 agent did not separate from placebo (Sanacora and Schatzberg, 2015;Sanacora et al., 2017). Based on this evidence, clinical development of lanicemine was discontinued.

SUBUNIT NR2B-SPECIFIC NMDAR ANTAGONISTS
The mechanism of action of NR2B-specific NMDA antagonists is thought to be similar to that of ketamine (Miller et al., 2014); however, few preclinical studies have been conducted to confirm this hypothesis.

CP-101,606/Traxoprodil
CP-101,606 is a nonselective, NR2B-specific, NMDAR antagonist with some sigma receptor effects. In a randomized, double-blind, placebo-controlled study of 30 TRD patients, monotherapy with CP-101,606 had significant antidepressant effects, as evidenced by a 50% reduction in HAM-D scores at day 5. Notably, investigators found a 60% response rate in patients receiving CP-101,606 compared with 20% in the matched placebo group; this effect lasted at least a week in 78% of treatment responders (Preskorn et al., 2008). However, during the trial, dissociative side effects were prominent and required both dose reductions and slower infusions, underscoring that NR2B antagonists also have dissociative side effects. Ultimately, development of this compound was discontinued due to cardiotoxicity (specifically, QTc prolongation) in certain patients.

MK-0657 (CERC-301)
In a 12-day, double-blind, randomized, placebo-controlled, crossover pilot study of 5 TRD patients, the oral NR2B antagonist MK-0657 showed no antidepressant effects over placebo on the primary efficacy measure; however some improvement in antidepressant symptoms was observed when other depression rating scales-specifically the HAM-D and the self-reported Beck Depression Inventory-were used (Ibrahim et al., 2012a). No serious or dissociative adverse effects were noted. MK-0657, subsequently known as CERC-301, received fast-track designation for the treatment of MDD. Results from a phase 2 trial (NCT02459236) using 12 or 20 mg of CERC-301 found that this agent had no significant antidepressant effects, though significant improvement in depressive symptoms was seen at day 20 with the 20-mg dose (https://www.cerecor.com/ pipeline/cerc-301). Another 28-day phase 2 study of adjunctive CERC-301 in patients with severe MDD with suicidal ideation (NCT01941043) found that 8 mg of CERC-301 had no antidepressant effects (Paterson et al., 2015).

D-Cycloserine
D-cycloserine (DCS) is a partial agonist at NMDARs containing GluN2A and GluN2B subunits, and a full agonist at the GluN2C and GluN2D subunits (Sheinin et al., 2001). It is thought to exert its antidepressant effects by attenuating the function of NMDAR-bearing GluN2A or GluN2B subunits, though it remains unknown whether DCS's agonist or antagonist properties account for its antidepressant efficacy; no relevant preclinical mechanistic studies are available.
In a placebo-controlled trial, 250 mg/d of adjunctive DCS had no antidepressant effects in 22 patients with TRD (Heresco-Levy et al., 2006). Interestingly, a second study of 26 TRD patients explored escalating-dose adjunctive DCS (up to 1000 mg/d) and found that one-half of the participants had a significant antidepressant response to DCS, as measured by the HAM-D and Beck Depression Inventory (Heresco-Levy et al., 2013).
A subsequent open-label study investigated adjunctive DCS as a maintenance treatment after a single ketamine infusion in 12 patients with bipolar depression (n = 7 completers) (Kantrowitz et al., 2015). Depressive symptoms improved from baseline through week 8 (except at the 2-week timepoint), and a large effect size was seen at day 1. Four of the 7 patients who completed the study remained in remission after 8 weeks. Furthermore, clinical improvement at the 8-week timepoint correlated with magnitude of improvement 24 hours post-ketamine. However, interpretation of the efficacy of this agent is limited by the fact that this study had no control group.
In a recent meta-analysis that drew its data from the studies cited above, DCS was linked to acute antidepressant response at high doses (1000 mg) but not at low doses (250 mg) (Newport et al., 2015).

