December 14, 2007

Gene’s role in schizophrenia drug effectiveness probed

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Research by Daniel Campbell, Ph.D., and others may help one day individualize treatment for schizophrenia. (photo by Neil Brake)

Gene’s role in schizophrenia drug effectiveness probed

A major obstacle for patients prescribed antipsychotic medications to treat schizophrenia is the trial-and-error process of pinpointing which drug will work best.

It can take months, even years, of dealing with unwanted side effects — which can cause some patients to drop off their medications.

Now, Vanderbilt Kennedy Center (VKC) researchers are using genetic links to predict the effectiveness of these drugs. Their findings are detailed in a multi-center study to be published in the January issue of Biological Psychiatry.

"We found that these (RGS4) genetic variants predict how well individuals with schizophrenia react to a certain type of drug," said Daniel Campbell, Ph.D., VKC research fellow and lead author of the study.

"Currently, individuals with schizophrenia are given antipsychotic drugs and the effectiveness of those drugs is unpredictable. Sometimes the chosen drug works, sometimes it doesn't, and sometimes it has bad side effects."

Researchers from Vanderbilt, University of North Carolina, Columbia University and Stockholm's Karolinska Institutet applied genetic analysis to the National Institute of Mental Health (NIMH)-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) in doing the study.

The NIMH trial gave different antipsychotic drugs to more than 1,000 people with schizophrenia and studied how well they reacted.

The new study used DNA samples from those same individuals to look at their genotypes in the RGS4 gene.

Campbell, VKC Director Pat Levitt, Ph.D., and research assistant professor Phillip Ebert, Ph.D., reviewed data from 678 individuals with schizophrenia who participated in CATIE. Among the 678 subjects, the inferred ancestries were 29 percent "Africa only," 59 percent "Europe only," and 12 percent "Other."

An interesting finding of their research is that the genotype at the RGS4 gene predicted different effectiveness of the five antipsychotic medications studied between persons of African and European ancestry.

"Our long-term goal was always to see whether we could use these results to inform better treatment regimens for patients," said Levitt.

"We were thrilled that our exploratory analysis revealed that there is some predictive value to the RGS4 genetic variants when we look at response to anti-psychotic drug treatment in patients of African and European descents.

“This is a first successful step in realizing the hope of individualized care in psychiatry," Levitt said.

Campbell said the results, if replicated, would allow doctors to get a blood sample from a person with schizophrenia, genotype them at RGS4, and make a better prediction about which drug to use.

"If we look at people with schizophrenia who are of African descent and have a particular genotype for RGS4, our data show that you really don't want to give these patients a drug called ziprasidone, because they won't stay on the drug very long, they will stop taking it, and while they are on it their symptoms may actually get worse," Campbell said.

"For the same RGS4 genotype, ziprasidone doesn't look like it is any better or any worse than any other drug for patients of European descent."

In 2000 Levitt's lab discovered, using gene microarray technology, that RGS4 was one of the most consistently altered genes in the frontal lobe of subjects with schizophrenia.

That was followed by human genetic studies, identifying variants in the RGS4 gene that showed association with schizophrenia.