rapastinel (GLYX-13) / AbbVie - LARVOL DELTA

Disrupted homeostatic plasticity in SCN2A+/- rat model (Neuroscience 2025) - "To determine whether this failure to induce intrinsic homeostatic plasticity was due to saturation of the system, we dissociated V1 neurons from WT and SCN2A+/- animals and treated cultures for 24 hours with Glyx-13, an NMDAR allosteric modulator known to reduce intrinsic excitability...Altogether, these findings suggest that SCN2A is dispensable for synaptic homeostatic plasticity but essential for intrinsic homeostatic plasticity in L2/3 pyramidal neurons. This supports a model in which loss of excitatory synaptic input leads to compensatory intrinsic changes that become saturated in the absence of functional SCN2A, potentially contributing to circuit dysfunction in ASD."

Preclinical • CNS Disorders • NAV1

New advances in small molecule drugs targeting NMDA receptors. (PubMed, Acta Pharmacol Sin) - "Among various therapeutic indications, depression has emerged as an especially active area of investigation, with mechanistically diverse compounds ranging from broad-spectrum channel blockers (ketamine, dextromethorphan, esmethadone) to glycine site modulators (rapastinel, 4-chlorokynurenine, D-cycloserine) and allosteric modulators (apimostinel, zelquistinel), progressing through clinical pipelines. Beyond depression, NMDA receptor-targeted drug discovery is also advancing in other challenging CNS disorders, including neurodegenerative diseases (salzanemdor, NYX-458), pain (NYX-2925), epilepsy (radiprodil), and stroke (nelonemdaz, NP10679). Collectively, these developments reflect the maturation of NMDA receptor pharmacology and reaffirm the broad therapeutic potential of NMDA receptor modulation, while highlighting promising directions for future drug discovery."

Journal • Review • Cardiovascular • CNS Disorders • Depression • Epilepsy • Mental Retardation • Pain • Psychiatry

All Roads Lead to Glutamate: NMDA and AMPA Receptors as Targets for Rapid-Acting Antidepressants. (PubMed, Pharmacol Res) - "Beyond established rapid-acting antidepressants (RAADs), such as (es)ketamine and dextromethorphan/bupropion (AXS-05), we highlight novel therapeutic directions involving esmethadone (REL-1017), nitrous oxide, and positive allosteric modulators (PAMs) of NMDA receptors (e.g. rapastinel, zelquistinel, and apimostinel). Moreover, we discuss forward-looking strategies using AMPA receptor PAMs (e.g. osavampator and tulrampator) and targeting of AMPA receptor-interacting proteins...Together, targeting glutamatergic signalling represents a transformative path for TRD treatment with high efficacy by more directly modulating pathologically affected signalling modules. These developments place glutamatergic agents at the forefront of next-generation AD strategies."

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

Role of CaMKII/CREB pathway in rapid-antidepressant-like effect: comparison of ketamine with rapastinel. (PubMed, Exp Brain Res) - "Overall, this study provides insights into the potential mechanisms underlying the antidepressant-like effects of ketamine and rapastinel. Understanding these mechanisms could aid in developing new treatments for depression that are both rapid-acting and long-lasting, without the side effects associated with current medications."

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

Advances in the study of NMDA receptors in depression pathogenesis and the antidepressant efficacy of their antagonists. (PubMed, Asian J Psychiatr) - "As a non-competitive NMDA receptor antagonist, ketamine quickly relieves depressive symptoms by decreasing the activity of extracellular NMDA receptors and activating the mTOR signaling pathway. Esketamine has demonstrated improvements in both side effects and efficacy and has received FDA approval, while other compounds with NMDA receptor modulating functions, such as memantine and rapastinel, are also showing potential in exploration. Future studies should concentrate on the molecular mechanisms of NMDA receptors, aiming to develop safer and more effective medications, and refine treatment strategies to offer personalized choices and longer-lasting efficacy for the treatment of depression."

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

Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor. (PubMed, Pharmaceuticals (Basel)) - "Stinels-rapastinel, apimostinel, and zelquistinel-are also plastogens not only with rapid and long-term antidepressant effects but also with improved safety and tolerability profiles compared to ketamine. In this review, we present the rationale behind targeting NMDARs for treatment-resistant depression and other psychiatric conditions, describe the various mechanisms by which NMDAR activity is regulated by different classes of therapeutics, and present evidence for the stinel mechanism. In contrast with previous descriptions of glycine-like NMDAR partial agonists, we define stinels as positive allosteric modulators of NMDAR activity with a novel regulatory binding site."

Journal • Review • CNS Disorders • Depression • Psychiatry

Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes. (PubMed, Cell Rep) - "By crossing the Fmr1 KO mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism."

