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.

Contents

Drugs that have been investigated but are not currently in development as antidepressants are given in italic.

Glutamatergics

NMDA receptor modulators

AMPA receptor modulators

Monoaminergics

Monoamine reuptake inhibitors

Monoamine reuptake inhibitors and receptor modulators

Monoamine releasing agents

Monoamine receptor modulators

Atypical antipsychotics

Others

GABAergics and neurosteroids

GABAA receptor positive modulators

Others

Opioidergics

κ-Opioid receptor antagonists

Nociceptin receptor antagonists

Cholinergics

Muscarinic acetylcholine receptor modulators

Others

Orexin receptor antagonists

Others

Mixed

Combinations

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:

See also

Related Research Articles

<span class="mw-page-title-main">Ketamine</span> Dissociative anesthetic and anti-depressant

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and pain management. It is a novel compound that was derived from phencyclidine in 1962 in pursuit of a safer anesthetic with fewer hallucinogenic effects.

<span class="mw-page-title-main">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for human and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<span class="mw-page-title-main">Esketamine</span> Medication

Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato, Ketanest, among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.

<span class="mw-page-title-main">Rapastinel</span> Chemical compound

Rapastinel is a novel antidepressant that was under development by Allergan as an adjunctive therapy for the treatment of treatment-resistant depression. It is a centrally active, intravenously administered amidated tetrapeptide that acts as a novel and selective modulator of the NMDA receptor. The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to enhance NMDA receptor-mediated signal transduction and synaptic plasticity.

<span class="mw-page-title-main">7-Chlorokynurenic acid</span> Chemical compound

7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.

<span class="mw-page-title-main">Rislenemdaz</span> Investigational antidepressant compound

Rislenemdaz is an orally active, selective NMDA receptor subunit 2B (NR2B) antagonist which is under development by Cerecor in the United States as an adjunctive therapy for treatment-resistant depression (TRD). In November 2013, phase II clinical trials were initiated, and in the same month, rislenemdaz received Fast Track Designation from the Food and Drug Administration for TRD.

<span class="mw-page-title-main">Tropoflavin</span> Chemical compound

Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF). Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier. A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13, is under development for the treatment of Alzheimer's disease.

<span class="mw-page-title-main">BTRX-246040</span> Nociceptin receptor antagonist

BTRX-246040, also known as LY-2940094, is a potent and selective nociceptin receptor antagonist which is under development by BlackThorn Therapeutics and Eli Lilly for the treatment of major depressive disorder (MDD). It has demonstrated proof-of-concept clinical efficacy for depression. As of 2017, it is in phase II clinical trials for the treatment of MDD. It was also under investigation for the treatment of alcoholism, and similarly reached phase II clinical studies for this indication, but development was discontinued.

<span class="mw-page-title-main">Arketamine</span> Chemical compound

Arketamine (developmental code names PCN-101, HR-071603), also known as (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the S(+) enantiomer of ketamine, arketamine is biologically active; however, it is less potent as an NMDA receptor antagonist and anesthetic and thus has never been approved or marketed for clinical use as an enantiopure drug. Arketamine is currently in clinical development as a novel antidepressant.

<span class="mw-page-title-main">4-Chlorokynurenine</span> Investigational antidepressant compound

L-4-Chlorokynurenine is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist. It was investigated as a potential rapid-acting antidepressant.

<span class="mw-page-title-main">Dextromethorphan/bupropion</span> Combination medication

Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). Its active components are dextromethorphan (DXM) and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.

<span class="mw-page-title-main">Navacaprant</span> Investigational antidepressant compound

Navacaprant, is an opioid antagonist medication which is under development for the treatment of depression. It is specifically a selective κ-opioid receptor antagonist and is under development for major depressive disorder. As of December 2023, NMRA-335140 is in phase 3 clinical trials for this indication.

<span class="mw-page-title-main">Willardiine</span> Chemical compound

Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.

<span class="mw-page-title-main">JNJ-18038683</span> Chemical compound

JNJ-18038683 is a potent and selective antagonist of the 5HT7 serotonin receptor discovered by Johnson & Johnson. It has nootropic and antidepressant effects in both animal and human studies and has progressed to Phase II trials as an adjunctive treatment for improving cognition and mood in stable bipolar disorder; it has been found to reduce REM sleep (the lightest stage of sleep, elevated in depression) in humans and block circadian rhythm phase-shift advances in mice.

