UNDERLYING MECHANISMS OF SCHIZOPHRENIA OFFER NEW TREATMENT TARGETS
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UNDERLYING MECHANISMS OF SCHIZOPHRENIA OFFER NEW TREATMENT TARGETS.
ORLANDO, Wednesday, Nov. 6 - Several new studies are leading to better treatments for the more than 3 million people estimated to have schizophrenia, a mental disorder characterized by disorganized thoughts, hallucinations and an inability to relate to others or function in society.
"These breakthroughs reveal how antipsychotic drugs treat schizophrenia and how genes play a role in schizophrenia," says C. Anthony Altar, PhD, of Psychiatric Genomics, Inc., in Maryland and the chair of a symposium on schizophrenia at the 32nd annual meeting of the Society for Neuroscience. "The future appears to be particularly promising for the discovery of drugs that are based on these mechanisms."
Researchers have had a hard time developing drugs for schizophrenia because the biological mechanisms that cause its many symptoms are unclear. Available treatments sometimes help patients, but their unspecific actions in the brain often trigger a number of side effects, such as weight gain, sedation and movement disorders.
Now new research reveals how techniques that target specific brain chemical activity may be able to quell symptoms without causing negative side effects. Work also shows how specific genes and brain areas are linked to the disease, indicating that methods that target these factors could also translate into better treatments in the future.
One of the studies, led by Nobel Prize winner Arvid Carlsson, MD, PhD, of Goteborg University and Carlsson Research in Sweden, identifies a new compound that targets activity of the brain chemical dopamine. The compound relieves psychosis in animal models of schizophrenia without causing the side effects characteristic of the currently used antipsychotic agents.
Carlsson won the 2001 Nobel Prize for his discovery of dopamine and its relevance to schizophrenia and another brain ailment known as Parkinson's disease. He predicted that the overactivity of dopamine led to schizophrenia and methods that decrease this activity could help treat it. Researchers have had some success treating the disease with drugs that blanket the brain and block the areas on brain cells where the chemical conducts its activity, termed receptors. But the widespread receptor blocking actions of the drugs cause some side effects, such as tremors and other movement disturbances characteristic of Parkinson's disease.
"In contrast to these known drugs, our newly identified molecule called ACR16 was able to normalize behavior in animal models of schizophrenia without causing side effects," says Carlsson. "We think that ACR16 is a better target of dopamine than current drugs, because instead of creating a widespread blockade of dopamine receptors it only partially blocks these receptors and can stabilize the system."
In the study, the researchers first treated rodents with certain compounds that spurred the development of a variety of psychotic characteristics seen in those with schizophrenia, such as hyperactivity and abnormal behavioral patterns. Next they gave the animals ACR16. Results indicate that the rodents' behavior normalized. Furthermore, they did not show signs of the movement disturbances characteristic of current treatments. ACR16 also did not appear to cause any other serious side effects.
"Our findings indicate that in the future ACR16 may help quell the symptoms of people with schizophrenia without causing any serious side effects," says Carlsson.
As a next step to the research on this drug, Carlsson and his colleagues gave it to 16 healthy volunteers and found that it was well-tolerated. Plans are underway to study ACR16's effects in patients with schizophrenia.
Carlsson holds equity in Carlsson Research. Therefore if ACR16 reaches the market in the future, it will have a positive effect on his private economy.
In other work, researchers find evidence that targeting a specific activity pathway of the brain chemical, serotonin, improves cognition in some patients with schizophrenia.
Many people with schizophrenia have deficits in cognitive functions, such as memory, learning and attention. "These cognitive deficits are equally or more important than hallucinations and delusions in causing those with schizophrenia to have work and social problems," says Herbert Meltzer, MD, of Vanderbilt University. "Our finding characterizes the role that serotonin plays in the cognitive effects and could facilitate the development of more effective drugs to help patients."
In the study Meltzer and his colleagues tested the effects of several newer schizophrenia drugs, including clozapine, risperidone, olanzapine, quetiapine, aripiprazole and ziprasidone, on 15 people with schizophrenia. In addition to targeting dopamine, like the older generation of schizophrenia drugs, such as haloperidol and chlorpromazine, these newer drugs also target serotonin.
