Table 1.
Summary of novel and emerging pharmacologic agents for major depressive disorder (MDD).
| Agent | Mechanism of action | Route of administration | Indication | Experimental evidence | FDA status | Year introduced | Notable adverse effects |
|---|---|---|---|---|---|---|---|
| Esketamine | NMDA receptor antagonist; increases glutamate signaling | Intranasal | Treatment-resistant depression (TRD) | Multiple RCTs (e.g., TRANSFORM, SUSTAIN trials); real-world data (e.g., REAL-ESK study) | Approved for TRD (2019) | 2019 | Dissociation, blood pressure elevation, abuse potential, sedation |
| Zuranolone | Positive allosteric modulator of GABA_A receptor | Oral | Postpartum depression, MDD | Phase 3 trials (e.g., MOUNTAIN, WATERFALL studies) showed efficacy over placebo | Approved for PPD (2023); MDD under review | 2023 | Somnolence, dizziness, sedation |
| Esmethadone (REL-1017) | Uncompetitive NMDA receptor antagonist | Oral | MDD (adjunctive or monotherapy) | Phase 2 and 3 trials demonstrated rapid antidepressant effects without dissociation or psychotomimetic effects | Not yet approved | – | Mild dizziness, headache, well-tolerated profile |
| AXS-05 (Dextromethorphan–bupropion) | Sigma-1 receptor agonist and NMDA receptor antagonist (dextromethorphan); dopamine/norepinephrine reuptake inhibitor (bupropion) | Oral | MDD | Strong efficacy in the GEMINI and ASCEND trials; comparative advantages in onset of action and symptom domains | Approved (2022) | 2022 | Dizziness, dry mouth, insomnia |
| Psilocybin | 5-HT2A receptor partial agonist; modulates default mode network (DMN) activity | Oral (single dose, supervised setting) | MDD, TRD, existential anxiety | Phase 2 RCTs (e.g., COMPASS trial); meta-analyses support sustained effects; neuroimaging studies show DMN modulation | Not FDA-approved; Breakthrough status | – | Hallucinations, emotional lability, anxiety during session |
| SAGE-217 (Zuranolone) | GABA_A receptor positive allosteric modulator | Oral | PPD, MDD | Similar to zuranolone profile; fast-acting with good tolerability | Same as above | – | See zuranolone |
| Navacaprant (MK-1942) | Selective kappa-opioid receptor antagonist | Oral | MDD (monotherapy or adjunctive) | Phase 2 trials ongoing; preclinical and early clinical data suggest promising anxiolytic and antidepressant effects | Investigational | – | Nausea, headache; long-term data limited |
PPD, postpartum depression; NMDA, N-methyl-d-aspartate; RCTs, randomized controlled trials.