Table 2.
Potential antidepressant compounds in development.
| Compound, route of administration | Pharmacology | Sponsor | Phase | Comments |
|---|---|---|---|---|
| Ketamine, various | Non-selective, non-competitive NMDA receptor antagonist | Multiple | -- | Several small trials from academia2; unlikely to be studied in phase III clinical trials required to receive FDA approval. |
| Esketamine, IN | Non-selective, non-competitive NMDA receptor antagonist | Janssen | III | Granted FDA approval in 2019 for TRD in conjunction with an oral antidepressant, with supplemental indication approved for major depression with suicidal ideation (Aug 2020). Esketamine has 4-5 times the NMDAR binding potency compared to (R)-ketamine. 46 |
| AVP-786, oral | Non-selective antagonist of NMDAR | Avanir/ Otsuka | II | Combination of dextromethorphan and quinidine. Phase II trial completed in Feb 2016 (results are not published); no additional studies for mood disorders registered as of March 2021. |
| AXS-05, oral | Non-selective antagonist of NMDAR | Axsome | III | Combination of dextromethorphan/ bupropion. Primary outcome was attained in Phase-II and Phase-III studies for MDD, but not in Phase-III study for TRD. Additional studies are ongoing. |
| REL-1017, oral | Noncompetitive NMDAR antagonist | Relmada | II | Being pursued for MDD. One phase-II study found statistically significant improvement in depression compared to placebo. A Phase-III study is ongoing. |
| MIJ821 | NMDAR NR2B antagonist | Novartis Pharmaceuticals | II | Two phase-II trials are completed (MDD, MDSI) but have not publicly released data. |
| AV-101, oral | Selective antagonist at glycine site of NMDA receptor NR1 subunit | VistaGen | II | The primary endpoint was not met in a recent phase-II trial. Another phase-II completed in Dec 2019 also did not meet primary endpoint. |
| Rapastinel/ GLYX-13, IV | Partial functional agonist at glycine site of NMDA receptor | Allergan/Abbvie | III | At least three phase-III studies did not differentiate from placebo on the primary outcome. A relapse-prevention study also did not meet primary endpoint. |
| NRX-100/NRX-101, oral | Partial NMDAR agonist at glycine-site | NeuroRx | III | Ketamine (NRX-100) followed by D-cycloserine plus lurasidone (NRX-101) to sustain effects in suicidal bipolar depression. Primary endpoint was positive for a phase-II trial.* Three Phase-II/III trials (suicidal BPD) and one biomarker trial are ongoing. |
| AGN-241751 | NMDAR modulator | Allergan | II | Being pursued for the treatment of MDD. Two phase-II trials completed in 2019 but data is not available publicly. |
| Brexanolone/ SAGE-547, Zulresso™.IV | PAM of GABAA receptor | Sage | III | Approved by FDA for PPD. Two phase-III trials for the treatment of PPD met their primary endpoints There is one ongoing open-label phase-III study in adolescents with PPD. |
| Ganaxolone, IV and oral | PAM of GABAA receptor | Marinus | II | Being pursued as a treatment for post-partum depression. The primary endpoint was met in an initial open label pilot study in postmenopausal MDD. Two phase-II studies (one IV study in moderate PPD and one oral study in severe PPD) have completed but full data are not publicly available. |
| Zuranolone, SAGE-217, oral | PAM of GABAA receptor | Sage | III | Being pursued as a treatment for MDD, BPD, and PPD. One Phase-II trials (MDD) and one Phase-III trials (PPD) achieved the primary endpoint, while another phase-III trial (MDD) did not meet the primary endpoint. A phase-II trial (BPD) recently completed but data is not available publicly. There are currently four active phase-III trials (3 in MDD, 1 in PPD). In July 2019, Sage announced that it would begin to investigate SAGE-217 in TRD, but no trials for TRD have been posted on clinicaltrials.gov. |
| PRAX-114 | PAM of GABAA receptor | Praxis Precision Medicines | II | There is one ongoing phase-II trial (MDD). IND submission for Prax-114 as treatment for MDD is on clinical hold by the FDA. |
Drugs are grouped according to purported mechanism of action. Abbreviations: AMPA – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA – gamma-aminobutryic acid; mGluR – metabotropic glutamate receptor; NAM – negative allosteric modulator; PAM – positive allosteric modulator; NMDAR – N-methyl-D-aspartate receptor; Route of administration: IV – intravenous; IN – intranasal. MDD – major depressive disorder; MDSI – major depression with suicidal ideation; IND – investigational new drug; PPD – post-partum depression; BPD – bipolar depression; TRD – treatment-resistant depression
*This data is still awaiting quality control at the US Clinical Trials Registry.