Chemistry:List of investigational antidepressants
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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 (GATE-202, NRX-1074) – NMDA receptor modulator[2]
- Arketamine (PCN-101, HR-071603) – unknown mechanism of action, indirect AMPA receptor activator[3][4]
- 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[5]
- Ketamine (PMI-100, PMI-150, R-107, SHX-001, SLS-002; TUR-002) – non-competitive NMDA receptor antagonist[6][2][3][4]
- MIJ-821 – NMDA receptor subunit 2B (NR2B) negative allosteric modulator [5]
- Rislenemdaz (CERC-301, MK-0657) – NMDA receptor NR2B antagonist[7]
- Zelquistinel (GATE-251, AGN-241751) – NMDA receptor positive allosteric modulator[8][9]
AMPA receptor modulators
Monoaminergics
Monoamine reuptake inhibitors
- OPC-64005 – serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) [7]
- PDC-1421 (BLI-1005) – norepinephrine reuptake inhibitor (NRI)[10]
Monoamine reuptake inhibitors and receptor modulators
- Hypidone (YL-0919) – SRI, 5-HT1A receptor partial agonist, and 5-HT6 receptor agonist [8]
- TGBA01AD (FKB01MD) – serotonin reuptake inhibitor (SRI), 5-HT1A and 5-HT1D receptor agonist, and 5-HT2 receptor antagonist[11]
- Vortioxetine (Trintellix) – SRI, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist, 5-HT1D, 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[12][13]
- Gepirone (TGFK07AD; Travivo) – 5-HT1A receptor partial agonist[14]
- Pramipexole (CTC-501, CTC-413) – D2, D3, and D4 receptor agonist[15][16]
- Psilocybin – 5-HT2A receptor agonist[17][12]
Atypical antipsychotics
- Brilaroxazine (RP-5063, RP-5000) – AA – specifically under development for the treatment of MDD[18]
- 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[19]
- Lurasidone (Latuda) – AA – specifically under development for the treatment of MDD [14]
- Pimavanserin (Nuplazid; ACP-103; BVF-048) – 5-HT2A receptor antagonist – specifically under development for the treatment of MDD[20]
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[21]
GABAergics and neurosteroids
GABAA receptor positive modulators
- Zuranolone (SAGE-217) – GABAA receptor positive allosteric modulator – specifically under development for the treatment of MDD and postpartum depression[22]
Others
- 3β-Methoxypregnenolone (MAP-4343) – selective microtubule-associated protein 2 (MAP2) stimulant[23]
- Itruvone (PH-10) – vomeropherine (precise mechanism of action unknown/undisclosed)[24]
Opioidergics
κ-Opioid receptor antagonists
- Aticaprant (JNJ-67953964, CERC-501, LY-2456302) – selective κ-opioid receptor antagonist[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]
- CVL-354 – selective κ-opioid receptor antagonist[29]
Nociceptin receptor antagonists
- BTRX-246040 (LY-2940094) – nociceptin receptor antagonist[30]
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[31]
Orexin receptor antagonists
- JNJ-61393215 (JNJ-3215; Orexin-1) – OX1 receptor antagonist[32][33]
- Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – OX2 receptor antagonist[34]
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[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]
- SNG-12 – undefined mechanism of action [19]
- TS-121 – vasopressin 1B receptor antagonist[40]
- WIP-DF17 – undefined mechanism of action [20]
- XEN1101 - KCNQ2/3 channel opener [41]
Mixed
- Tramadol (ETS6103; Viotra) – μ-opioid receptor agonist, serotonin–norepinephrine reuptake inhibitor (SNRI) and possible serotonin releasing agent (SRA), 5-HT2C receptor antagonist, and other actions[42][43][44]
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[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]
- Mesembrine is an alkaloid present in Sceletium tortuosum (kanna). It has been shown to act as a serotonin reuptake inhibitor.[48][49]
- 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[50][51]
- Nitrous oxide – NMDA receptor antagonist and other actions[52][53][54]
- R13 – an orally active prodrug of tropoflavin with improved pharmacokinetics[55]
- Tropoflavin (7,8-dihydroxyflavone; 7,8-DHF) – TrkB agonist[56][57][58][59][60][61][62][63]
See also
References
- ↑ "AV 101". http://adisinsight.springer.com/drugs/800019948.
- ↑ "Apimostinel". http://adisinsight.springer.com/drugs/800038114.
- ↑ 3.0 3.1 "Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective". Psychiatry and Clinical Neurosciences 73 (10): 613–627. October 2019. doi:10.1111/pcn.12902. PMID 31215725.
- ↑ "Arketamine - Jiangsu Hengrui Medicine - AdisInsight". https://adisinsight.springer.com/drugs/800056158.
