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

Glutamatergics

NMDA receptor modulators

• 4-Chlorokynurenine (AV-101) – NMDA receptor glycine site antagonist
• Apimostinel (GATE-202, NRX-1074) – NMDA receptor modulator
• 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" [1]
• Esmethadone (dextromethadone; REL-1017) – NMDA receptor antagonist open channel blocker
• Ketamine (PMI-100, PMI-150, R-107, SHX-001, SLS-002; TUR-002) – non-competitive NMDA receptor antagonist[2][3][4]
• MIJ-821 – NMDA receptor subunit 2B (NR2B) negative allosteric modulator [5]
• Rislenemdaz (CERC-301, MK-0657) – NMDA receptor NR2B antagonist

AMPA receptor modulators

• TAK-653 (NBI-1065845) – AMPA receptor positive allosteric modulator [6]

Monoaminergics

Monoamine reuptake inhibitors

• OPC-64005 – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) [7]
• PDC-1421 (BLI-1005) – norepinephrine reuptake inhibitor (NRI)

Monoamine reuptake inhibitors and receptor modulators

• Hypidone (YL-0919) – SRI, 5-HT_1A receptor partial agonist, and 5-HT₆ receptor agonist [8]
• TGBA01AD (FKB01MD) – serotonin reuptake inhibitor (SRI), 5-HT_1A and 5-HT_1D receptor agonist, and 5-HT₂ receptor antagonist
• Vortioxetine (Trintellix) – SRI, 5-HT_1A receptor agonist, 5-HT_1B receptor partial agonist, 5-HT_1D, 5-HT₃, and 5-HT₇ receptor antagonist – approved for MDD, under development for bipolar depression [9]

Monoamine releasing agents

• Lisdexamfetamine (Elvanse, LDX, NRP-104, S-877489, SHP-489, SPD-489, Tyvense, Venvanse, Vyvanse) – norepinephrine–dopamine releasing agent (NDRA) [10]
• Midomafetamine (MDMA; ecstasy) – serotonin–norepinephrine–dopamine releasing agent (SNDRA) [11]

Monoamine receptor modulators

• 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
• Gepirone (TGFK07AD; Travivo) – 5-HT_1A receptor partial agonist
• Pramipexole (CTC-501, CTC-413) – D₂, D₃, and D₄ receptor agonist
• Psilocybin – 5-HT_2A receptor agonist[12]

Atypical antipsychotics

• Brilaroxazine (RP-5063, RP-5000) – AA – specifically under development for the treatment of MDD
• Cariprazine (Reagila, Vraylar) – AA – approved for bipolar depression, under development for MDD [13]
• Lumateperone (ITI-007) – AA – specifically under development for the treatment of MDD and bipolar depression
• Lurasidone (Latuda) – AA – specifically under development for the treatment of MDD [14]
• Pimavanserin (Nuplazid; ACP-103; BVF-048) – 5-HT_2A receptor antagonist – specifically under development for the treatment of MDD

Others

• Ademetionine (SAMe; MSI-190, MSI-195, Strada) – cofactor in monoamine neurotransmitter biosynthesis – specifically under development in the United States and Europe for the adjunctive treatment of MDD

GABAergics and neurosteroids

GABA_A receptor positive modulators

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

Others

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

Opioidergics

κ-Opioid receptor antagonists

• Aticaprant (JNJ-67953964, CERC-501, LY-2456302) – selective κ-opioid receptor antagonist
• 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

Cholinergics

Muscarinic acetylcholine receptor modulators

• Scopolamine (DPI-386) – muscarinic acetylcholine receptor antagonist [15]

Others

• OnabotulinumtoxinA (botulinum toxin A, Botox) – acetylcholine release inhibitor – specifically under development for the treatment of MDD in women as a local injection to paralyze facial muscles

Orexin receptor antagonists

• JNJ-61393215 (JNJ-3215; Orexin-1) – OX₁ receptor antagonist
• Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – OX₂ receptor antagonist

Others

• BI-1358894 – TRPC4 and TRPC5 inhibitor [16]
• Crisdesalazine (AAD-2004) – MPGES-1 inhibitor [17]
• Erteberel – selective ERβ receptor agonist [18]
• 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 [19]
• TS-121 – vasopressin 1B receptor antagonist
• WIP-DF17 – undefined mechanism of action [20]
• XEN1101 - KCNQ2/3 channel opener

Mixed

• Tramadol (ETS6103; Viotra) – μ-opioid receptor agonist, serotonin–norepinephrine reuptake inhibitor (SNRI) and possible serotonin releasing agent (SRA), 5-HT_2C receptor antagonist, and other actions

Combinations

• Carbidopa/oxitriptan (EVX-101) – serotonin precursor and aromatic L-amino acid decarboxylase inhibitor [21]
• 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:

• Hydroxynorketamine ((2R,6R)-HNK) – metabolite of ketamine which may be involved in ketamine's antidepressant-like effects in mice
• Mesembrine is an alkaloid present in Sceletium tortuosum (kanna). It has been shown to act as a serotonin reuptake inhibitor.
• 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

See also

• List of antidepressants
• List of investigational drugs

Further reading

External links

• AdisInsight - Springer