References

  1. ↑ "AV 101". adisinsight.springer.com. Retrieved 7 May 2017.
  2. ↑ "Apimostinel". adisinsight.springer.com. Retrieved 7 May 2017.
  3. 1 2 Hashimoto K (October 2019). "Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective". Psychiatry and Clinical Neurosciences. 73 (10): 613–627. doi:10.1111/pcn.12902. PMC   6851782 . PMID   31215725.
  4. ↑ "Arketamine - Jiangsu Hengrui Medicine - AdisInsight".
  5. ↑ "Dextromethadone - Relmada Therapeutics". adisinsight.springer.com. Retrieved 10 November 2018.
  6. ↑ "Ketamine intranasal - Vyera Pharmaceuticals". adisinsight.springer.com. Archived from the original on 24 September 2017. Retrieved 7 May 2017.
  7. ↑ "CERC 301". adisinsight.springer.com. Retrieved 7 May 2017.
  8. ↑ Burgdorf JS, Zhang XL, Stanton PK, Moskal JR, Donello JE (December 2022). "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. doi:10.1093/ijnp/pyac043. PMC   9743962 . PMID   35882204.
  9. ↑ "Gate Neurosciences Hones in on Precision Medicine with Expanded Research Operations Supporting Its Synaptic Function-Enhancing Molecules" (PDF). Gate Neurosciences, Inc. 3 May 2023. Retrieved 26 May 2023.
  10. ↑ "PDC-1421". adisinsight.springer.com. Retrieved 24 March 2018.
  11. ↑ "FKB 01MD". adisinsight.springer.com. Retrieved 7 May 2017.
  12. ↑ "SEP 4199 - AdisInsight".
  13. ↑ Hopkins SC, Wilkinson S, Corriveau TJ, Nishikawa H, Nakamichi K, Loebel A, Koblan KS (May 2021). "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. doi: 10.1002/cpt.2282 . PMC   8453756 . PMID   33961287.
  14. ↑ "Pramipexole - Chase Therapeutics - AdisInsight". adisinsight.springer.com. Retrieved 2020-01-25.
  15. ↑ "Product Discovery and Development". Chase Therapeutics. Retrieved 2020-01-25.
  16. ↑ "Psilocybin". adisinsight.springer.com. Retrieved 26 October 2018.
  17. ↑ "RP 5063". adisinsight.springer.com. Retrieved 7 May 2017.
  18. ↑ "Lumateperone". adisinsight.springer.com. Retrieved 7 May 2017.
  19. ↑ "Pimavanserin". adisinsight.springer.com. Retrieved 25 September 2017.
  20. ↑ "Ademetionine". adisinsight.springer.com. Retrieved 7 May 2017.
  21. ↑ "SAGE 217". adisinsight.springer.com. Retrieved 9 February 2018.
  22. ↑ "Pregnenolone methyl ether". adisinsight.springer.com. Retrieved 7 May 2017.
  23. ↑ "PH 10 nasal spray". adisinsight.springer.com. Retrieved 7 May 2017.
  24. ↑ "Aticaprant (JNJ-67953964, CERC-501, LY-2456302) - AdisInsight". adisinsight.springer.com. Retrieved 2022-08-29.
  25. ↑ "Buprenorphine/samidorphan". adisinsight.springer.com. Retrieved 7 May 2017.
  26. ↑ "CVL-354". adisinsight.springer.com. Retrieved 2 February 2023.
  27. ↑ "BTRX 335140 - AdisInsight". adisinsight.springer.com. Retrieved 2020-01-25.
  28. ↑ "BlackThorn Therapeutics Advances Phase 2 Clinical Development for Selective KOR Antagonist, BTRX-140, in Neuropsychiatric Disorders". BlackThorn Therapeutics. Archived from the original on 2020-01-25. Retrieved 2020-01-25.
  29. ↑ "BTRX-246040". adisinsight.springer.com. Retrieved 24 March 2018.
  30. ↑ "Botulinum toxin A injectable - Allergan". adisinsight.springer.com. Retrieved 7 May 2017.
  31. ↑ "JNJ 61393215 - AdisInsight". adisinsight.springer.com. Retrieved 2020-01-25.
  32. ↑ "A Study of JNJ-61393215 in the Treatment of Depression - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-01-25.
  33. ↑ "JNJ 42847922". adisinsight.springer.com. Retrieved 7 May 2017.
  34. ↑ "JNJ-54175446". adisinsight.springer.com. Retrieved 24 March 2018.
  35. ↑ "NSI 189". adisinsight.springer.com. Retrieved 7 May 2017.
  36. ↑ "NV 5138". adisinsight.springer.com. Retrieved 7 November 2018.
  37. ↑ Duman RS (2018). "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Research. 7: 659. doi: 10.12688/f1000research.14344.1 . PMC   5968361 . PMID   29899972.
  38. ↑ Duman R, Kato T, Liu RJ, Duman C, Terwilliger R, Vlasuk G, Hahm S, Sajah E (November 2017). "Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling" (PDF). Neuropsychopharmacology. 43: S195. doi: 10.1038/npp.2017.264 .
  39. ↑ "TS 121". adisinsight.springer.com. Retrieved 7 May 2017.
  40. ↑ "Xenon Pharmaceuticals".
  41. ↑ Costi S, Han MH, Murrough JW (March 2022). "The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants". CNS Drugs . 36 (3): 207–216. doi:10.1007/s40263-021-00885-y. PMID   35258812. S2CID   247294637.
  42. ↑ Sakurai H, Yonezawa K, Tani H, Mimura M, Bauer M, Uchida H (July 2022). "Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry". Pharmacopsychiatry. 55 (4): 193–202. doi:10.1055/a-1714-9097. PMC   9259184 . PMID   35045580.
  43. ↑ "Tramadol controlled release - e-Therapeutics". adisinsight.springer.com. Retrieved 7 May 2017.