- ↑ "Dextromethadone - Relmada Therapeutics". http://adisinsight.springer.com/drugs/800038927.
- ↑ "Ketamine intranasal - Vyera Pharmaceuticals". http://adisinsight.springer.com/drugs/800042128.
- ↑ "CERC 301". http://adisinsight.springer.com/drugs/800024703.
- ↑ "Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects". The International Journal of Neuropsychopharmacology 25 (12): 979–991. December 2022. doi:10.1093/ijnp/pyac043. PMID 35882204.
- ↑ "Gate Neurosciences Hones in on Precision Medicine with Expanded Research Operations Supporting Its Synaptic Function-Enhancing Molecules". Gate Neurosciences, Inc.. 3 May 2023. https://www.gateneuro.com/wp-content/uploads/2023/05/Gate-Research-Expansion-Press-Release_v10_final.docx.pdf.
- ↑ "PDC-1421". https://adisinsight.springer.com/drugs/800037456.
- ↑ "FKB 01MD". http://adisinsight.springer.com/drugs/800029513.
- ↑ "SEP 4199 - AdisInsight". https://adisinsight.springer.com/drugs/800052192.
- ↑ "Discovery of Non-racemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders". Clin Pharmacol Ther 110 (3): 808–815. May 2021. doi:10.1002/cpt.2282. PMID 33961287.
- ↑ "Gepirone ER". http://adisinsight.springer.com/drugs/800000684.
- ↑ "Pramipexole - Chase Therapeutics - AdisInsight". https://adisinsight.springer.com/drugs/800052837.
- ↑ "Product Discovery and Development" (in en-US). http://www.chasetherapeutics.com/product-discovery-development/.
- ↑ "Psilocybin". https://adisinsight.springer.com/drugs/800050861.
- ↑ "RP 5063". http://adisinsight.springer.com/drugs/800035778.
- ↑ "Lumateperone". http://adisinsight.springer.com/drugs/800026498.
- ↑ "Pimavanserin". http://adisinsight.springer.com/drugs/800014997.
- ↑ "Ademetionine". http://adisinsight.springer.com/drugs/800038499.
- ↑ "SAGE 217". http://adisinsight.springer.com/drugs/800043382.
- ↑ "Pregnenolone methyl ether". http://adisinsight.springer.com/drugs/800034216.
- ↑ "PH 10 nasal spray". http://adisinsight.springer.com/drugs/800043336.
- ↑ "Aticaprant (JNJ-67953964, CERC-501, LY-2456302) - AdisInsight". https://adisinsight.springer.com/drugs/800032395.
- ↑ "BTRX 335140 - AdisInsight". https://adisinsight.springer.com/drugs/800054451.
- ↑ "BlackThorn Therapeutics Advances Phase 2 Clinical Development for Selective KOR Antagonist, BTRX-140, in Neuropsychiatric Disorders" (in en). https://www.blackthornrx.com/publications/blackthorn-therapeutics-advances-phase-2-clinical-development-for-selective-kor-antagonist-btrx-140-in-neuropsychiatric-disorders/.
- ↑ "Buprenorphine/samidorphan". http://adisinsight.springer.com/drugs/800034331.
- ↑ "CVL-354". http://adisinsight.springer.com/drugs/800057691.
- ↑ "BTRX-246040". https://adisinsight.springer.com/drugs/800033400.
- ↑ "Botulinum toxin A injectable - Allergan". http://adisinsight.springer.com/drugs/800008810.
- ↑ "JNJ 61393215 - AdisInsight". https://adisinsight.springer.com/drugs/800045658.
- ↑ "A Study of JNJ-61393215 in the Treatment of Depression - Full Text View - ClinicalTrials.gov" (in en). https://clinicaltrials.gov/ct2/show/NCT04080752.
- ↑ "JNJ 42847922". http://adisinsight.springer.com/drugs/800040115.
- ↑ "JNJ-54175446". https://adisinsight.springer.com/drugs/800042709.
- ↑ "NSI 189". http://adisinsight.springer.com/drugs/800033776.
- ↑ "NV 5138". https://adisinsight.springer.com/drugs/800052663.
- ↑ "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Research 7: 659. 2018. doi:10.12688/f1000research.14344.1. PMID 29899972.
- ↑ "Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling". Neuropsychopharmacology 43: S195. November 2017. doi:10.1038/npp.2017.264. https://www.nature.com/articles/npp2017264.pdf.
- ↑ "TS 121". http://adisinsight.springer.com/drugs/800041804.
- ↑ "Xenon Pharmaceuticals". https://www.xenon-pharma.com/product-pipeline/xen1101/.
- ↑ "Tramadol controlled release - e-Therapeutics". http://adisinsight.springer.com/drugs/800030018.
