Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia

Anand, Ravi; Turolla, Alessio; Chinellato, Giovanni; Roy, Arjun; Hartman, Richard D

doi:10.1093/ijnp/pyad035

Cited by 10 publications

(3 citation statements)

References 25 publications

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“…Another approach would be to limit the overactivity of hippocampal pyramidal neurons. One compound that can achieve this effect is evenamide, which will normalize excess glutamate release without affecting baseline levels, which would be ideal for normalizing overactive hippocampal neurons [117]. This drug was found to be effective in reversing selective symptoms produced by amphetamines, phencyclidine, MK-801, or ketamine [118,119], all of which act via hippocampal hyperactivity [73,120,121].…”

Section: Novel Target Agentsmentioning

confidence: 99%

“…This drug was found to be effective in reversing selective symptoms produced by amphetamines, phencyclidine, MK-801, or ketamine [118,119], all of which act via hippocampal hyperactivity [73,120,121]. When tested as an adjunct to standard-of-care treatment of patients that were showing worsening on their current medications, evenamide produced a significant improvement in positive and negative symptom scales [117]. Testing whether this will also be effective as a monotherapy could yield important insights into how normalizing glutamate overdrive may reverse schizophrenia symptomatology.…”

Section: Novel Target Agentsmentioning

confidence: 99%

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Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets

Grace

Uliana

2023

IJMS

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Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated.

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Section: Novel Target Agentsmentioning

confidence: 99%

Section: Novel Target Agentsmentioning

confidence: 99%

Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets

Grace

Uliana

2023

IJMS

View full text Add to dashboard Cite

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“…Indeed, the results from a pilot, 6-week, randomized, open-label, rater-blinded study with a 46-week extension indicate very good tolerability with an exceptional, clinically important, increase in the efficacy of evenamide (7.5, 15, and 30 mg bid) as an add-on treatment to antipsychotics in treatment-resistant schizophrenia patients [128]. 4.9.2.…”

Section: Nmda Function Enhancersmentioning

confidence: 99%

Novel Compounds in the Treatment of Schizophrenia—A Selective Review

Tsapakis,

Diakaki,

Miliaras

et al. 2023

Brain Sciences

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Schizophrenia is a chronic neuropsychiatric syndrome that significantly impacts daily function and quality of life. All of the available guidelines suggest a combined treatment approach with pharmacologic agents and psychological interventions. However, one in three patients is a non-responder, the effect on negative and cognitive symptoms is limited, and many drug-related adverse effects complicate clinical management. As a result, discovering novel drugs for schizophrenia presents a significant challenge for psychopharmacology. This selective review of the literature aims to outline the current knowledge on the aetiopathogenesis of schizophrenia and to present the recently approved and newly discovered pharmacological substances in treating schizophrenia. We discuss ten novel drugs, three of which have been approved by the FDA (Olanzapine/Samidorphan, Lumateperone, and Pimavanserin). The rest are under clinical trial investigation (Brilaroxazine, Xanomeline/Trospium, Emraclidine, Ulotaront, Sodium Benzoate, Luvadaxistat, and Iclepertin). However, additional basic and clinical research is required not only to improve our understanding of the neurobiology and the potential novel targets in the treatment of schizophrenia, but also to establish more effective therapeutical interventions for the syndrome, including the attenuation of negative and cognitive symptoms and avoiding dopamine blockade-related adverse effects.

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Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

Ye,

Wang,

et al. 2024

Medicinal Research Reviews

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Since the first discovery of antipsychotics in the 1950s, targeting dopaminergic drugs has manifested to well manage the positive symptoms of schizophrenia with limited efficacy for the negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards the development of innovative agents that can effectively stabilize the dopamine and serotonin systems or target to nondopaminergic pathways, leading to various promising drug candidates entering into clinical trials. Notably, the sigma‐2, 5‐HT2A, and α1A receptor antagonist roluperidone, as well as a fixed‐dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5‐HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small‐molecule entities and fixed‐dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics.

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Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia

Cited by 10 publications

References 25 publications

Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets

Insights into the Mechanism of Action of Antipsychotic Drugs Derived from Animal Models: Standard of Care versus Novel Targets

Novel Compounds in the Treatment of Schizophrenia—A Selective Review

Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

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