GLYX-13 (Rapastinel)
GLYX-13 is a glycine B -like functional partial agonist. In preclinical studies, GLYX-13 was found to exert rapid antidepressantlike effects without the dissociative and sedative side effects of ketamine (Burgdorf et al., 2013). Proposed mechanisms of action for this agent include directly modulating NR2B-containing NMDARs (Burgdorf et al., 2013), improving hippocampal longterm potentiation (Burgdorf et al., 2015), and enhancing BDNF exocytosis via voltage-gated calcium channels and TrkB signaling  as well as via the mTORC1 pathway (Liu et al., 2017). In addition, recent theories regarding the mechanism of action of GLYX-13 have evolved and implicate NMDAR activation (Zanos et al. 2018a).
Clinically, one large phase 2b study randomized 116 unmedicated TRD patients to receive GLYX-13 i.v. at doses of either 1, 5, 10, or 30 mg/kg or placebo over 3 to 15 minutes. Patients in the 5-mg/kg and 10-mg/kg groups had the most significant antidepressant response, and no serious adverse effects were reported (Moskal et al., 2014). Building on this work, the same investigators then studied adjunctive GLYX-13 in a randomized, doubleblind study of 116 TRD patients (Preskorn et al., 2015). Subjects were randomized to weekly infusions of i.v. GLYX-13 at doses of 1, 5, or 10 mg/kg or placebo. After an interim safety and efficacy analysis, an additional cohort was added who received i.v. GLYX-13 (30 mg/kg) or placebo. As with the first study, those who received 5 or 10 mg/kg of i.v. GLYX-13 had significantly reduced HAM-D scores compared with placebo. No antidepressant effects were observed after day 7. Due to these promising preliminary findings, GLYX-13 received breakthrough therapy designation from the FDA for adjunctive treatment of MDD. A number of clinical trials looking at the safety and efficacy of GLYX-13 as monotherapy or adjunctive treatment in subjects with MDD and suicidality are underway (active trials available here).

Sarcosine
Sarcosine is a glycine transporter-1 inhibitor whose mechanism of action is thought to depend on NMDAR modulation, though no mechanistic studies are available to confirm this hypothesis.
In a 6-week, randomized, double-blind, citalopram-controlled clinical trial of 40 patients with MDD, sarcosine was associated with higher remission and response rates than the selective serotonin reuptake inhibitor citalopram, as assessed by the HAM-D and other rating scales. Furthermore, those treated with sarcosine were less likely to drop out of the study. No significant adverse effects were reported (Huang et al., 2013). No active studies are presently investigating use of this agent for depression.

AV-101
AV-101 is a novel prodrug that crosses the blood brain barrier, where it is converted to 7-Chlorokynurenic acid, a potent and highly selective competitive glycine binding site antagonist at the NMDAR (Wallace et al., 2017); no preclinical mechanistic studies have explored its mechanism of action.
Two independent phase 2 trials are underway. The first is an NIMH-funded, randomized, controlled trial studying the efficacy of AV-101 in TRD individuals who will receive 2 weeks of either 1080 mg/d or 1440 mg/d of AV-101. The primary outcome measure is change in HAM-D total score (NCT02484456). Another larger, multicenter, randomized, placebo-controlled clinical trial is examining the efficacy and safety of adjunctiveuse oral AV-101 in 180 patients with TRD. Patients will concomitantly receive either a selective serotonin reuptake inhibitor or a serotonin norepinephrine reuptake inhibitor. The primary outcome measure is change from baseline to study endpoint as measured by the MADRS (NCT03078322).

METABOTROPIC GLUTAMATE RECEPTORS
The metabotropic glutamate receptors (mGluRs) are expressed widely throughout the brain and modulate the glutamate signaling pathway outside of the NMDAR and AMPAR pathways.
Several preclinical studies have explored the antidepressant effects of mGluR modulators. In this context, AMPAR stimulation was consistently found to be necessary for the antidepressant effects of mGluR2/3 antagonists (Karasawa et al., 2005;Witkin et al., 2016). At the synaptic level, both BDNF/TrkB signaling and the mTORC1 pathway were also found to be key to the antidepressant effects of mGluR2/3 antagonists, echoing the antidepressant effects of other glutamatergic agents (Koike et al., 2011). The antidepressant effects of presynaptic mGluR2 agonists would hypothetically occur by reducing excessive glutamate release; in contrast, GluR2/3