List of investigational antidepressants explained

This is a list of investigational antidepressants, or drugs that are currently under development for clinical use in the treatment of depression but are not yet approved. Specific indications include major depressive disorder, treatment-resistant depression, bipolar depression, and postpartum depression, among others.

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

This list was last comprehensively updated in August 2024. It is likely to become outdated with time.

Under development

Preregistration

Phase 3

Phase 2/3

Phase 2

Phase 1/2

Phase 1

Preclinical

Research

Phase unknown

Not under development

Development suspended

No development reported

Development discontinued

Preregistration submission withdrawal

Formal development never or not yet started

Clinically used drugs

See main article: List of antidepressants.

Approved drugs

See also

Further reading

External links

Notes and References

  1. Web site: Taylor . Nick Paul . FDA rejects Alkermes' depression drug ALKS 5461 . Fierce Biotech . 4 February 2019 . 8 August 2024.
  2. Abad VC, Guilleminault C . Solriamfetol for the treatment of daytime sleepiness in obstructive sleep apnea . Expert Rev Respir Med . 12 . 12 . 1007–1019 . December 2018 . 30365900 . 10.1080/17476348.2018.1541742 . Solriamfetol hydrochloride, previously known as JZP-110, SKLN05, ARL-N05, YKP-10A, R-228060, ADX-N05, was initially developed by the SK Group as YKP-10A, a drug to treat depression. SK Group licensed rights outside of 11 countries in Asia to Aerial BioPharma in 2011. [...].
  3. Grimm S, Keicher C, Paret C, Niedtfeld I, Beckmann C, Mennes M, Just S, Sharma V, Fuertig R, Herich L, Mack S, Thamer C, Schultheis C, Weigand A, Schmahl C, Wunder A . The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder . Eur Neuropsychopharmacol . 65 . 44–51 . December 2022 . 36343427 . 10.1016/j.euroneuro.2022.10.009 .
  4. Klein AK, Austin EW, Cunningham MJ, Dvorak D, Gatti S, Hulls SK, Kiss L, Kruegel AC, Marek GJ, Papp M, Sporn J, Hughes ZA . GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents . Neuropsychopharmacology . 49 . 6 . 905–914 . May 2024 . 38177696 . 11039472 . 10.1038/s41386-023-01783-1 .
  5. Canal CE, Morgan D . Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model . Drug Test Anal . 4 . 7–8 . 556–576 . 2012 . 22517680 . 3722587 . 10.1002/dta.1333 . Regardless, a more parsimonious explanation is that certain 5-HT2 receptor-activating compounds, such as DOI and psilocin, cause specific conformations of 5-HT2 receptors that lead to LSD-like psychedelic effects.[94,232] Moreover, although the 5-HT2 agonists mCPP, lorcaserin, and quipazine, are often considered 'non-hallucinogenic', they actually do produce perceptual, cognitive, and emotional changes that may be considered 'hallucinogenic'.[15,233,234] These effects, however, are generally not considered LSD-like. Finally, it is noteworthy that novel, partial 5-HT2A/D2 receptor agonists also attenuate the DOI-elicited HTR.[235,236].
  6. Mirchandani-Duque M, Choucri M, Hernández-Mondragón JC, Crespo-Ramírez M, Pérez-Olives C, Ferraro L, Franco R, Pérez de la Mora M, Fuxe K, Borroto-Escuela DO . Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor-Receptor Interactions . Membranes (Basel) . 14 . 5 . April 2024 . 96 . 38786931 . 11122807 . 10.3390/membranes14050096 . free . This concept is also supported by experiments on OSU-6162, a selective Sigma 1R ligand in low doses [176]. This Sigma1R ligand produced in the nucleus accumbens shell substantial increases in the density of the D2R–Sigma1R and A2AR–D2R heterocomplexes, supporting the existence of A2AR–D2R–Sigma1R trimeric complexes in which the Sigma1R agonist can strongly enhance the antagonistic allosteric A2AR–D2R interaction. This mechanism may mediate the enhanced antagonistic A2AR–D2R interaction, causing marked inhibition of cocaine reward, leading to cocaine addiction..