  44. ↑ "Another depression drug flops as e-Therapeutics tallies PhIIb data - FierceBiotech". www.fiercebiotech.com. 15 February 2016. Retrieved 28 August 2018.
  45. ↑ "E-Therapeutics defends PhIIb fail, claiming drug has 'pretty much' the hoped-for profile - FierceBiotech". www.fiercebiotech.com. 17 February 2016. Retrieved 28 August 2018.
  46. ↑ "Cycloserine/lurasidone - NeuroRx". adisinsight.springer.com. Retrieved 7 May 2017.
  47. ↑ "Deudextromethorphan". adisinsight.springer.com. Retrieved 7 May 2017.
  48. ↑ Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. (May 2016). "NMDAR inhibition-independent antidepressant actions of ketamine metabolites". Nature. 533 (7604): 481–6. Bibcode:2016Natur.533..481Z. doi:10.1038/nature17998. PMC   4922311 . PMID   27144355.
  49. ↑ Harvey AL, Young LC, Viljoen AM, Gericke NP (October 2011). "Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids". Journal of Ethnopharmacology. 137 (3): 1124–1129. doi:10.1016/j.jep.2011.07.035. PMID   21798331.
  50. ↑ Coetzee DD, López V, Smith C (January 2016). "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology. 177: 111–116. doi:10.1016/j.jep.2015.11.034. PMID   26615766.
  51. ↑ Rosenblat JD, McIntyre RS (February 2018). "Efficacy and tolerability of minocycline for depression: A systematic review and meta-analysis of clinical trials". Journal of Affective Disorders. 227: 219–225. doi:10.1016/j.jad.2017.10.042. PMID   29102836.
  52. ↑ Cohen IV, Makunts T, Atayee R, Abagyan R (May 2017). "Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications". Scientific Reports. 7 (1): 1450. Bibcode:2017NatSR...7.1450C. doi:10.1038/s41598-017-01590-x. PMC   5431207 . PMID   28469132.
  53. ↑ Nagele P, Zorumski CF, Conway C (April 2018). "Exploring Nitrous Oxide as Treatment of Mood Disorders: Basic Concepts". Journal of Clinical Psychopharmacology. 38 (2): 144–148. doi:10.1097/JCP.0000000000000837. PMC   5825282 . PMID   29360650.
  54. ↑ Lener MS, Kadriu B, Zarate CA (March 2017). "Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression". Drugs. 77 (4): 381–401. doi:10.1007/s40265-017-0702-8. PMC   5342919 . PMID   28194724.
  55. ↑ Zorumski CF, Nagele P, Mennerick S, Conway CR (2015). "Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy". Frontiers in Psychiatry. 6: 172. doi: 10.3389/fpsyt.2015.00172 . PMC   4673867 . PMID   26696909.
  56. ↑ Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, Ye K (January 2018). "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. Bibcode:2018PNAS..115..578C. doi: 10.1073/pnas.1718683115 . PMC   5777001 . PMID   29295929.
  57. ↑ Zeng Y, Wang X, Wang Q, Liu S, Hu X, McClintock SM (November 2013). "Small molecules activating TrkB receptor for treating a variety of CNS disorders". CNS & Neurological Disorders Drug Targets. 12 (7): 1066–77. doi:10.2174/18715273113129990089. PMID   23844685.
  58. ↑ Zhang JC, Yao W, Hashimoto K (2016). "Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets". Current Neuropharmacology. 14 (7): 721–31. doi:10.2174/1570159X14666160119094646. PMC   5050398 . PMID   26786147.
  59. ↑ Liu C, Chan CB, Ye K (2016). "7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders". Translational Neurodegeneration. 5: 2. doi: 10.1186/s40035-015-0048-7 . PMC   4702337 . PMID   26740873.
  60. ↑ Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K (December 2010). "A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect". Journal of Medicinal Chemistry. 53 (23): 8274–86. doi:10.1021/jm101206p. PMC   3150605 . PMID   21073191.
  61. ↑ Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, Li SX, Shirayama Y, Hashimoto K (October 2014). "Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation". The International Journal of Neuropsychopharmacology. 18 (4). doi:10.1093/ijnp/pyu077. PMC   4360225 . PMID   25628381.
  62. ↑ Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, Han M, Hashimoto K (December 2015). "Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression". Psychopharmacology. 232 (23): 4325–35. doi:10.1007/s00213-015-4062-3. PMID   26337614. S2CID   15076700.
  63. ↑ Chang HA, Wang YH, Tung CS, Yeh CB, Liu YP (September 2016). "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. doi:10.4306/pi.2016.13.5.531. PMC   5067348 . PMID   27757132.
  64. ↑ Zhang MW, Zhang SF, Li ZH, Han F (December 2016). "7,8-Dihydroxyflavone reverses the depressive symptoms in mouse chronic mild stress". Neuroscience Letters. 635: 33–38. doi:10.1016/j.neulet.2016.10.035. PMID   27773794. S2CID   157620.

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