Pitt Research Identifies New Target in Brain for Treating Schizophrenia

A November 3rd news release from the University of Pittsburgh:

Study published in Proceedings of National Academy of Sciences shows that orbitofrontal cortex responds to current and experimental antipsychotic drugs

PITTSBURGH- Research from the University of Pittsburgh could expand the options for controlling schizophrenia by identifying a brain region that responds to more than one type of antipsychotic drug. The findings illustrate for the first time that the orbitofrontal cortex could be a promising target for developing future antipsychotic drugs-even those that have very different mechanisms of action. The study will be published during the week of Nov. 3 in the online edition of the Journal Proceedings of National Academy of Sciences, with a print version to follow.

Bita Moghaddam [pictured], a professor in the Department of Neuroscience in Pitt's School of Arts and Sciences and the paper's lead author, found that schizophrenia-like activity in the orbitofrontal cortex - a brain region responsible for cognitive activity such as decision making - could be triggered by the two different neurotransmitters linked to schizophrenia: dopamine and glutamate. Brain activity was then normalized both by established antipsychotic medications that regulate only dopamine and by experimental treatments that specifically target glutamate.

“The orbitofrontal cortex is an area that's been somewhat neglected in schizophrenia research. This study should encourage researchers to focus on this brain region in imaging and other human studies, and also to use as a model for developing antipsychotic drugs,” Moghaddam said. “Schizophrenia appears to be caused by very diverse and sometimes rare genetic mutations. Diverse mutations can end up causing the same disease if they disrupt the function of a common group of neurons or networks of neurons. We think that the key to understanding the pathophysiology of schizophrenia and finding better treatments is to identify these networks. This data suggests that the orbitofrontal cortex may be a critical component in networks affected by schizophrenia.”

Working with UPMC neurology resident Houman Homayoun, Moghaddam first established that dopamine and glutamate could, separately, produce schizophrenia-like symptoms in the orbitofrontal cortex. They first simulated symptoms brought on by irregular neural receptors of glutamate. Studies within the last few years - including work by Moghaddam at Yale University - have shown that under-functioning glutamate receptors known as NMDA receptors can produce schizophrenia-like symptoms. Moghaddam and Homayoun found that stunting the NMDA receptors resulted in schizophrenia-like effects in the orbitofrontal cortex. The team also used a dose of amphetamine to simulate dopamine-related schizophrenia symptoms in the orbitofrontal cortex; schizophrenia is often linked to an excess of dopamine in the brain.

Moghaddam and Homayoun then tested the currently prescribed medication - a treatment developed more than 50 years ago that targets neural receptors of dopamine - and new experimental drugs that work on the glutamate system. They found that both medications normalized brain activity.

The paper can be found on the Proceedings of National Academy of Sciences' Website at www.pnas.org/content/early/recent or by contacting Morgan Kelly at 412-624-4356 (office); 412-897-1400 (cell); or by sending an email to mekelly@pitt.edu.

Identification of a serotonin/glutamate receptor complex implicated in psychosis

Medical News TODAY
Article Date: 25 Feb 2008

Mount Sinai researchers have identified a new receptor complex in the brain that responds to several types of antipsychotic drugs used to treat schizophrenia and also reacts to hallucinogenic drugs such as LSD (molecular structure illustrated above). Stuart Sealfon, MD, Professor of Neurology and Director of the Center for Translational Systems Biology at Mount Sinai School of Medicine and colleagues discovered the receptor complex, which could help provide new treatments for schizophrenia and other diseases associated with psychosis. This new study was published online in Nature.

"The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. The discovery of this receptor complex could provide a new target for developing drugs to treat schizophrenia," said Dr. Sealfon.

The study done in mice identified that the two receptors, [for the] neurotransmitters glutamate and serotonin, interact and work as a hybrid complex. Hallucinogenic drugs, such as LSD and psilocybin, act at serotonin receptors to cause responses similar to some of the core symptoms of schizophrenia. The researchers showed that the glutamate receptor interacts with the serotonin receptor to form functional complexes in brain cortex. This receptor complex triggers unique cellular responses when targeted by hallucinogenic drugs.

Activation of the glutamate receptor blocks hallucinogen-specific signaling and changes behavioral responses in mice.