- ↑ "Another depression drug flops as e-Therapeutics tallies PhIIb data - FierceBiotech". 15 February 2016. http://www.fiercebiotech.com/r-d/another-depression-drug-flops-as-e-therapeutics-tallies-phiib-data.
- ↑ "E-Therapeutics defends PhIIb fail, claiming drug has 'pretty much' the hoped-for profile - FierceBiotech". 17 February 2016. http://www.fiercebiotech.com/financials/e-therapeutics-defends-phiib-fail-claiming-drug-has-pretty-much-hoped-for-profile.
- ↑ "Cycloserine/lurasidone - NeuroRx". http://adisinsight.springer.com/drugs/800042772.
- ↑ "Deudextromethorphan". http://adisinsight.springer.com/drugs/800035704.
- ↑ "NMDAR inhibition-independent antidepressant actions of ketamine metabolites". Nature 533 (7604): 481–6. May 2016. doi:10.1038/nature17998. PMID 27144355. Bibcode: 2016Natur.533..481Z.
- ↑ "Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids". Journal of Ethnopharmacology 137 (3): 1124–1129. October 2011. doi:10.1016/j.jep.2011.07.035. PMID 21798331.
- ↑ "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology 177: 111–116. January 2016. doi:10.1016/j.jep.2015.11.034. PMID 26615766.
- ↑ "Efficacy and tolerability of minocycline for depression: A systematic review and meta-analysis of clinical trials". Journal of Affective Disorders 227: 219–225. February 2018. doi:10.1016/j.jad.2017.10.042. PMID 29102836.
- ↑ "Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications". Scientific Reports 7 (1): 1450. May 2017. doi:10.1038/s41598-017-01590-x. PMID 28469132. Bibcode: 2017NatSR...7.1450C.
- ↑ "Exploring Nitrous Oxide as Treatment of Mood Disorders: Basic Concepts". Journal of Clinical Psychopharmacology 38 (2): 144–148. April 2018. doi:10.1097/JCP.0000000000000837. PMID 29360650.
- ↑ "Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression". Drugs 77 (4): 381–401. March 2017. doi:10.1007/s40265-017-0702-8. PMID 28194724.
- ↑ "Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy". Frontiers in Psychiatry 6: 172. 2015. doi:10.3389/fpsyt.2015.00172. PMID 26696909.
- ↑ "The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America 115 (3): 578–583. January 2018. doi:10.1073/pnas.1718683115. PMID 29295929.
- ↑ "Small molecules activating TrkB receptor for treating a variety of CNS disorders". CNS & Neurological Disorders Drug Targets 12 (7): 1066–77. November 2013. doi:10.2174/18715273113129990089. PMID 23844685.
- ↑ "Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets". Current Neuropharmacology 14 (7): 721–31. 2016. doi:10.2174/1570159X14666160119094646. PMID 26786147.
- ↑ "7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders". Translational Neurodegeneration 5: 2. 2016. doi:10.1186/s40035-015-0048-7. PMID 26740873.
- ↑ "A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect". Journal of Medicinal Chemistry 53 (23): 8274–86. December 2010. doi:10.1021/jm101206p. PMID 21073191.
- ↑ "Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation". The International Journal of Neuropsychopharmacology 18 (4). October 2014. doi:10.1093/ijnp/pyu077. PMID 25628381.
- ↑ "Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression". Psychopharmacology 232 (23): 4325–35. December 2015. doi:10.1007/s00213-015-4062-3. PMID 26337614.
- ↑ "7,8-Dihydroxyflavone, a Tropomyosin-Kinase Related Receptor B Agonist, Produces Fast-Onset Antidepressant-Like Effects in Rats Exposed to Chronic Mild Stress". Psychiatry Investigation 13 (5): 531–540. September 2016. doi:10.4306/pi.2016.13.5.531. PMID 27757132.
- ↑ "7,8-Dihydroxyflavone reverses the depressive symptoms in mouse chronic mild stress". Neuroscience Letters 635: 33–38. December 2016. doi:10.1016/j.neulet.2016.10.035. PMID 27773794.
Further reading
- "Experimental medication treatment approaches for depression". Translational Psychiatry 7 (3): e1068. March 2017. doi:10.1038/tp.2017.33. PMID 28323287.
- "Investigational drugs in recent clinical trials for treatment-resistant depression". Expert Review of Neurotherapeutics 17 (6): 593–609. June 2017. doi:10.1080/14737175.2017.1283217. PMID 28092469.
- "Investigational drugs for treating major depressive disorder". Expert Opinion on Investigational Drugs 26 (1): 9–24. January 2017. doi:10.1080/13543784.2017.1267727. PMID 27960559.
External links
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