Novel Schizophrenia Treatments Target Glutamate Receptors

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Antagonism or partial agonism at the dopamine D2 receptor and antagonism at the serotonin 5-HT2A receptor are what most schizophrenia drugs target in the brain. While these medications have been effective, other drugs are typically added to a treatment regimen to deal with negative symptoms or cognitive impairment.

However, new agents are in development for the treatment of schizophrenia. As Leslie Citrome, MD, of the Department of Psychiatry and Behavioral Sciences, New York Medical College, in Valhalla, says, many new treatment on the horizon involve the neurotransmitter glutamate. 

Activating glutamate can produce either an increase or decrease in the release of dopamine in the brain, which in turn impacts areas related to the symptoms of schizophrenia.

While both metabotropic and ionotropic glutamate receptors have been researched, Citrome said in Psyclopedia that most schizophrenia drugs under development target MNDA receptors, which have seen positive results in trials.

He also describes a non-glutamate treatment, encenicline (EVP-6124), which is a selective α7 nicotinic acetylcholine (N-A7A) receptor agonist. These receptors are located in brain areas involved in cognitive functions.

“Effective treatments for negative and cognitive symptoms remain an unmet need in schizophrenia management,” Citrome concludes. “Strategies such as combining antipsychotics and adding adjunctive agents to antipsychotics have yielded mostly disappointing results for both of these symptom domains.

“The NMDA receptor hypofunction hypothesis, with its focus on the glutamate system’s effect on dopamine, may potentially explain the positive, negative, and cognitive symptoms of schizophrenia. Therapeutic targets different from those of current antipsychotic agents are actively being investigated. Research includes adjunctive agents that bind to sites on NMDA receptors (glycine, d-serine, d-cycloserine), adjunctive glycine reuptake inhibitors (sarcosine, bitopertin), as well as agents that work through different pathways (encenicline).”

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A paradigm shift in schizophrenia treatment is focusing on the glutamate system for new agents to address all symptom domains. Learn what adjunctive agents are in development to treat negative and cognitive symptoms as well as agents that work through different pathways.
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