Gene Testing Could Help Predict Drug Responses

The field of psychiatric pharmacogenomics got under way about five to 10 years ago. Since then, scientists in the United States, Canada, England, Germany, Spain, Sweden, and elsewhere have become enthusiastic about it. Moreover, the field has been given a big push by some pharmaceutical companies.

GlaxoSmithKline is studying the relationship between patients' genetic variability and their response to medications, with the aim of using the information in drug development and in helping clinicians prescribe medications and doses for patients that are most likely to benefit them. In 2001 Allen Roses, M.D., senior vice president of genetics research at GlaxoSmithKline, predicted that before long, psychiatric pharmacogenomics would become a reality (Psychiatric News, April 20, 2001).

Roche Molecular Systems has developed a technique for screening gene variants of two drug-metabolizing enzymes involved in psychotropic drug metabolism. This AmpliChip CYP450 Genotyping test was approved by the U.S. Food and Drug Administration in January to help clinicians make more informed drug-prescribing decisions.

Such keen interest and technological advances have in turn spurred some provocative discoveries, the bulk having to do with the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6).

In the middle of the last century, scientists discovered that liver enzymes are involved in drug metabolism. Then in the 1970s they found that one liver enzyme—CYP2D6—is important for metabolizing psychotropic drugs. Since then, they have learned that CYP2D6 is involved in breaking down some 75 percent of all psychotropic medications. And thanks to the new field of psychiatric pharmacogenomics, they now know that there are more than 100 variations in the gene that codes for CYP2D6; that whereas most of these variants decrease enzyme activity, some can increase it; and that the CYP2D6 gene has the peculiar propensity to accumulate in multiple copies on the chromosome that contains it (chromosome 22).

So persons who have multiple copies of the gene metabolize psychotropic medications very rapidly.

Such findings have led to testing for such gene variants. Depending on which variant or variants they possess, people are usually categorized as being ultra-rapid, extensive, intermediate, or poor CYP2D6 metabolizers. This information can give psychiatrists some idea of how patients are going to metabolize psychotropic medications before patients receive them.

Most such testing has been done on a research basis. For example, Adrian Llerena, M.D., Ph.D., an associate professor of pharmacology at the University of Extremadura Medical School in Spain, is testing subjects for variants in genes that code for the CYP2D6 enzyme, as well as for some other enzymes.

Drug companies are also starting to use such testing to stratify subjects before clinical trials into good drug metabolizers and poor drug metabolizers, Mario Masellis, M.D., a postdoctoral fellow in psychiatry and neurology at the University of Toronto, told Psychiatric News.

Some testing for gene variants is beginning to be applied clinically as well.

Mark Linder, an associate professor of pathology at the University of Louisville, and coworkers operate a lab where psychiatrists can have patients tested for variants in genes coding for both the CYP2D6 enzyme and the cytochrome P450 2C19 enzyme (CYP2C19), he told Psychiatric News. The CYP2C19 enzyme is known to break down some psychotropic medications, but not nearly as many as the CYP2D6 enzyme does.

“We perform CYP2D6 and CYP2C19 gene analysis on psychiatric patients both as a routine service for psychiatrists and on a research basis,” Marja-Liisa Dahl, M.D., Ph.D., a professor of clinical pharmacology at Uppsala University in Sweden, told Psychiatric News. “The genotype analysis is also performed by at least two other clinical pharmacology laboratories in Sweden—the Karolinska University Hospital in Stockholm and the Linkoping University Hospital.”

For several years the Mayo Clinic has had a lab in which patients can be tested for variants in genes that code for both the CYP2D6 and CYP2C19 enzymes. David Mrazek, M.D., chair of psychiatry at Mayo, avails himself of these tests before putting patients on antidepressants or antipsychotics. For instance, he said, “The antidepressant paroxetine is primarily metabolized by the CYP2D6 enzyme. So if you discover that a patient is a poor CYP2D6 metabolizer, you would be careful about prescribing paroxetine for him or her and perhaps prescribe something else instead.”

“Any doctor in the country, or in the world, can send a small sample of blood from a patient to our laboratory,” Mrazek continued.“ Every day lots of specimens come in, and we send results back. So Mayo does a very good job, but there are lots of other choices as well, especially now that any hospital lab can buy the AmpliChip.”

Even with the ever-widening availability of labs where psychiatrists can have patients tested for such gene variants, challenges still need to be met before such gene-variant testing is widely embraced by psychiatrists.

For one, such testing must have practical value in a real-life clinical setting, and some evidence is building in this regard. For example, Jose de Leon, M.D., an associate professor of psychiatry at the University of Kentucky, along with fellow researchers, had the DNA of some 500 subjects taking risperidone tested using the AmpliChip assay. The investigators then looked to see whether subjects who turned out to be poor CYP2D6 enzyme metabolizers were the same subjects who had experienced adverse reactions to risperidone. The answer was generally yes, they reported in the January Journal of Clinical Psychiatry.

For patients to be open to gene-variant testing, they must see it as being in their best financial interests. Testing patients for variants in the genes that code for the CYP2D6 and CYP2C19 enzymes costs between $200 and $500.“ But you only have to do this test once in patients' lifetimes since their genes do not change,” Mrazek stressed.

For psychiatric hospitals to use such testing, it must make financial sense. De Leon is conducting a study on some 4,000 inpatients in Kentucky state psychiatric hospitals to determine whether testing for variants in the genes that code for the CYP2D6 and CYP2C19 enzymes is cost-effective.

Scientists in the field are optimistic that such challenges can be met. Masellis anticipates that such testing will become clinically widespread within the next five years. Mrazek, in fact, believes that “the field is about ready to explode.”

“Right now,” he said, “most doctors just get a history from patients, then think about the symptoms and think about the diagnosis, and give a drug they are familiar with a try. Ninety-five percent of the doctors do that. I think 10 years from now probably no one will do that! They will have a small sample of blood from the patient tested and will then conclude, `Oh, this patient would most likely respond well to drug X, but not to drug Y, so I will prescribe drug X.' In other words, it's just an extra window of information that most doctors don't have today, but that you will have five to 10 years from now.” ▪