  7. Carlsson ML, Burstein ES, Kloberg A, Hansson S, Schedwin A, Nilsson M, Rung JP, Carlsson A . I. In vivo evidence for partial agonist effects of (-)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors . J Neural Transm (Vienna) . 118 . 11 . 1511–1522 . November 2011 . 21874578 . 10.1007/s00702-011-0704-8 .
  8. Burstein ES, Carlsson ML, Owens M, Ma JN, Schiffer HH, Carlsson A, Hacksell U . II. In vitro evidence that (-)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors . J Neural Transm (Vienna) . 118 . 11 . 1523–1533 . November 2011 . 21866391 . 10.1007/s00702-011-0701-y .
  9. Sahlholm K, Århem P, Fuxe K, Marcellino D . The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-1 receptor . Mol Psychiatry . 18 . 1 . 12–14 . January 2013 . 22349783 . 10.1038/mp.2012.3 .
  10. Borroto-Escuela DO, Romero-Fernandez W, Wydra K, Zhou Z, Suder A, Filip M, Fuxe K . OSU-6162, a Sigma1R Ligand in Low Doses, Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes . Neurotox Res . 37 . 2 . 433–444 . February 2020 . 31782100 . 6989596 . 10.1007/s12640-019-00134-7 .
  11. Wang . Kean . Chen . Feiyang . Wang . Jiang . Liu . Hong . Drug discovery targeting thyroid hormone receptor β (THRβ) for the treatment of liver diseases and other medical indications . Acta Pharmaceutica Sinica B . 2024 . 10.1016/j.apsb.2024.07.025 . free .
  12. Web site: ALTO-300 . Carilion Clinic . 2024-08-09 . ALTO-300 is a 25 mg formulation of the atypical antidepressant agomelatine, which targets the melatonin and serotonin signaling systems and has been shown to modulate mood and circadian rhythms. This medication is approved for the treatment of depression in several countries outside of the United States..
  13. Carlini SV, Osborne LM, Deligiannidis KM . Current pharmacotherapy approaches and novel GABAergic antidepressant development in postpartum depression . Dialogues Clin Neurosci . 25 . 1 . 92–100 . December 2023 . 37796239 . 10557560 . 10.1080/19585969.2023.2262464 . BRII-296 is an extended-release injectable aqueous suspension formulation of brexanolone. Phase 1 trials in 116 subjects testing 6 dose regimens are complete with the sponsor reporting that a single intramuscular injection of 600 mg achieved dose linearity, early drug absorption, and gradual and extended-release profiles without the need for dose titration or tapering, however results have not been published (Brii Biosciences Limited 2023b)..
  14. Web site: Viage Therapeutics . Viage Therapeutics . 20 July 2023 . 9 August 2024 . DGX-001, Viage's clinical drug candidate, represents a first-in-class oral drug candidate targeting the gut-brain axis. The proposed mechanism of action of DGX-001 is to modulate the vagus nerve through specific receptor interactions on enteroendocrine cells in the gut, resulting in a regulation of brain cell activity..
  15. M Ro Rsted E, Jensen AA, Smits G, Frydenvang K, Kristensen JL . Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists . J Med Chem . 67 . 9 . 7224–7244 . May 2024 . 38648420 . 11089506 . 10.1021/acs.jmedchem.4c00082 .
  16. Web site: Lipocine Inc. . Lipocine Announces LPCN 1154 Meets Bioequivalence with IV Brexanolone in Pivotal Study . PR Newswire . 25 June 2024 . 9 August 2024.
  17. Web site: 20241Q.pdf . May 2024 . 8 August 2024.
