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, dysthymia, 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 It is likely to become outdated with time.
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. [...]
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]
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.
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.
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).
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.
[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.]
Centpropazine, possessing the 1-aryloxy-3-(piperazin-1-yl)propan-2-ol scaffold is an antidepressant, only marketed in India, and has never been clinically approved likely due to its low bioavailability (Figure 2).10 To the best of our knowledge, the exact modes of action of centpropazine are unclear. The fact that centpropazine possesses antidepressant effects is remarkable. Although its efficacy in treating depressive symptoms has been previously investigated,11-13 its pharmacological studies of the specific monoamines affected have not been reported.
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
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
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].
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: [3H]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)
The close structural analog of DETQ, LY3154207, is currently in phase 2 testing for Lewy Body dementias, including patients with Parkinson's disease.