Journal • Autism Spectrum Disorder • CNS Disorders • Depression • Developmental Disorders • Epilepsy • Fragile X Syndrome • Genetic Disorders • Mental Retardation • Psychiatry • GRIN2A • GRIN2B

Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: a systematic review and meta-analysis. (PubMed, Mol Psychiatry) - "These data suggest that peripheral BDNF levels do not change after psychoplastogen administration in humans. It is possible that peripheral BDNF is not an informative marker of rapid changes in neuroplasticity, or that preclinical findings on psychoplastogens and neuroplasticity may not translate to human subjects. Limitations of this analysis include the reliability and validity of BDNF measurement and low variation in some potential moderators. More precise methods of measuring rapid changes in neuroplasticity, including neuroimaging and stimulation-based methods, are recommended for future studies attempting to translate preclinical findings to humans."

Journal • Retrospective data • Review • Psychiatry • BDNF

A circuit-based, neurobehavioral assay for preclinical antidepressant profiling (Neuroscience 2024) - "Data were analyzed using a linear mixed effects model (LMM) with condition (baseline, post-treatment) and dose (vehicle, low, moderate, high) as fixed effects, focusing on 15 metrics for drug profiling and comparative analysis.We tested a panel of 12 compounds developed for Major Depressive Disorder (MDD) including Ketamine, Rapastinel, Traxoprodil, and Psilocin, all of which have “antidepressant” effects in canonical behavioral assays but vary in their clinical efficacy. This approach can enhance clinical trial predictability and reduce failure rates in antidepressant development. Our results emphasize the importance of incorporating detailed neurobehavioral investigation into preclinical research programs, paving the way for more effective and targeted MDD treatments."

Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

A circuit-based, neurobehavioral assay for preclinical antidepressant profiling (ECNP 2024) - "We profiled a panel of 9 compounds (each at 1-3 doses) developed for Major Depressive Disorder (MDD) including Ketamine (effective in patients), Traxoprodil (effective in Phase 2 trials, but terminated for safety reasons), Rapastinel (ineffective in patients), N,N DMT (effective in Phase 2 trials, Phase 3 pending), and Psilocin (effective in Phase 2 trials, Phase 3 ongoing), all of which have "antidepressant" effects in the canonical behavioral assay Forced Swim Test. This approach has the potential to enhance the predictability of clinical trial outcomes, reducing the high rates of failure in antidepressant development by better identifying compounds with true therapeutic potential before advancing to human trials. Our Results underscore the necessity of integrating detailed neurophysiological insights into the preclinical phase of drug development, paving the way for more effective and targeted treatments for MDD."

Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

NV-5138, an Orally-Administered Investigational Rapid-Acting Antidepressant, Acutely Alters Prefrontal Cortical Neuronal Responses in Mice: Comparison to Ketamine and Rapastinel (SOBP 2024) - "Background: NV-5138, a Phase-2, rapid-acting antidepressant (RAAD) candidate, activates mechanistic target of rapamycin complex 1 (mTORC1) through a novel intracellular mechanism and without psychotomimetic effects. NV-5138 (160-mg/kg) and ketamine (10-mg/kg) moderately increased locomotor activity (p<0.05), whereas ketamine (30-mg/kg) produced strong hyperlocomotion (consistent with psychotomimetic effects). NV 5138 increased average spike rate (p=0.05) without changing the number of active cells; both metrics were reduced by ketamine (10, 30-mg/kg, p<0.05). NV 5138 increased the proportion of up-modulated neurons (p<0.05) without impacting the proportion of down-modulated neurons, whereas ketamine conferred opposite effects, increasing the proportion of down-modulated neurons (p<0.01) without impacting the proportion of up modulated neurons."

Late-breaking abstract • Preclinical • CNS Disorders

In Vivo Cellular-Resolution Calcium Imaging Reveals Functional Biomarkers of the Antidepressant Ketamine and Guides Preclinical Efficacy Testing (ACNP 2023) - "We conducted similar studies to assess the efficacy of the putative antidepressant scopolamine and the failed candidate rapastinel (GLYX-13), and found that their impact on neuronal function significantly diverges from ketamine... In conflict with the “disinhibition hypothesis”, we observe multiple functional ensembles with divergent responses to acute ketamine treatment, with suppression of neuronal event rate being the dominant effect. Furthermore, we observed enhanced cell-cell correlation of mPFC pyramidal neurons at dissociative, but not at antidepressant dosages suggesting that we are able to resolve correlative features of side effects with the model. We additionally observe signatures of ketamine’s durable antidepressant effects, three and 24 hours after dosing, potentially providing a functional biomarker of sustained antidepressant effects."

Preclinical • CNS Disorders • Depression • Mental Retardation • Psychiatry

In vivo neural circuit imaging reveals functional biomarkers of antidepressant ketamine and guides preclinical efficacy testing (Neuroscience 2023) - "We observed changes in depression-related behavior and neural circuit function at both timepoints, providing a neural biomarker of sustained antidepressant effects.We conducted similar studies to assess the efficacy of the putative antidepressant scopolamine and the failed candidate rapastinel (GLYX-13), and found that their impact on neuronal function significantly diverges from ketamine. These studies are the first of their kind imaging large populations of individual mPFC neurons during active behavior and provide novel signatures of ketamine's effects at antidepressant and dissociative doses. Furthermore the data suggests that functional brain imaging can serve as a predictive tool for efficacy testing of novel drugs in development."

