List of investigational antidepressants

This is a list of investigational antidepressants, or antidepressants that are currently under development for clinical use in the treatment of mood disorders but are not yet approved.

All drugs listed are specifically under development for major depressive disorder (MDD) and/or treatment-resistant depression (TRD) unless noted otherwise. Other forms of depression may include bipolar depression and postpartum depression.

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

Negative modulator

 * Ketamine (PMI-100, PMI-150, R-107, SHX-001, SLS-002; TUR-002) – non-competitive NMDA receptor antagonist. (hydroxynorketamine ((2R,6R)-HNK) – metabolite of ketamine which may be involved in ketamine's antidepressant-like effects in mice )
 * Arketamine (PCN-101, HR-071603) – unknown mechanism of action, indirect AMPA receptor activator
 * Esketamine (Esketamine DPI, Falkieri, PG061) – non-competitive NMDA receptor antagonist – approved for TRD, specifically under development for bipolar depression and "depressive disorders"
 * Esmethadone (dextromethadone; REL-1017) – NMDA receptor antagonist open channel blocker

Positive modulator

 * Zelquistinel (GATE-251, AGN-241751) – NMDA receptor positive allosteric modulator
 * Apimostinel (GATE-202, NRX-1074) – NMDA receptor modulator

AMPA receptor modulators

 * TAK-653 (NBI-1065845) – AMPA receptor positive allosteric modulator

GABAA receptor positive modulators

 * Zuranolone (SAGE-217) – GABAA receptor positive allosteric modulator – specifically under development for the treatment of MDD and postpartum depression

Monoamine reuptake inhibitors

 * OPC-64005 – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)
 * PDC-1421 (BLI-1005) – norepinephrine reuptake inhibitor (NRI)

Monoamine reuptake inhibitors and receptor modulators

 * Hypidone (YL-0919) – SRI, 5-HT1A receptor partial agonist, and 5-HT6 receptor agonist
 * TGBA01AD (FKB01MD) – serotonin reuptake inhibitor (SRI), 5-HT1A and 5-HT1D receptor agonist, and 5-HT2 receptor antagonist

Monoamine receptor activators

 * Pramipexole (CTC-501, CTC-413) – D2, D3 and D4 receptor agonist

Monoamine receptor inhibitors

 * Amisulpride (Aramisulpride/esamisulpride (85:15 ratio)) (SEP-4199) – 5-HT7 receptor antagonist (aramisulpride) and D2 and D3 receptor antagonist (esamisulpride) – specifically under development for the treatment of bipolar depression
 * Brilaroxazine (RP-5063, RP-5000) – AA – specifically under development for the treatment of MDD
 * Lumateperone (ITI-007, Caplyta) – AA – specifically under development for the treatment of MDD and bipolar. Has been approved to treat BP 1 and BP 2 disorder under the brand name Caplyta.
 * Lurasidone (Latuda) – AA – specifically under development for the treatment of MDD
 * Pimavanserin (Nuplazid; ACP-103; BVF-048) – 5-HT2A receptor antagonist – specifically under development for the treatment of MDD

Monoamine releasing agents

 * Midomafetamine (MDMA; ecstasy) – serotonin–norepinephrine–dopamine releasing agent (SNDRA)
 * Tramadol (ETS6103; Viotra) – μ-opioid receptor agonist, serotonin–norepinephrine reuptake inhibitor (SNRI) and indirect serotonin releasing agent (SRA) by GABA mechanisms, 5-HT2C receptor antagonist, and other actions

Cofactor in monoamine biosynthesis

 * Ademetionine (SAMe; MSI-190, MSI-195, Strada) specifically under development in the United States and Europe for the adjunctive treatment of MDD

κ-Opioid receptor antagonists

 * Aticaprant (JNJ-67953964, CERC-501, LY-2456302) – selective κ-opioid receptor antagonist
 * Navacaprant (BTRX-335140; BTRX-140) – selective k-opioid receptor antagonist
 * Buprenorphine/samidorphan (ALKS-5461) – κ-opioid receptor antagonist and μ-opioid receptor antagonist
 * CVL-354 – selective κ-opioid receptor antagonist

Nociceptin receptor antagonists

 * BTRX-246040 (LY-2940094) – nociceptin receptor antagonist

Muscarinic acetylcholine receptor modulators

 * Scopolamine (DPI-386) – muscarinic acetylcholine receptor antagonist

OX1 receptor antagonists

 * JNJ-61393215 (JNJ-3215; Orexin-1) – OX1 receptor antagonist

OX2 receptor antagonists

 * Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – OX2 receptor antagonist

Neurosteroids

 * Itruvone (PH-10) – vomeropherine (precise mechanism of action unknown/undisclosed)
 * 3β-Methoxypregnenolone (MAP-4343) – selective microtubule-associated protein 2 (MAP2) stimulant

Others

 * BI-1358894 – TRPC4 and TRPC5 inhibitor
 * Crisdesalazine (AAD-2004) – MPGES-1 inhibitor
 * Erteberel – selective ERβ receptor agonist
 * JNJ-54175446 – P2RX7 purinoceptor antagonist
 * NSI-189 – hippocampal neurotrophic agent (precise mechanism of action unknown)
 * NV-5138 – sestrin2 modulator and consequent mammalian target of rapamycin complex 1 (mTORC1) activator
 * SNG-12 – undefined mechanism of action
 * TS-121 – vasopressin 1B receptor antagonist
 * WIP-DF17 – undefined mechanism of action
 * XEN1101 – KCNQ2/3 channel opener
 * Casopitant – NK1 receptor antagonist
 * Psilocybin – undefined mechanism of action (monoaminergic (5-HT2A receptor agonist) and glutamatergic (mGlu2/3 receptor modulator))

Combinations

 * Carbidopa/oxitriptan (EVX-101) – serotonin precursor and aromatic L -amino acid decarboxylase inhibitor
 * Cycloserine/lurasidone (NRX-101; Cyclurad) – NMDA receptor glycine site partial agonist and AA combination – specifically under development for the treatment of bipolar depression
 * Deudextromethorphan/quinidine (AVP-786, CTP-786) – σ1 receptor agonist, SRI, uncompetitive NMDA receptor antagonist, and other actions

Not under development
The following notable drugs are of investigational interest as potential antidepressants but are not formally under clinical development for approval at this time:


 * Minocycline – microglia inhibitor and other actions; a 2018 systematic review and meta-analysis reported that the overall antidepressant effect size of minocycline compared to placebo was -0.78 (95% CI: -0.4 to -1.33, P=0.005), indicative of a large and statistically significant antidepressant effect
 * Nitrous oxide – NMDA receptor antagonist and other actions
 * R13 – an orally active prodrug of tropoflavin with improved pharmacokinetics
 * Tropoflavin (7,8-dihydroxyflavone; 7,8-DHF) – TrkB agonist