A glutamate modulator improves schizophrenia-related dysfunction, may open new treatment paths

New preclinical research in Neuropsychopharmacology focuses on the unique mechanism and site of action of evenamide as a potential treatment for schizophrenia.

The findings by researchers at the University of Pittsburgh, using the neurodevelopmental methylazoxymethanol acetate (MAM) animal model, indicate that evenamide, a glutamate modulator made by Newron Pharmaceuticals, could offer a novel therapeutic strategy capable of addressing positive, cognitive, and negative symptoms of schizophrenia.

Schizophrenia is a neurodevelopmental disorder affecting approximately 1% of the world’s population, and is characterized by positive, negative, and cognitive symptoms. However, current dopamine D2 antagonist‑based antipsychotic drugs only address primarily positive symptoms.

It is known that limbic hippocampus hyperexcitability is a key pathological state of schizophrenia and therefore represents an ideal therapeutic target. This newly published research shows how evenamide, a selective voltage‑gated sodium channel blocker, uniquely targets hippocampal hyperexcitability and selectively inhibits hyperactive neurons.

Additionally, time‑course analysis indicates the effects of a single dose of evenamide last long after its elimination, suggesting evenamide may have an effect on neuronal plasticity. Studies to date suggest evenamide is devoid of activity at any other central nervous system target, and it normalizes excessive synaptic glutamate induced by NMDA hypofunction.

“The study examined the effect of acute evenamide treatment on the hyperdopaminergic state, hippocampal hyperexcitability, social deficits, and recognition memory in the methylazoxymethanol acetate (MAM) neurodevelopmental model,” explained Daniela L. Uliana, first author of the study, from the Departments of Neuroscience, Psychiatry and Psychology of the University of Pittsburgh.

“The MAM model consists of injecting MAM during gestational day 17 into pregnant rats at a time that approximates the human second trimester; a period of vulnerability in pregnancy during which prenatal disruptions can result in increased schizophrenia incidence in adults. The MAM‑treated rats show multiple anatomical, behavioral, neurochemical, and physiological changes consistent with schizophrenia.”

“The study findings suggest that evenamide has high therapeutic potential for treating multiple symptom domains of schizophrenia,” said senior study author Dr. Anthony A. Grace of the University of Pittsburgh.

“Evenamide is a unique NCE agent in acting at the site of the deficit in schizophrenia by reducing hippocampal hyperexcitability. This represents a significant advancement in treatment, as evenamide can downregulate the hyperdopaminergic state without producing D2 blockade‑related side effects while also improving behavioral deficits that are not properly treated by D2-blocking antipsychotic agents.

“The recognition memory improvement induced by evenamide in the study’s MAM model may indicate that it may also enhance cognitive function in patients with schizophrenia and ultimately lead to a better functional outcome. Current D2‑based antipsychotic agents do not effectively address cognitive symptoms, which limits their overall efficacy and produces a significant functional burden on patients. Therefore, evenamide would offer advantages over existing antipsychotic drugs by targeting positive symptoms, cognitive deficits and social isolation.”

Ravi Anand, Newron’s CMO, added, “This study provides important learnings that explain the results of our earlier Phase II and Phase III trials in patients with chronic schizophrenia. The prolonged effect in the MAM model explains the continuing improvement in symptoms even one year after starting treatment with evenamide in TRS patients in our phase 2 trial.

“In the Phase 3 trial in patients who were not responding to their current 2nd‑generation antipsychotic drugs, including clozapine, the addition of evenamide led to significant improvements in the primary efficacy measure (PANSS total) as well as clinically and statistically significant increases in responder rates.

“The preclinical and clinical results suggest a high likelihood of success for our ongoing pivotal Phase III program and to potentially offering a completely new treatment paradigm to patients with schizophrenia.”

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