The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
Tianeptine, sold under the brand names Stablon, Tatinol, and Coaxil among others, is an atypical tricyclic antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel syndrome.
Esketamine, sold under the brand names Spravato and Ketanest among others, 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. 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).
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.
ALTO-100, previously known as NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.
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.
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.
Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of late 2019, (2R,6R)-HNK is in clinical trials for the treatment of depression.
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.
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.
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.
A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). They are closely related and similar to GABAA receptor antagonists. The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.
Lisa M. Monteggia is an American neuroscientist who is a Professor in the Department of Pharmacology, Psychiatry & Psychology as well as the Barlow Family Director of the Vanderbilt Brain Institute at Vanderbilt University in Nashville, Tennessee. Monteggia probes the molecular mechanisms underlying psychiatric disorders and has made critical discoveries about the role of the neurotrophins in antidepressant efficacy, the antidepressant mechanisms of Ketamine, as well as the epigenetic regulation of synaptic transmission by MeCP2.