  18. Web site: 8741810.PDF . 7 August 2024 . [SK2110 - Buprenorphine implant for the treatment of major depressive disorder SK2110 is an implant of buprenorphine hydrochloride for patients with major depression and refractory depression who cannot be relieved by taking at least two drugs. Buprenorphine hydrochloride was developed by Indivior and is a KOR1 antagonist and MOR1 agonist. Currently, the highest development stage of the drug is approval for marketing, which is used to treat opioid dependence, chronic pain, pain and substance-related disorders. The company changes the route of administration to prepare an implant, which can reduce the frequency of administration, improve the bioavailability of the drug, improve patient compliance, and maintain a stable blood drug concentration, thereby reducing adverse drug reactions. At the same time, the implanted administration method can also play a role in avoiding drug abuse. At present, the project is conducting laboratory preparation small-scale trial prescription process exploration and preliminary pharmacodynamic studies. SK2110 can take effect quickly and quickly relieve patients' depressive symptoms. It is expected to submit an IND application to my country's drug regulatory authorities in 2024.].
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  20. Hwi KK, Lay WB . Pharmacological, electrophysiological and toxicity studies of Limacia scanden Lour. (Menispermaceae) . J Ethnopharmacol . 62 . 2 . 137–148 . September 1998 . 9741886 . 10.1016/s0378-8741(98)00045-2 .
  21. Web site: Delving into the Latest Updates on Mitizodone Phosphate with Synapse . Synapse . 2 August 2024 . 15 August 2024.
  22. Rupniak NM, Kramer MS . NK1 receptor antagonists for depression: Why a validated concept was abandoned . J Affect Disord . 223 . 121–125 . December 2017 . 28753469 . 10.1016/j.jad.2017.07.042 .
  23. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, Hargreaves R, Hietala J, Lines C, Beebe K, Reines S . Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder . Biol Psychiatry . 59 . 3 . 216–223 . February 2006 . 16248986 . 10.1016/j.biopsych.2005.07.013 .
  24. Web site: Aprepitant Completed Phase 3 Trials for Major Depressive Disorder (MDD) Treatment . DrugBank Online . 9 August 2024.
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  26. Kost GC, Selvaraj S, Lee YB, Kim DJ, Ahn CH, Singh BB . Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking . Neurosci Lett . 504 . 2 . 170–175 . October 2011 . 21964384 . 3195833 . 10.1016/j.neulet.2011.09.032 .
  27. Schifano F, Catalani V, Sharif S, Napoletano F, Corkery JM, Arillotta D, Fergus S, Vento A, Guirguis A . Benefits and Harms of 'Smart Drugs' (Nootropics) in Healthy Individuals . Drugs . 82 . 6 . 633–647 . April 2022 . 35366192 . 10.1007/s40265-022-01701-7 .
  28. Zarate CA, Machado-Vieira R . Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders . Mol Psychiatry . 22 . 3 . 324–327 . March 2017 . 28070122 . 5641407 . 10.1038/mp.2016.249 . Because AMPA appeared critical to ketamine's antidepressant effects, researchers reasoned that AMPA positive modulators—also known as AMPAkines—could positively influence mood. Previous studies evaluating AMPAkines in mood disorders achieved mixed results, potentially due to low bioavailability and toxicity profile.20 To overcome the issue of low bioavailability, other AMPAkines were recently developed and tested in initial Phase 1 and 2 studies, particularly coluracetam (BCI-540)21 and ORG-26576.22 Both agents showed preliminary therapeutic effects in major depressive disorder when tested in small samples.23,24.
  29. Borbély É, Simon M, Fuchs E, Wiborg O, Czéh B, Helyes Z . Novel drug developmental strategies for treatment-resistant depression . Br J Pharmacol . 179 . 6 . 1146–1186 . March 2022 . 34822719 . 9303797 . 10.1111/bph.15753 .
  30. Dale E, Pehrson AL, Jeyarajah T, Li Y, Leiser SC, Smagin G, Olsen CK, Sanchez C . Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function . CNS Spectr . 21 . 2 . 143–161 . April 2016 . 26346726 . 4825106 . 10.1017/S1092852915000425 . The 5-HT1B/1D receptor antagonist elzasonan (CP-448187) was recently under development for the treatment of MDD and was tested in several phase-2 clinical trials, but its development program was also discontinued.140.