Preclinical • CNS Disorders • Depression • Mental Retardation • Psychiatry

Psychoplastogens: A Novel Therapeutic Approach for Neurological Diseases and Disorders. (PubMed, ACS Med Chem Lett) - "Substances like ketamine, scopolamine, N,N-dimethyltryptamine, and rapastinel have psychoplastogenic properties. In clinical trials, psychedelic psychoplastogens have demonstrated antidepressant, anxiolytic, and anti-addictive effects. The research described in this Patent Highlight suggests the potential for novel therapies in neurological disorders that leverage psychoplastogens, which modulate synaptic connections and plasticity."

Journal • CNS Disorders • NTRK2

Effects of GLYX-13 on Learning and Memory in Healthy Individuals and Those With Psychiatric Illness (clinicaltrials.gov) - P2 | N=44 | Terminated | Sponsor: Northwestern University | N=104 ➔ 44

Enrollment change • Mental Retardation • Psychiatry

Models of Affective Illness: Chronic Mild Stress in the Rat. (PubMed, Curr Protoc) - "For example, the CMS-induced deficits can be reversed by acute or sub-chronic application of treatments that act rapidly in depressed patients, such as deep brain stimulation (DBS), ketamine, and scopolamine, as well as several compounds that have yet to be tested in humans but have fast-onset antidepressant-like effects in animals, such as the 5-HT-1A biased agonists NLX-101 and GLYX-13...Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Induction of chronic mild stress in rats as a model of depression and treatment-resistant depression."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Psychiatry

ERK/mTOR signaling may underlying the antidepressant actions of rapastinel in mice. (PubMed, Transl Psychiatry) - "Based on previous and our supplementary data that showed the pivotal role of on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in the rapid release of VGF and BDNF and activation of TrkB by a single dose of rapastinel, we postulate that the antidepressant-like effects of single or repeated administration of rapastinel may result in the rapid release of VGF and BDNF or ERK/mTOR signaling pathway-mediated VGF/BDNF/TrkB autoregulatory feedback loop respectively. Our current work adds new knowledge to the molecular mechanisms that underlie the antidepressant-like actions of rapastinel in mice."

Journal • Preclinical • EIF4EBP1

Rapastinel accelerates loss of withdrawal signs after repeated morphine and blunts relapse to conditioned place preference. (PubMed, Pharmacol Biochem Behav) - "Rapastinel did not affect extinction of CPP, but rapastinel-treated animals spent significantly less time in the previously morphine-paired side than saline-treated animals during the relapse trial. These findings of accelerated loss of withdrawal signs and blunted relapse to CPP suggest that rapastinel could provide an adjunctive therapy for opioid dependence during initiation of pharmacotherapy for opioid dependence."

Journal • Addiction (Opioid and Alcohol)

Region-specific enhancement of c-fos expression by combined treatment with NMDA receptor agonists and antagonists with antidepressant potential. (PubMed, Int J Neuropsychopharmacol) - No abstract available

Journal • FOS

Repeated administration of rapastinel produces exceptionally prolonged rescue of memory deficits in phencyclidine-treated mice. (PubMed, Behav Brain Res) - "Both rapastinel (3mg/kg) and ketamine (30mg/kg), moderately increased the efflux of dopamine, norepinephrine, and serotonin in medial prefrontal cortex; however, only ketamine increased cortical glutamate efflux. This observation was likely the basis for the contrasting effects of the two drugs on cognition."

Journal • Preclinical • mTOR

Extracellular application of the N-methyl-D-aspartate receptor allosteric modulator rapastinel acts remotely to regulate Ca2+ inactivation at an intracellular locus. (PubMed, Neuroreport) - "Extracellular binding of RAP to the NMDAR produces a novel, long-range reduction in affinity of the Ca2+ inactivation site on the NMDAR C-terminus accessible to the intracellular space. This action underlies enhancement in NMDAR-gated conductance elicited by RAP."

Journal

Glutamatergic receptor and neuroplasticity in depression: Implications for ketamine and rapastinel as the rapid-acting antidepressants. (PubMed, Biochem Biophys Res Commun) - "Ketamine is an NMDAR antagonist and is proven effective in depression for the rapid and sustained antidepressant response, while rapastinel is an NMDAR positive allosteric modulator, producing antidepressant effects like ketamine with no severe side effects. The common antidepressant effects of ketamine and rapastinel are BDNF and mTORC1 pathway in synaptic plasticity."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • BDNF

Effects of GLYX-13 on Learning and Memory in Healthy Individuals and Those With Psychiatric Illness (clinicaltrials.gov) - P2; N=104; Terminated; Sponsor: Northwestern University; Completed ➔ Terminated; Study sponsor was acquired by another company.

Clinical • Trial termination • Mental Retardation • Psychiatry

Quick Access to High-Purity Peptide Drugs Bradykinin, Leuprolide Analogue, 2(PZ-128), and Rapastinel with Minimal Reagents. (PubMed, J Org Chem) - "These drugs of commercial utility and complex structures are obtained in 2-5.5 h with no epimerization and >95% purity using only 1.2 equivalents of amino acids and coupling reagents. The peptide yield and purity are comparable or superior to the reported methods."

Journal

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