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) or treatment-resistant depression (TRD) unless noted otherwise.

Glutamatergics

NMDA receptor modulators

• 4-Chlorokynurenine (AV-101) – NMDA receptor glycine site antagonist[1]
• AGN-241751 – NMDA receptor modulator[2][3]
• Apimostinel (NRX-1074) – NMDA receptor glycine site partial agonist[4]
• Arketamine (PCN-101, HR-071603) – unknown mechanism of action, indirect AMPA receptor activator[5][6]
• Dextromethadone (REL-1017) – NMDA receptor antagonist open channel blocker[7]
• EVT-101 (ENS-101) – NR2B antagonist[8]
• Ketamine (Ketalar) – non-competitive NMDA receptor antagonist[9]
• Rislenemdaz (CERC-301, MK-0657) – NMDA receptor subunit 2B (NR2B) antagonist[10]

Others

• Basimglurant (RG-7090) – mGluR₅ negative allosteric modulator[11][12][13]

Monoaminergics

Monoamine reuptake inhibitors

• AN-788 (NSD-788) – serotonin–dopamine reuptake inhibitor (SDRI)[14]
• Ansofaxine (LY03005, LPM570065) – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI)[15]
• PDC-1421 (BLI-1005) – norepinephrine reuptake inhibitor (NRI)[16]

Monoamine reuptake inhibitors and receptor modulators

• MIN-117 (WF-516) – SDRI, 5-HT_1A receptor antagonist, 5-HT_2A, α_1A-adrenergic, and α_1B-adrenergic receptor ligand[17]
• TGBA01AD (FKB01MD) – serotonin reuptake inhibitor (SRI), 5-HT_1A and 5-HT_1D receptor agonist, and 5-HT₂ receptor antagonist[18]

Monoamine receptor modulators

• Gepirone (TGFK07AD; Travivo) – 5-HT_1A receptor partial agonist[19]
• Pimavanserin (Nuplazid; ACP-103; BVF-048) – 5-HT_2A receptor antagonist[20]
• Psilocybin – 5-HT_2A receptor partial agonist[21]

Atypical antipsychotics

• Brilaroxazine (RP-5063, RP-5000) – AA – specifically under development for the treatment of MDD and depressive episodes in bipolar disorder[22]
• Lumateperone (ITI-007) – AA – specifically under development for the treatment of depressive episodes in bipolar disorder[23]

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[24]

Neurosteroids

GABA_A receptor positive modulators

• Ganaxolone (CCD-1042) – GABA_A receptor positive allosteric modulator – specifically under development for the treatment of postpartum depression[25]
• Zuranolone (SAGE-217) – GABA_A receptor positive allosteric modulator – specifically under development for the treatment of both MDD and postpartum depression[26]

Others

• 3β-Methoxypregnenolone (MAP-4343) – selective microtubule-associated protein 2 (MAP2) stimulant[27]
• PH-10 – vomeropherine (precise mechanism of action unknown/undisclosed)[28]

Opioidergics

κ-Opioid receptor antagonists

• Aticaprant (JNJ-67953964, CERC-501, LY-2456302) – κ-opioid receptor antagonist[29][30]
• BTRX-335140 (BTRX-140) – selective k-opioid receptor antagonist[31][32]
• Buprenorphine/samidorphan (ALKS-5461) – κ-opioid receptor antagonist[33]

Others

• BTRX-246040 (LY-2940094) – nociceptin receptor antagonist[34]

Others

• Hydroxynorketamine ((2R,6R)-HNK) – metabolite of ketamine which may be involved in ketamine's antidepressant-like effects in mice[5][35]
• JNJ-39393406 – α₇ nicotinic acetylcholine receptor positive allosteric modulator[36]
• JNJ-54175446 – P2RX7 purinoceptor antagonist[37]
• JNJ-61393215 – (JNJ-3215, JNJ-61393215; Orexin-1) Orexin receptor antagonists(type 1)[38][39]
• NNI-351 – DYRK1A inhibitor/"nerve growth factor stimulant"[40]
• NSI-189 – hippocampal neurotrophic agent (precise mechanism of action unknown)[41]
• NV-5138 – sestrin2 modulator and consequent mammalian target of rapamycin complex 1 (mTORC1) activator[42][43][44]
• 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[45]
• Pramipexole (CTC-501, CTC-413) – Dopamine D2 and D3 receptor agonists.[46][47]
• Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – OX₂ receptor antagonist[48]
• Sirukumab (CNTO-136) – monoclonal antibody against interleukin-6[49]
• SUVN-911 – α₄β₂ nicotinic acetylcholine receptor antagonist or negative allosteric modulator[50]
• TS-121 – vasopressin 1B receptor antagonist[51]

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[52][53][54]

Combinations

• Bupropion/dextromethorphan (AXS-05) – σ₁ receptor agonist, SNRI, non-competitive nicotinic acetylcholine receptor antagonist, uncompetitive NMDA receptor antagonist, and other actions[55]
• Cycloserine/lurasidone (NRX-101; Cyclurad) – NMDA receptor glycine site partial agonist and AA combination – specifically under development for the treatment of depressive episodes in bipolar disorder[56]
• Dextromethorphan/quinidine (AVP-786/AVP-923) – σ₁ receptor agonist, SNRI, uncompetitive NMDA receptor antagonist, and other actions[57]

Not under development

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

• 7,8-Dihydroxyflavone (7,8-DHF) – TrkB agonist[58][59][60][61][62][63][64][65]
• 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[66][67]
• Nitrous oxide – NMDA receptor antagonist and other actions[68][13][69]
• Pramipexole – partial or full agonist of the D₂, D₃, and D₄ receptors[70]
• R13 – an orally active prodrug of 7,8-DHF with improved pharmacokinetics[71]
• LSD[72]

See also

• List of antidepressants
• List of investigational drugs

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Further reading

• Ionescu DF, Papakostas GI (March 2017). "Experimental medication treatment approaches for depression". Translational Psychiatry. 7 (3): e1068. doi:10.1038/tp.2017.33. PMC 5416676. PMID 28323287.
• Garay RP, Zarate CA, Charpeaud T, Citrome L, Correll CU, Hameg A, Llorca PM (June 2017). "Investigational drugs in recent clinical trials for treatment-resistant depression". Expert Review of Neurotherapeutics. 17 (6): 593–609. doi:10.1080/14737175.2017.1283217. PMC 5418088. PMID 28092469.
• Dhir A (January 2017). "Investigational drugs for treating major depressive disorder". Expert Opinion on Investigational Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559.

External links

• AdisInsight - Springer
• 2016 Medicines in Development for Mental Health - PhRMA