DNA Testing Pinpoints Metabolic Differences That Cause Adverse Drug Reactions

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Applying a major advance in genetic research called DNA micoarray technology, NARSAD Investigator Jose de Leon, M.D., and his team at the University of Kentucky, screened 4,532 psychiatric patients to determine individual genetic variations that can alter the effectiveness of antipsychotic and antidepressant medications. The results were published in the January 2009 issue of the journal CNS Spectrums.

Cytochrome P450 (CYP) is the collective name for a group of enzymes, among them CYP2D6 and CYP2C19, critical to the metabolism of a number of drugs. CYP2D6 and CYP2C19 genes are highly polymorphic, meaning their DNA sequences can vary from person to person. These variations correlate with the frequency and severity of serious drug reactions, length of treatment and cost of treatment for patients with severe mental illness.

DNA microarray technology, which has revolutionized medical genetics, provides a relatively simple and inexpensive system for simultaneously testing thousands of DNA sequences. Through their screening and analysis, Dr. de Leon and his group were able to classify metabolic variations and to propose a numeric system for expression of CYP2D6 and CYP2C19 enzyme activity to aid clinicians in determining treatment strategy for patients receiving therapeutics metabolized by these gene products.

The patients, recruited from three state hospitals, were tested with the antipsychotic risperidone, one of the most frequently used psychiatric drugs.

The tests revealed the prevalence of CYP2D6 poor metabolizers to be 7.6 percent, CYP2DC ultrarapid metabolizers 1.5 percent and CYP2C19 poor metabolizers 2 percent. The report noted that the proposed numeric system “is a preliminary, rough approximation that serves as a useful teaching tool and predicts risperidone levels.”

Dr. de Leon is professor of psychiatry at the University of Kentucky and medical director of the Mental Health Research Center at Eastern State Hospital, in Lexington, where he first conducted pilot patient studies with the support of a NARSAD Independent Investigator grant in 2000. A second NARSAD grant, in 2005, helped to fund the current study.

Dr. de Leon has stated: “Adverse drug reactions are the fourth to fifth leading cause of death in the United States, cause an additional 2.2 million hospitalizations, and cost the health care system $4 billion annually in direct treatment costs.” The goal of his research, is to provide “a body of evidence that will help doctors to select the best therapy sooner, minimize the risks to the patient, and avoid unnecessary treatment costs by testing individual metabolic status before they write a prescription or set a dosing level.”

(This article was adapted with permission from CNS Spectrums and the University of Kentucky.)

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