List of investigational antidepressants

Glutamatergics

NMDA receptor modulators

• 4-Chlorokynurenine – NMDA receptor glycine site antagonist
• AGN-241751 – NMDA receptor modulator
• Apimostinel – NMDA receptor glycine site partial agonist
• Arketamine – unknown mechanism of action, indirect AMPA receptor activator
• Dextromethadone – NMDA receptor antagonist open channel blocker
• EVT-101 – NR2B antagonist
• Ketamine – non-competitive NMDA receptor antagonist
• Rislenemdaz – NMDA receptor subunit 2B antagonist

  Others

• Basimglurant – mGluR₅ negative allosteric modulator

  Monoaminergics

Monoamine reuptake inhibitors

• AN-788 – serotonin–dopamine reuptake inhibitor
• Ansofaxine – serotonin–norepinephrine–dopamine reuptake inhibitor
• PDC-1421 – norepinephrine reuptake inhibitor

  Monoamine reuptake inhibitors and receptor modulators

• MIN-117 – SDRI, 5-HT_1A receptor antagonist, 5-HT_2A, α_1A-adrenergic, and α_1B-adrenergic receptor ligand
• TGBA01AD – serotonin reuptake inhibitor, 5-HT_1A and 5-HT_1D receptor agonist, and 5-HT₂ receptor antagonist

  Monoamine receptor modulators

• Gepirone – 5-HT_1A receptor partial agonist
• Pimavanserin – 5-HT_2A receptor antagonist
• Psilocybin – 5-HT_2A receptor partial agonist

  Atypical antipsychotics

• Brilaroxazine – AA – specifically under development for the treatment of MDD and depressive episodes in bipolar disorder
• Lumateperone – AA – specifically under development for the treatment of depressive episodes in bipolar disorder

  Others

• Ademetionine – cofactor in monoamine neurotransmitter biosynthesis – specifically under development in the United States and Europe for the adjunctive treatment of MDD

  Neurosteroids

GABA_A receptor positive modulators

• Ganaxolone – GABA_A receptor positive allosteric modulator – specifically under development for the treatment of postpartum depression
• Zuranolone – GABA_A receptor positive allosteric modulator – specifically under development for the treatment of both MDD and postpartum depression

  Others

• 3β-Methoxypregnenolone – selective microtubule-associated protein 2 stimulant
• PH-10 – vomeropherine

  Opioidergics

κ-Opioid receptor antagonists

• Aticaprant – κ-opioid receptor antagonist
• BTRX-335140 – selective k-opioid receptor antagonist
• Buprenorphine/samidorphan – κ-opioid receptor antagonist

  Others

• BTRX-246040 – nociceptin receptor antagonist

  Others

• Hydroxynorketamine – metabolite of ketamine which may be involved in ketamine's antidepressant-like effects in mice
• JNJ-39393406 – α₇ nicotinic acetylcholine receptor positive allosteric modulator
• JNJ-54175446 – P2RX7 purinoceptor antagonist
• JNJ-61393215 – Orexin receptor antagonists
• NNI-351 – DYRK1A inhibitor/"nerve growth factor stimulant"
• NSI-189 – hippocampal neurotrophic agent
• NV-5138 – sestrin2 modulator and consequent mammalian target of rapamycin complex 1 activator
• OnabotulinumtoxinA – acetylcholine release inhibitor – specifically under development for the treatment of MDD in women as a local injection to paralyze facial muscles
• Pramipexole – Dopamine D2 and D3 receptor agonists.
• Seltorexant – OX₂ receptor antagonist
• Sirukumab – monoclonal antibody against interleukin-6
• SUVN-911 – α₄β₂ nicotinic acetylcholine receptor antagonist or negative allosteric modulator
• TS-121 – vasopressin 1B receptor antagonist

  Mixed

• Tramadol – μ-opioid receptor agonist, serotonin–norepinephrine reuptake inhibitor and possible serotonin releasing agent, 5-HT_2C receptor antagonist, and other actions

  Combinations

• Bupropion/dextromethorphan – σ₁ receptor agonist, SNRI, non-competitive nicotinic acetylcholine receptor antagonist, uncompetitive NMDA receptor antagonist, and other actions
• Cycloserine/lurasidone – NMDA receptor glycine site partial agonist and AA combination – specifically under development for the treatment of depressive episodes in bipolar disorder
• Dextromethorphan/quinidine – σ₁ receptor agonist, SNRI, uncompetitive NMDA receptor antagonist, and other actions

  Not under development

• 7,8-Dihydroxyflavone – TrkB agonist
• 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, indicative of a large and statistically significant antidepressant effect
• Nitrous oxide – NMDA receptor antagonist and other actions
• Pramipexole – partial or full agonist of the D₂, D₃, and D₄ receptors
• R13 – an orally active prodrug of 7,8-DHF with improved pharmacokinetics
• LSD