Table 1.
Novel glutamatergic modulators in human studies for depression
| Compound | Reference or NCT | Completed studies | Current studies | Notes |
|---|---|---|---|---|
| Broad NMDA receptor modulators | ||||
| (R,S)-Ketamine | Reviewed in [43–47]; see ClinicalTrials.gov* | Used in the clinic | Ongoing* (Phase II, III, and IV) | |
| (S)-Ketamine (esketamine) | [59–61]; NCT03965871; NCT03185819; NCT04425473; NCT02782104; NCT03434041; NCT04338321; NCT04476446 | FDA-approved | Ongoing (Phase II, III, and IV) | FDA approved for adults with TRD or major depression with acute suicidal ideation/behavior (March 2019); also approved by the European Union for the same indications |
| (R)-Ketamine (arketamine) | [76]; NCT04108234 | Phase I and II | Phase I | |
| Hydroxynorketamine (HNK) | NCT03977675 | No completed studies | Phase I | |
| Dextromethorphan | [82]; NCT04226352 | Phase I and II | Phase II | |
| Nuedexta | [84–86] | Phase II | No active trials | FDA approved for treatment of pseudobulbar affect (October 2010); EU approval for treatment of pseudobulbar affect (June 2013) |
| Deudextromethorphan (AVP-786) | NCT02153502 | Phase I and II (results not posted) | Phase III for Alzheimer’s; no active trials for depression | FDA Fast-Track designation for agitation in Alzheimer’s disease (November 2015) |
| Axsome (AXS-05) | NCT04019704; NCT04039022; NCT02741791; NCT03495579 | No completed studies | Phase III | FDA Fast-Track designation for TRD and for agitation in Alzheimer’s disease (February 2017) |
| Dextromethadone (REL-1017) | NCT03051256 | Phase II | Phase III | FDA Fast-Track designation as adjunctive treatment for MDD (April 2017) |
| Nitrous oxide | [94]; NCT03283670; NCT03869736; NCT03932825; NCT02757521; NCT03736538 | Phase II | Phase I and II | |
| AZD6765 | [95–97] | Phase II | No active trials | |
| CLE100 | NCT04103892 | No completed studies | Phase II | |
| AGN-241751 | NCT03726658; NCT03486427 | No completed studies | Phase II and III | FDA Fast-Track designation for TRD (July 2018) |
| Glycine site modulators | ||||
| D-cycloserine (DCS) | [101–103] NCT03937596 with rTMS | Phase II and IV | Phase II | |
| NRX-101 | NCT02974010; NCT03396068; NCT03396601; NCT03395392 | No published studies | Phase II and III | FDA Breakthrough Therapy (November 2018) and Fast-Track Therapy (September 2017) designations for suicide in bipolar depression |
| Rapastinel (GLYX-13) | [105, 106, 134] | Phase II and III | No active trials | FDA Fast-Track (March 2014) and Breakthrough Therapy (January 2016) designations for adjunctive treatment of MDD |
| Apimostinel (NRX-1074) | NCT02067793; NCT02366364 | Phase I and II (results not posted) | No active trials | |
| Sarcosine | [108] | Phase II | No active trials | |
| 4-Chlorokynurenine (4-Cl-KYN/AV-101) | [109]; NCT03078322 | Phase II | Phase II | FDA Fast-Track designation as adjunctive treatment for MDD (January 2018) |
| Subunit (NR2B)-specific NMDA receptor antagonists | ||||
| Eliprodil (EVT-101) | NCT01128452 | No completed studies | No active trials | Trial terminated early due to an FDA-issued clinical hold |
| Traxoprodil (CP-101,606) | [111] | Phase II | No active trials | Development halted due to potential cardiovascular effects |
| Rislenemdaz (MK-0657/CERC-301) | [112, 113] | Phase II | No active trials | |
| mGIuR modulators | ||||
| Basimglurant | [114] | Phase II | No active trials | |
| AZD2066 | NCT01145755 | Phase II | No active trials | |
| RG1578 (decoglurant) | [116] | Phase II | No active trials | |
| TS-161 | NCT03919409 | Phase I (results not posted) | Phase II for TRD | |
*
Ongoing NCTs for (R,S)-ketamine are too numerous to list here; see ClinicalTrials.gov for a full listing
FDA US Food and Drug Administration, MDD major depressive disorder, NCT National Clinical Trial, NMDA N-methyl-D-aspartate, rTMS repetitive transcranial magnetic stimulation, TRD treatment-resistant depression