Tailor-Made Treatment: The Advent of Pharmacogenomics

Jose de Leon, MD

Director, University of Kentucky Research Office, Director, Residency Education, Eastern State Hospital

This interview was conducted by Peter Cook on July 20, 2006.

Introduction

Opinions differ regarding the respective domains of pharmacogenetics and pharmacogenomics—some say the former refers to the study of single-gene-mediated drug responses while the latter refers to responses governed by multiple genes. Others use pharmacogenetics to refer to the impact of genetics on drug metabolism and pharmacogenomics to cover the impact of genetics on drug binding in the brain. Few, however, would disagree that Dr. Jose de Leon is one of the foremost US experts on the role of genetics in the metabolism and binding of psychopharmaceuticals. Dr. de Leon emigrated from Spain 19 years ago in search of research opportunities not then available in his home country. He’s spent the last 15 years working in state hospitals with the most difficult of patients, many of them treatment-refractory schizophrenics.

Genetic Variation and Drug Metabolism

“In the early ‘90s,” Dr. de Leon says, “I learned of work being done by research scientists at the Karolinska Institute in Stockholm. When one takes oral medications, they’re destroyed, or metabolized, in the liver. The Swedish researchers had been leaders in finding relevant polymorphisms in the cytochrome 450 (CYP) enzymes that do much of the liver’s work. Some people didn’t have CYP, and were, consequently, poor metabolizers. Others, however, had multiple copies of the enzyme, and were, in effect, rapid metabolizers.” The breakthrough came in the strange case of 2 families, each with 3 family members taking antidepressants, none responding, and all evidencing very low rates of the drug in their blood. The treating psychiatrists would normally have suspected non-compliance, but with several family members all claiming to be taking their prescriptions, the psychiatrists decided to double-check. They sent DNA samples to the Karolinska Institute, where researchers found that patients from one family had 3 copies of CYP2D6, and patients from the other had 13 copies. Normal metabolizers have 1 or 2 functioning copies of CYP2D6, so antidepressants were being destroyed very quickly in these patients’ livers, and, thus, they were not benefiting from the drugs.

“I began to wonder if genetic polymorphisms affecting drug metabolism might be accounting for some of the difficulties in the patients I treated at my hospital,” Dr. de Leon says. “Medications come with average dosing recommendations, but any clinician can tell you that many patients aren’t actually average. Not long after my learning of the research being done at the Karolinska Institute, a colleague presented me the case of one of her patients who was taking clozapine at a regular dose, but had very high levels of the drug in her blood; the patient was also excessively sleepy. It turned out the patient was taking caffeine, in an effort to treat her sleepiness, and the caffeine was interfering with the metabolism of the clozapine, making her more sleepy. I became convinced that drug metabolism was a very important and overlooked issue in psychiatry.”

Genetic Testing

Dr. de Leon began researching genetics and their impact on enzymes and brain receptors in earnest. “Many of my patients were taking risperidone, which is metabolized by CYP2D6. However, there are more than 90 described variations of CYP2D6, so testing for it can be costly and complex.” Approximately 10–15% of whites and, generally, a lower percentage of people of other races, have CYP2D6 polymorphisms resulting in their either over-metabolizing or not metabolizing a number of antidepressants and antipsychotics. Working with Roche, Dr. de Leon helped to develop the AmpliChip, which tests for variations in CYP2D6 and CYP2C19 (another gene involved in some antidepressant metabolism with salient clinical polymorphisms). The AmpliChip comprises a glass microarray of DNA chain pieces (oligonucleotides). The DNA of the patient, labeled with a fluorescent marker, is added to the microarray and binds in a specific way, establishing which allele is present and allowing for quick and easy genetic testing. It’s a significant advance, and Dr. de Leon hopes to make similar inroads on genetic testing for polymorphisms affecting chemical receptors in the brain.

“Testing for polymorphisms in the liver is relatively easy,” Dr. de Leon explains. “Variations in blood medication levels can be used to detect genetic variations in liver enzymes. It’s much more difficult to test polymorphisms in the brain because we don’t have any agreed-on functional yardstick for measuring effects in the brain. PET scans are of some use for examining chemical binding, but they are not yet precise enough, and we still don’t fully understand how our psychiatric drugs affect the brain.”

Environmental factors further complicate the picture, as substance use and the presence of other medications can significantly impact the metabolism and binding of psychiatric drugs.

Adoption

Dr. de Leon stresses that he has no financial interest in the AmpliChip besides his ongoing study supported by Roche, but he hopes it is adopted into clinical practice. “The problem with this sort of technology is that it is much easier to convince patients of its value than doctors. With increasing costs and increasing patient populations, many hospital directors bristle at the idea that they might have to pay for genetic testing for every new patient. Of course, every patient is unique, but resources are limited.” Dr. de Leon is finishing a study that has already recruited 4,500 patients to test for the cost-efficiency of genetic testing in the psychiatric hospital setting. “Rapid metabolizers may not respond to typical doses of some medications while poor metabolizers may have dangerous side effects. Both extremes may be more expensive, according to a pilot study, so it’s quite possible that the costs of implementing genetic testing for high-risk patient populations will be overshadowed by the costs such testing would obviate. Of course, we just won’t know until the study is complete.”

The Future of Pharmacogenomics

Dr. de Leon has grown increasingly focused on studying the effect of genetics on drug response. “It’s a complex problem, and it’s difficult to get money,” Dr. de Leon says. “The NIH has traditionally avoided studies that aren’t double-blind and placebo- controlled, and they’ve favored studies involving patients taking only one medication. Recently, as demonstrated by the CATIE study, they’ve started putting energy into studies that more closely mirror the real world. In my hospital, patients take multiple medications, 70% are smokers, and 50% are or have been substance abusers. These are the real patients whose response to drugs, both in the liver and in the brain, we need to better understand.”

The other piece of the puzzle is convincing clinicians of the importance of better understanding pharmacogenomics. “I try to get people to understand that drug metabolism affects everyone,” Dr. de Leon says. “Take codeine or oxycodone. Both of these analgesics are commonly prescribed by the dentist, and both are metabolized by CYP2D6. Up to 15% of white people out there might have adverse reactions or do not respond to these analgesic drugs just based on polymorphisms in CYP2D6. Our medicine will be more precise and more humane if, when prescribing medicine, we acknowledge that many of our patients are not average.”

Disclosure: Dr. de Leon reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Source: http://www.postgradmed.com/issues/1999/11_99/cadieux.htm