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^[1]
• Apimostinel (NRX-1074) – NMDA receptor glycine site partial agonist^[2]
• Arketamine (PCN-101, HR-071603) – unknown mechanism of action, indirect AMPA receptor activator^[3][4]
• Dextromethadone (REL-1017) – NMDA receptor antagonist open channel blocker^[5]
• Esketamine (Esketamine DPI, Falkieri, PG061) – non-competitive NMDA receptor antagonist – approved for TRD, specifically under development for bipolar depression and "depressive disorders" [1]
• Ketamine (PMI-100, PMI-150, R-107, SHX-001, SLS-002; TUR-002) – non-competitive NMDA receptor antagonist^[6][2][3][4]
• – NMDA receptor subunit 2B (NR2B) negative allosteric modulator [5]
• Rislenemdaz (CERC-301, MK-0657) – NMDA receptor NR2B antagonist^[7]

AMPA receptor modulators[]

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

Monoaminergics[]

Monoamine reuptake inhibitors[]

• – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) [7]
• (BLI-1005) – norepinephrine reuptake inhibitor (NRI)^[8]
• Toludesvenlafaxine (ansofaxine; LY03005, LPM570065) – SNDRI^[9]

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^[10]
• 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[]

• (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^[11][12]
• Gepirone (TGFK07AD; Travivo) – 5-HT_1A receptor partial agonist^[13]
• Pramipexole (CTC-501, CTC-413) – D₂, D₃, and D₄ receptor agonist^[14][15]
• Psilocybin – 5-HT_2A receptor agonist^[16][12]

Atypical antipsychotics[]

• Brilaroxazine (RP-5063, RP-5000) – AA – specifically under development for the treatment of MDD^[17]
• 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^[18]
• 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^[19]

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^[20]

GABAergics and neurosteroids[]

GABA_A receptor positive modulators[]

• – GABA_A receptor positive allosteric modulator [15]
• Zuranolone (SAGE-217) – GABA_A receptor positive allosteric modulator – specifically under development for the treatment of MDD and postpartum depression^[21]

Others[]

• 3β-Methoxypregnenolone (MAP-4343) – selective microtubule-associated protein 2 (MAP2) stimulant^[22]
• PH-10 – vomeropherine (precise mechanism of action unknown/undisclosed)^[23]

Opioidergics[]

κ-Opioid receptor antagonists[]

• Aticaprant (JNJ-67953964, CERC-501, LY-2456302) – κ-opioid receptor antagonist^[24][25]
• BTRX-335140 (BTRX-140) – selective k-opioid receptor antagonist^[26][27]
• Buprenorphine/samidorphan (ALKS-5461) – κ-opioid receptor antagonist and μ-opioid receptor antagonist^[28]

Nociceptin receptor antagonists[]

• BTRX-246040 (LY-2940094) – nociceptin receptor antagonist^[29]

Cholinergics[]

Muscarinic acetylcholine receptor modulators[]

• Scopolamine (DPI-386) – muscarinic acetylcholine receptor antagonist [16]

Nicotinic acetylcholine receptor modulators[]

• JNJ-39393406 – α₇ nicotinic acetylcholine receptor positive allosteric modulator^[30]

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^[31]

Orexin receptor antagonists[]

• (JNJ-3215; Orexin-1) – OX₁ receptor antagonist^[32][33]
• Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – OX₂ receptor antagonist^[34]

Others[]

• – TRPC4 and TRPC5 inhibitor [17]
• (AAD-2004) – MPGES-1 inhibitor [18]
• Erteberel – selective ERβ receptor agonist [19]
• – P2RX7 purinoceptor antagonist^[35]
• NSI-189 – hippocampal neurotrophic agent (precise mechanism of action unknown)^[36]
• NV-5138 – sestrin2 modulator and consequent mammalian target of rapamycin complex 1 (mTORC1) activator^[37][38][39]
• – undefined mechanism of action [20]
• TS-121 – vasopressin 1B receptor antagonist^[40]
• – undefined mechanism of action [21]

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^[41][42][43]

Combinations[]

• Bupropion/dextromethorphan (AXS-05) – σ₁ receptor agonist, SRI, NDRI, non-competitive nicotinic acetylcholine receptor antagonist, uncompetitive NMDA receptor antagonist, and other actions^[44]
• Carbidopa/oxitriptan (EVX-101) – serotonin precursor and aromatic L-amino acid decarboxylase inhibitor [22]
• Cycloserine/lurasidone (NRX-101; Cyclurad) – NMDA receptor glycine site partial agonist and AA combination – specifically under development for the treatment of bipolar depression^[45]
• Deudextromethorphan/quinidine (AVP-786, CTP-786) – σ₁ receptor agonist, SRI, uncompetitive NMDA receptor antagonist, and other actions^[46]

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^[3][47]
• 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^[48][49]
• Nitrous oxide – NMDA receptor antagonist and other actions^[50][51][52]
• R13 – an orally active prodrug of tropoflavin with improved pharmacokinetics^[53]
• Tropoflavin (7,8-dihydroxyflavone; 7,8-DHF) – TrkB agonist^{[54][55][56][57][58][59][60][61]}

See also[]

• List of antidepressants
• List of investigational drugs

References[]

Further reading[]

External links[]

• AdisInsight - Springer