In untreated [individuals living with schizophrenia], the serotonin receptor is up-regulated and the glutamate receptor is downregulated, a pattern that could predispose to psychosis. These findings suggest that the newly identified serotonin/glutamate complex may be involved in the altered cortical processes of schizophrenia.

"The findings further our understanding of how hallucinations occur. They suggest a brain abnormality that may contribute to the abnormal brain function in schizophrenia," said Dr. Sealfon. "We can now use this information to do further study and hopefully develop more specific drug therapies for treating patients who suffer from hallucinations and psychosis."

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center.

Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic-science research, as well as having an innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants.

Mount Sinai Medical Center
One Gustave Levy Place
New York, NY 10029
United States
www.mountsinai.org

Daring to Think Differently About Schizophrenia

An interesting article in today's The New York Times. To read the article, click here.

Darryle D. Schoepp (right) has helped develop new drugs for treating schizophrenia, relying on a novel approach for combating some symptoms of the disorder.



Photograph by Aaron Houston for The New York Times.

Eli Lilly drug lessens schizophrenia symptoms in trial

An article published in the September 2nd edition of the International Herald Tribune:

By Alex Berenson

In a clinical trial of about 200 patients, an experimental drug from Eli Lilly lessened schizophrenia symptoms without the serious side effects of current treatments, according to a paper published Sunday in the journal Nature.

The drug must still be tested on many more patients and is at least three to four years from completing regulatory review. But schizophrenia researchers said the trial's results were surprising and impressive, especially since the drug works in a different way from existing antipsychotic medicines, all of which have serious side effects including weight gain and tremors.

Lilly will begin a new and larger clinical trial for the drug this month. If that trial confirms the results seen so far, the new drug could mark a breakthrough in the treatment of schizophrenia - and open the way to a broad new class of treatments for the disease. Schizophrenia, a devastating mental illness that affects 1 percent of adults and usually begins in the late teens or 20s, is marked by psychotic delusions as well as social withdrawal and cognitive impairment.

"This is potentially one giant step forward for patients," said Dr. Jeffrey Lieberman, chairman of the psychiatry department at Columbia and the lead investigator on a federally sponsored clinical trial of schizophrenia medicines.

Lieberman has not been involved with the development of the Lilly medicine and does not receive any payments or consulting fees from Lilly.

The new drug also has the potential to be a blockbuster for Lilly. Medicines for schizophrenia and bipolar disorder had sales of $12 billion in the United States and $18 billion worldwide last year.

The troubled history of Zyprexa, another antipsychotic medicine from Lilly, will lead regulators and psychiatrists to scrutinize the new medicine closely for hidden dangers, Lieberman said. When it introduced Zyprexa in 1996, Lilly hailed it as a breakthrough with fewer side effects than older drugs. But Zyprexa causes severe weight gain, and the American Diabetes Association has linked it to diabetes. Internal Lilly documents show that the company played down Zyprexa's side effects, worrying that they would hurt sales.

Despite that history, psychiatrists will be eager to see whether the new Lilly medicine works, since the existing drugs are of limited help for many patients. Existing schizophrenia medicines, whether older drugs such as Thorazine or newer medicines like Zyprexa, all work the same way, by blocking the brain's dopamine receptors.

But the new Lilly drug does not directly affect dopamine. Instead, it modulates brain activity through a different set of receptors. As a result, it has the potential to be the first truly novel treatment for schizophrenia since Thorazine was introduced 1954, Lieberman and other researchers said.

Lilly's new drug - which does not have a name yet and is referred to only as LY2140023 - emerged from almost two decades of research into the similarities between symptoms of users of PCP, a street drug sometimes called angel dust, and schizophrenia. By the 1980s, scientists had discovered that PCP blocked brain receptors that are triggered by an amino acid called glutamate.

The Lilly clinical trial validated the theory that modulating glutamate receptors may control the symptoms of schizophrenia, said Dr. Joseph Coyle, a professor of psychiatry and neuroscience at Harvard Medical School.

Click here for a related story from BBC News.

Click here for more information from the Schizophrenia Research Forum.

Click here for a Psychiatric News article entitled Drug Bypassing Dopamine Could Broaden Antipsychotic Arsenal.