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Gene Variations Linked to Ethnicity May Hint at Response to Schizophrenia Drugs

Variations in the regulator of G protein signaling 4 (RGS4) may help predict how well patients of different ethnicities respond to certain schizophrenia medications — a noteworthy discovery because treatments for the disorder have notoriously varying efficacy and adverse-event profiles that greatly affect compliance.
Earlier this month, researchers funded by the National Institute of Mental Health published in Biological Psychiatry results from a study showing that patients with European or African ancestry that participated in a large study carried variations in the 5َ region of RGS4, which predisposed them to respond differently than other populations to five schizophrenia medications.
“These types of experiments should help to individualize treatment for schizophrenia,” said Daniel Campbell, lead author of the study, the Clinical Antipsychotic Trials of Intervention and Effectiveness trial.
“Instead of the current trial-and-error approach to finding the antipsychotic that is effective for a particular patient, genetics may help to identify an antipsychotic that is most likely to be effective for that patient,” added Campbell, who is also research assistant professor at Vanderbilt University’s Kennedy Center for Research on Human Development.
While the genetic associations to drug response found in this study may, in the future, help physicians personalize schizophrenia treatment, the study results will need to be replicated in a larger trial.
“As with all association studies, replication of the findings in this first report is essential,” the study authors state in their paper. “However, together with numerous association analyses, these results provide additional support for the hypothesis that RGS4 is part of a complex biological mechanism that underlies schizophrenia pathophysiology and continues to influence treatment outcomes throughout life by affective antipsychotic treatments.”
Ethnicity was self-reported in the study. However, researchers considered a combination of self-reported ethnicity and genetic variation within the RGS4 gene to predict antipsychotic treatment response.
Campbell’s team genotyped eight SNPs spanning RGS4 on Applied Biosystems’ TaqMan platform. The drugs considered in the study included one older drug, perphenazine, and four newer therapies, including Pfizer’s Geodon (ziprasidone), Eli Lilly’s Zyprexa (olanzapine), AstraZeneca’s Seroquel (quetiapine), and Janssen’s Risperdal (risperidone).
In the study, inferred ancestries of 198 patients were “Africa only,” 397 patients were categorized as “Europe only,” and 83 patients were considered “Other.” The study authors identified patients of African and European ancestry with rs2661319 and rs2842030 variations within RGS4 had more severe baseline total scores on the Positive and Negative Symptom Scale (PANSS). In addition, the rs2842030 and rs10759 SNPs yielded particularly positive PANSS responses among patients of African ancestry.
Additionally, African-descendant patients homozygous for the rs951439 CC or rs2842030TT genotype reacted more positively to the older perphenazine and Zyprexa than they did to other second-generation treatments.
“Differences in response to ziprasidone [Geodon] were striking,” the NIMH said in a statement. During treatment with Geodon, schizophrenia symptoms worsened in African-ancestry patients with rs951439 CC and rs2842030 TT genotypes. However, in those with rs951439 TT and 2842030 GG genotypes, ziprasidone was as effective as other treatments in patients of African descent.
“The same genetic variations did not have the same predictive value for ziprasidone in European-ancestry patients,” the researchers said.

“Although these analyses are exploratory and replication is required, these data provide support for RGS4 in schizophrenia pathogenesis and suggest a functional role for RGS4 in differential antipsychotic treatment efficacy of schizophrenia.”

Among nearly 400 European patients in the study, researchers identified “no significant global differences” between response to perphenazine and second-generation antipsychotics. In this group, the only differential responses were found with Risperdal treatment: European patients with rs951439 TT and rs2842030 GG genotypes responded more positively to the drug than patients with rs951439 CC and rs2842030 TT genotypes.
The results led Campbell’s team to conclude that the “RGS4 genotypes predicted both the severity of baseline symptoms and relative responsiveness to antipsychotic treatment.
“Although these analyses are exploratory and replication is required, these data provide support for RGS4 in schizophrenia pathogenesis and suggest a functional role for RGS4 in differential antipsychotic treatment efficacy of schizophrenia,” the study authors stated in the paper.
According to Campbell, study size may be the foremost confounding element of this study. Although it involved 678 schizophrenia patients from the CATIE trial, “following stratification by ethnicity and assigned drug, some of the analyzed groups contained less than 50 samples,” Campbell explained in an e-mail.
The researchers noted in the paper that while these results suggest that more than one functional variant in RGS4 might be linked to antipsychotic treatment response, the study also “emphasize[s] the importance of including multiple ethnic groups in a study design and the importance of substantially larger samples of under-represented ethnic groups than typically done in such studies.”
Campbell noted that there are several ongoing studies, funded by the National Institute of Mental Health, that seek to understand the genetics and pharmacogenetics of schizophrenia.
The NIMH is currently funding a study called “The Genetic Basis of Inherited Neurologic Deficits in People With Schizophrenia” looking at the genetic basis of brain dysfunction in adults with schizophrenia.
Another study, titled “Molecular Genetics of Schizophrenia,” aims to create a DNA collection with blood samples from families with at least two siblings who have schizophrenia symptoms in order to help scientists identify genes that predispose people to schizophrenia.
Additionally, the Pritzker Neuropsychiatric Disorders Research Consortium – which involves researchers from the University of Michigan, Weill Medical College of Cornell University, Stanford University, the University of California at Irvine, and the University of California at Davis – has announced it will use Ingenuity Pathway Analysis software to analyze the genetic and biological causes of depression, manic depression, bipolar disorder, and schizophrenia in order to identify treatments targets.
There are several companies looking into pharmacogenomic strategies to improve treatment for psychiatric disorders.
Roche has also sponsored a study that evaluated CYP2D6 testing with its AmpliChip in patients being treated for serious psychiatric disorders, such as schizophrenia or bipolar disorder in an in-patient setting [see PGx Reporter 01-09-2008].
Johnson & Johnson has currently amassed approximately 7,000 samples related to schizophrenia and around 3,000 samples associated with Alzheimer’s disease that it can tap to help it look for drug targets for these indications.
Additionally, J&J and Illumina have recently developed a DNA chip covering 1,000 genes and 30,000 SNPs associated with various psychiatric indications [see PGx Reporter 12-12-2007].

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