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Novel treatment for schizophrenia

Posted by SLS on December 9, 2021, at 8:42:24

A potential new approach for the treatment for both positive and negative
symptoms of schizophrenia:


From MDLinks:

A potential new approach for the treatment of schizophrenia:

"A new study led by Jeff Conn, Lee E. Limbird Chair in Pharmacology, James
Maksymetz, a former graduate student in the Conn laboratory, and other
collaborators at the Warren Center for Neuroscience Drug Discovery has
identified a protein in the central nervous system, known as mGlu1, as a
potential target for novel treatments of schizophrenia.

Schizophrenia, which affects approximately 1 percent of the global population,
has been historically difficult to treat. Current clinically approved antipsychotics
are effective at reducing "positive symptoms" like hallucinations and delusions in
some patients, but they fail to treat "negative symptoms," such as social
withdrawal, lack of motivation and cognitive deficits associated with the disease.
The new research focused on identifying a new approach that would treat
positive and negative symptoms, Maksymetz said.

Schizophrenia is thought to occur when a region of the brain called the
prefrontal cortex becomes abnormally active because interneurons, which
connect neuron circuits or neuron groups, become dysfunctional and stop
regulating neuronal activity. Conn's team sought to modulate the activity of those

After identifying mGlu1an abbreviation of metabotropic glutamate receptor
subtype 1as a potentially druggable target, they tested it with a compound that
enhances its function: a positive allosteric modulator. The PAM was previously
developed by Conn in close collaboration with other labs in the WCNDD,
including those of Craig Lindsley, University Professor of Chemistry and
Pharmacology, and Colleen Niswender, associate professor of pharmacology.
Using this compound, they found that enhancing the activity of mGlu1 selectively
increased the activity of specific inhibitory interneurons, restoring their ability to
inhibit the neuronal circuits they control.

Further, the researchers saw that by working with the PAM, symptoms
characteristic of schizophrenia in human patients were reversed. These results
suggest that using a PAM to enhance mGlu1 activity is an effective treatment for

Why it matters

Schizophrenia is an important clinical and societal concern. "Inadequate
treatment responses and failures to address 'negative symptoms' and cognitive
deficits result in poor patient outcomes," Maksymetz said. "And they incur a
huge financial burden on the U.S. and global economies."

Researchers hope that this novel treatment strategy "may eventually provide
relief for patients, allow them to reintegrate into and contribute to society, and
diminish the burden on our health care systems." The results of this research are
particularly exciting because the drug reverses working memory deficits, a
hallmark of schizophrenia for which there is currently no treatment.

Today's pharmaceutical schizophrenia treatments were serendipitously
discovered half a century ago and were not derived from good understanding of
disease biology. Decades of clinical findings have improved researchers'
understanding of the biological basis of the disease, opening the door for the
development of better-targeted, more efficacious drugs. "We reasoned that if
we addressed the underlying disease biology by boosting the function of these
interneurons, then we might be able to rescue cognitive deficits associated with
prefrontal cortex dysfunction," Maksymetz said.

What's next

The results of this study raise a number of questions about mGlu1 biology.
Ongoing studies in the Conn lab are investigating the role and effects of mGlu1
in various regions within the brain.

To translate these findings to the clinic, scientists will need to investigate the
efficacy of PAMs when used chronically rather than in the short term, evaluate
potential side-effects, and determine whether enhancing mGlu1 reduces other
symptoms in schizophrenia, especially "negative symptoms" like a lack of
motivation and social withdrawal, which are frequently treatment-resistant.

"We think this study is a good foundation to build upon," Maksymetz said.
"Hopefully we will be able to test the hypothesis that mGlu1 PAMs can actually
treat patients with schizophrenia someday soon. I truly believe that
understanding how neural circuits function and dysfunction will lead to a
revolution in treating neuroscience-related diseases, and I'm excited to be a part
of it."

The research was published in Cell Reports."

Some see things as they are and ask why.
I dream of things that never were and ask why not.

The only thing necessary for the triumph of evil is that good men do nothing.




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