Table 1.
Rapid-acting antidepressants and newer compounds under development.
| Compound | Mechanism | Disease | Predicted Safety |
|---|---|---|---|
| Brexanolone (Zulresso®) |
GABAAR agonist | Approved as i.v. infusion for severe post-partum depression | In-hospital monitoring for sedation and other |
| (S)-Ketamine (Spravato®) | NMDAR antagonist and possible other | Nasal spray approved as an adjunct therapy for TRD | Generally well tolerated with in-patient dosing |
| Racemic ketamine intranasal (SLS-002) | NMDAR antagonist and possible other | ASIB, MDD, PTSD | Generally well tolerated with in-patient dosing |
| Racemic ketamine (oral formulation) KET01 | NMDAR antagonist and possible other | TRD | No dissociative or psychotomimetic effects |
| Dextromethorphan/Bupropion (Auvelity®) | Low-affinity NMDAR antagonist, monoamine uptake blocker | MDD | Generally well tolerated |
| Zuranolone (Zurzuvae®) 1 | GABAAR potentiator, Oral drug |
Approved as oral medication for post-partum depression | Drowsiness, dizziness |
| (R)-Ketamine (PNC-101) 2 | NMDAR antagonism and possible other | TRD | No dissociative or psychotomimetic effects |
| (S)-Methadone 2 | NMDAR antagonism and possible other | MDD and TRD | Low dissociative and psychotomimetic liability |
| MIJ821 (CAD-927) (Onfasprodil) | Low-affinity NMDAR antagonist |
TRD | Transient mild dissociative effects |
| Lanicemine (AZD6765) | Low-affinity NMDAR antagonist |
MDD and TRD | No dissociative or psychotomimetic effects |
| Dextromethorphan/ quinidine (Neudexta®) |
Low-affinity NMDAR Antagonist and σ1 |
Approved for use in PBA. Possible development for MDD |
Dizziness |
| Eliprodil, (EVT-101, ENS-101) 4 | NR2B-selective NMDA antagonist |
MDD and TRD | Generally well tolerated |
| D-cycloserine | NMDAR glycine site partial agonist |
TRD | Without dissociation or psychotomimetic effects |
| Psilocybin formulations 3 | 5-HT2A agonist | MDD and TRD | Psychedelic effects |
| GLYX-13 (Rapastinel®) | NMDA receptor modulator (i.v.) |
TRD | Without dissociation or psychotomimetic effects |
| Gate-251 (AGN-241751) (Zelquistenel®) |
NMDA receptor modulator (oral) |
MDD and TRD | Without dissociation or psychotomimetic effects |
| Gate-202 (NRX-1074) (Apimostinel®) |
NMDA receptor modulator (i.v.) |
MDD and TRD | Without dissociation or psychotomimetic effects |
| Synthetic psychedelics 3 | 5-HT2A agonist and other | TRD | Data needed to assess |
| TS-161 | mGlu2/3 receptor prodrug oral |
TRD | Without dissociation or psychotomimetic effects |
| TAK-653 (NBI-1065845) 5 | AMPAR potentiator | MDD and TRD | Without dissociation or psychotomimetic effects |
5-HT: 5-hydroxytryptamine or serotonin; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ASIB: acute suicidal ideation and behavior; GABA: gamma amino butyric acid; MDD: major depressive disorder; mGlu: metabotropic glutamate; NMDA: N-methyl-D-aspartate; PBA: pseudobulbar affect; PTSD: post-traumatic stress syndrome; TRD: treatment-resistant depression. 1 Approved by US FDA in 2023. 2 Recent clinical trial findings for both (R)-ketamine and (S)-methadone have not met their sponsor-decided a priori clinical endpoints (see individual discussion of these compounds in text above). 3 See [9] for more details. 4 Development was discontinued in 2021. 5 Phase 2 data were just disclosed showing positive efficacy with primary and secondary endpoints in MDD patients with good tolerability.