects and in some studies in depressed subjects. More recently, rapastinel, an NMDA receptor modulator that allosterically alters glycine site activity in a partial agonist like manner but does not actually bind to the glycine site (functional partial agonism) has been found to be antidepressant without inducing psychotomimetic effects. Here we review glycine site modulation of NMDA receptors and discuss data that support glycine site modulators as antidepressant agents. We focus on recent studies of rapastinel, a glycine site functional partial agonist, as an antidepressant agent.