"We found that the newer serotonin-targeting drugs significantly improved some patients' ability to perform cognitive tasks requiring attention, long-term memory, word generation and fine motor skills," says Meltzer. "The older drugs that do not target serotonin do not have this effect."
Earlier findings led Meltzer to suspect that the cognitive improvements of the newer drugs were due to their ability to stimulate a specific serotonin activity site on nerve cells, termed the 5-HT1A receptor. Studies in rats indicated that the drugs increased the release of dopamine and another brain chemical acetylcholine to improve some types of cognition. Other work showed that stimulating the 5-HT1A receptor increases these chemicals in the brain. To add to this picture, brain imaging studies from another lab indicated that patients with schizophrenia have decreased amounts of these receptors in their brains.
In a second part of the new work, Meltzer and his colleagues further confirm the theory that 5-HT1A receptor activity is behind the cognitive improvements. They gave the schizophrenia patients either tandospirone or buspirone, drugs known to target this receptor. Both drugs were more effective than a placebo at improving cognition.
"The drugs we tested in this research also cause some side effects because they have many actions in the brain other than at the serotonin receptor," says Meltzer. "Developing new drugs specially designed to specifically target the serotonin receptor may be able to create cognitive improvements without these negative effects."
In gene-based studies, researchers find that a specific genetic variation helps trigger symptoms of schizophrenia by increasing the activity of dopamine in a specific brain area.
"The finding is important because it shows that this gene and the mechanisms it triggers could be targeted to create more effective therapies for those with schizophrenia," says Daniel Weinberger, MD, of the National Institute of Mental Health.
In earlier research, Weinberger and his colleagues determined that a variation in the gene, termed COMT, which produces an enzyme called catechol-O-methyltransferase, links to schizophrenia and cognitive problems. For one, they found that those with one version of COMT have a slightly increased risk of developing schizophrenia. Furthermore, studies including more than 450 people indicate that this same version of the gene can affect the function of the frontal part of the brain, known as the prefrontal cortex, and hinder complex cognitive processes, such as the ability to use a form of memory, known as working memory, to solve problems.
In the new work, the researchers studied the actions of this version of the COMT gene in brain tissue to determine how it affects the activity of dopamine at the nerve cells that process the chemical. An analysis measured the effect of inheriting this version of the catechol-O-methyltransferase gene on a measure of the synthesis of dopamine in the cells. Results indicate that the version of the COMT gene associated with increased risk for schizophrenia and for diminished function of the prefrontal cortex, also produces increased synthesis and increased dopamine activity in these dopamine nerve cells.
"Together the findings show that the gene's combined effect on cognition, the prefrontal cortex and dopamine help increase the risk for a person to develop psychosis," says Weinberger.
The researchers plan to further investigate how this gene as well as three others, known as G70, NRG-1 and dysbindin, affect brain functions to spur schizophrenia.
Work on humans also indicates that malfunctions in another brain area relate to schizophrenia. "We found that the front region of the hippocampus, a brain area known for aiding memory, does not function properly in people with schizophrenia," says Carol Tamminga, MD, of the University of Maryland. "Understanding the disease's specific pathology may help us develop specific drugs that could combat it."
In one part of the study, Tamminga and her colleagues used the imaging technique of positron emission tomography to map the brain activity of 18 people with schizophrenia and 12 healthy individuals as controls. Each participant completed tasks that tested attention and short-term memory. "The findings indicate that the activity in the anterior cingulate cortex brain area was lower than normal during the performance of the tasks," says Tamminga. "Since this area normally interacts with the hippocampus, we believe that the signal from the hippocampus to the anterior cingulate cortex is abnormal."
A second part of the study confirmed this theory. The researchers examined brain tissue from eight people with schizophrenia who died and tissue from eight healthy individuals as controls. Using molecular techniques the researchers found that in the front portion of the hippocampus, activity of N-methyl-D-aspartate receptors was lower than normal. These brain cell areas process the chemical glutamate to aid memory.
"Ultimately we would like to test a drug that targets the glutamate activity in the hippocampus to see if we can relieve symptoms in patients with schizophrenia without causing side effects," says Tamminga.
