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.
Levomilnacipran is an antidepressant which was approved in the United States in 2013 for the treatment of major depressive disorder (MDD) in adults. It is the levorotatory enantiomer of milnacipran, and has similar effects and pharmacology, acting as a serotonin–norepinephrine reuptake inhibitor (SNRI).
Brexpiprazole, sold under the brand name Rexulti among others, is a medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease. It is an atypical antipsychotic.
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.
Buprenorphine/samidorphan is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD).
Apimostinel is an investigational antidepressant, acting as a novel and selective modulator of the NMDA receptor. It is currently under development for the acute treatment of major depressive disorder (MDD) by Gate Neurosciences, and previously by Naurex and Allergan. As of February 2015, an intravenous formulation of apimostinel has completed a phase IIa clinical trial for MDD.
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.
Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 receptor (2-SORA). The medication is taken by mouth. As of February 2022, seltorexant is in phase 3 clinical trials for treatment of major depressive disorder (MDD) and phase 2 trials for treatment of insomnia. It was also under investigation for the treatment of sleep apnea, but no recent development has been reported for this indication. Seltorexant is under development by Minerva Neurosciences and Johnson & Johnson's Janssen Pharmaceuticals.
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.
MIN-117 is an investigational antidepressant which is under development by Minerva Neurosciences for the clinical treatment of major depressive disorder (MDD). It is described as a 5-HT1A and 5-HT2A receptor antagonist and inhibitor of serotonin and dopamine reuptake, and is also reported to possess affinity for the α1A- and α1B-adrenergic receptors. As of May 2015, MIN-117 is in phase II clinical trials for MDD. In December 2019, Minerva announced that MIN-117 was no longer in clinical development for MDD after disappointing results in a phase IIb trial.
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.
Aripiprazole/sertraline is a combination formulation of aripiprazole (Abilify), an atypical antipsychotic, and sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), which was under development by Otsuka Pharmaceutical for the treatment of major depressive disorder (MDD). It combines serotonin reuptake inhibition from sertraline and modulation of dopamine and serotonin receptors from aripiprazole. In July 2017, it was in preregistration in Japan for the treatment of MDD. However, in September 2018, the regulatory submission in Japan for MDD was withdrawn.
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.
TS-121 (THY1773) is an orally active, selective vasopressin V1B receptor antagonist which is under development by Taisho Pharmaceutical for the adjunctive treatment of major depressive disorder. As of May 2017, it is in phase II clinical trials for this indication.
Tulrampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals and Servier for the treatment of major depressive disorder, Alzheimer's disease, dementia, and mild cognitive impairment. Tulrampator was in phase II clinical trial for depression, but failed to show superiority over placebo. There are also phase II clinical trials for Alzheimer's disease and phase I trials for dementia and mild cognitive impairment.
Zuranolone, sold under the brand name Zurzuvae, is a medication used for the treatment of postpartum depression. It is taken by mouth.
JNJ-39393406 is an experimental medication which is under development by Janssen Pharmaceutica, a division of Johnson & Johnson, for the treatment of depressive disorders and smoking withdrawal. It acts as a selective positive allosteric modulator of the α7 nicotinic acetylcholine receptor (nAChR). It does not act on the α4β2 or α3β4 nAChRs or the serotonin 5-HT3 receptor, and does not interact with a panel of 62 other receptors and enzymes. The drug has been found to lower the agonist and nicotine threshold for activation of the α7 nAChR by 10- to 20-fold and to increase the maximum agonist response of the α7 nAChR by 17- to 20-fold.
EVT-101, also known as ENS-101, is an experimental medication which originated from Roche and is under development by Evotec AG for the treatment of major depressive disorder. It acts as a selective NMDA receptor subunit 2B (NR2B) antagonist. The drug was first claimed by Roche in 2002. By 2017, EVT-101 was in phase II clinical trials for major depressive disorder; however, development of the drug was discontinued in 2021.
NV-5138 is an orally and centrally active small-molecule drug which is under development by Navitor Pharmaceuticals for the treatment of major depressive disorder (MDD). It directly and selectively activates the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway by binding to and modulating sestrin2, a leucine amino acid sensor and upstream regulatory pathway. The mTORC1 pathway is the same signaling pathway that the NMDA receptor antagonist ketamine activates in the medial prefrontal cortex (mPFC) to mediate its rapid-acting antidepressant effects. A single oral dose of NV-5138 has been found to increase mTORC1 signaling and produce synaptogenesis in the mPFC and to induce rapid antidepressant effects in multiple animal models of depression. Like those of ketamine, these actions require the signaling of brain-derived neurotrophic factor (BDNF). The antidepressant effects following a single dose of NV-5138 are long-lasting, with a duration of up to 7 days, and are similar to those of ketamine. Based on these promising preclinical findings, efforts are underway to assess NV-5138 in clinical trials with human subjects. By November 2019, NV-5138 had completed three phase I studies for the treatment of MDD. In these studies, preliminary evidence of efficacy, tolerability, safety, and pharmacokinetics was observed, and as of 2021 it was into Phase II trials.
