decoglurant (RG1578) / Roche - LARVOL DELTA

mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development. (PubMed, Eur Arch Psychiatry Clin Neurosci) - "Triggered by the ground-breaking finding that ketamine exerts robust and rapid-acting antidepressant effects in patients with treatment-resistant depression, glutamatergic systems have attracted attention as targets for the development of novel antidepressants. Despite some discouraging results for an mGlu2/3 receptor antagonist decoglurant (classified as a negative allosteric modulator [NAM]) in patients with major depressive disorder, clinical trials of two mGlu2/3 receptor antagonists, a phase 2 trial of TS-161 (an orthosteric antagonist) and a phase 1 trial of DSP-3456 (a NAM), are presently on-going. mGlu2/3 receptors still hold promise for the development of safer and more efficacious antidepressants."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Ketamine and Other Glutamate Receptor Modulating Agents for Treatment-Resistant Depression: A Systematic Review of Randomized Controlled Trials. (PubMed, Iran J Psychiatry) - "Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK-0657); the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo...Nevertheless, ketamine could be used as an efficacious drug in TRD; still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Clinical investigations of compounds targeting metabotropic glutamate receptors. (PubMed, Pharmacol Biochem Behav) - "PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059...Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression...The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders."

Journal • CNS Disorders • Depression • Developmental Disorders • Epilepsy • Fragile X Syndrome • Gastroenterology • Gastroesophageal Reflux Disease • Genetic Disorders • Mental Retardation • Mood Disorders • Movement Disorders • Pain • Parkinson's Disease • Psychiatry • Schizophrenia

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. (PubMed, Cochrane Database Syst Rev) - "Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy."

Clinical • Journal • Review • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (PubMed, CNS Drugs) - "This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1..."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Gastrointestinal Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry

Negative allosteric modulators of group II metabotropic glutamate receptors: A patent review (2015 ‒ present). (PubMed, Expert Opin Ther Pat) - "Several small molecules that act as negative allosteric modulators (NAMs) on these receptors have demonstrated efficacy and/or target engagement in animal models, and one molecule (decoglurant) has been advanced into clinical trials...The process of elucidating the precise role of each receptor in the diseases associated with group II receptors has begun. Continued studies in animals with selective NAMs for both receptors will be critical in the coming years to inform researchers on the right compound profile and patient population for clinical development."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Developmental Disorders • Mood Disorders • Psychiatry

Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder. (PubMed, J Clin Psychiatry) - P2 | "Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects."

Clinical • Journal • CNS Disorders • Depression • Mood Disorders

In vitro and in vivo characterization of group II mGlu receptor negative allosteric modulators as an alternative to ketamine for depression (Neuroscience 2019) - "The noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine produces rapid antidepressant effects in patients with major depressive disorder (MDD), which has led to the recent FDA approval of intranasal (S)-ketamine (Spravato, Esketamine) for the treatment of patients with treatment-resistant depression (TRD) in conjunction with an oral anti-depressant. Thus, decoglurant failed to produce ketamine-like pharmacokinetic, neurophysiological and behavioral effects in rats, which may partly explain its lack of efficacy in depression. Moreover, our results suggest that targeting mGlu2/3 holds promise for the development of effective, fast-acting antidepressant treatments."

Preclinical

A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. (PubMed, Drug Discov Today) - "Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217."

Journal • Review

Glutamatergic Modulators in Depression. (PubMed, Harv Rev Psychiatry) - "These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578])."

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