  31. Connolly JJ, Glessner JT, Elia J, Hakonarson H . ADHD & Pharmacotherapy: Past, Present and Future: A Review of the Changing Landscape of Drug Therapy for Attention Deficit Hyperactivity Disorder . Ther Innov Regul Sci . 49 . 5 . 632–642 . September 2015 . 26366330 . 4564067 . 10.1177/2168479015599811 .
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  36. Yoshii . Mitsunobu . Watabe . Shigeo . Murashima . Yoshiya L. . Nukada . Toshihide . Shiotani . Tadashi . Nishizaki . Tomoyuki . Neuronal Ca 2+ Channels and Nicotinic ACh Receptors as Functional Targets of the Nootropic Nefiracetam . Psychogeriatrics . 1 . 1 . 2001 . 1346-3500 . 10.1111/j.1479-8301.2001.tb00071.x . 39–49.
  37. Gualtieri F, Manetti D, Romanelli MN, Ghelardini C . Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs . Curr Pharm Des . 8 . 2 . 125–38 . 2002 . 11812254 . 10.2174/1381612023396582 . In general, piracetam-like nootropics show no affinity for the most important central receptors (Ki > 10 μM). A modest affinity for muscarinic receptors is shown by aniracetam (Ki = 4.4 μM [58]) and nebracetam (Ki = 6.3 μM [61]). Nefiracetam is the only one showing affinity in the nanomolar range (Ki = 8.5 nM on the GABAA receptor [58]). [...] Nefiracetam (chart (1)) is awaiting approval. It presents a variety of pharmacological actions as it is reported to activate the cholinergic, GABAergic and other monaminergic systems and to modulate N-type calcium channels [78-81]..
  38. Gouliaev AH, Senning A . Piracetam and other structurally related nootropics . Brain Res Brain Res Rev . 19 . 2 . 180–222 . May 1994 . 8061686 . 10.1016/0165-0173(94)90011-6 . As mentioned above, no commonly accepted mechanism for the racetam nootropics has yet been established, They do not seem to act on any well characterised receptor site with the exception of nefiracetam which has high affinity for GABA, receptors (see Table 1). [...] Receptor: GABAA. Receptor ligand: [<sup>3</sup>H]muscimolA. Compound: nefiracetam. IC50: 8.5 nMB. Refs.: 222. [...] From Table 1 it is, however, evident that the piracetam-like nootropics do not exhibit high affinity for any of the receptor types tested so far (except for nefiracetam, which shows some activity at GABAA receptors).
  39. Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M . Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies . J Psychopharmacol . 27 . 5 . 424–434 . May 2013 . 23539641 . 10.1177/0269881113480990 .
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  41. Namiot ED, Smirnovová D, Sokolov AV, Chubarev VN, Tarasov VV, Schiöth HB . Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov . Transl Psychiatry . 14 . 1 . 315 . July 2024 . 39085220 . 11291508 . 10.1038/s41398-024-03031-6 .
  42. Book: Svensson KA, Hao J, Bruns RF . Neuropsychotherapeutics . Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders . Adv Pharmacol . 86 . 273–305 . 2019 . 31378255 . 10.1016/bs.apha.2019.06.001 . 978-0-12-816668-0 . The close structural analog of DETQ, LY3154207, is currently in phase 2 testing for Lewy Body dementias, including patients with Parkinson's disease..
  43. Web site: 인하대병원 임상시험센터 . 인하대병원 . 15 April 2019 . ko . 8 August 2024 .
  44. Web site: [환인제약] [정정]분기보고서(일반법인) ]. 대한민국 대표 기업공시채널 KIND . ko . 8 August 2024.
  45. Yáñez M, Padín JF, Arranz-Tagarro JA, Camiña M, Laguna R . History and therapeutic use of MAO-A inhibitors: a historical perspective of MAO-A inhibitors as antidepressant drug . Curr Top Med Chem . 12 . 20 . 2275–2282 . 2012 . 23231399 . 10.2174/156802612805220011 .
  46. Sharma H, Santra S, Dutta A . Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? . Future Med Chem . 7 . 17 . 2385–406 . 2015 . 26619226 . 4976848 . 10.4155/fmc.15.134 .

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