Psychiatric Times
June 2005
Vol. XXII
Issue 7
When a 9-year-old diagnosed with attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and Tourette's disorder died, the medical examiner attributed the cause of death to fluoxetine(Drug information on fluoxetine) (Prozac) toxicity (Sallee et al., 2000). Genetic testing of autopsy tissue confirmed the presence of a gene defect at the cytochrome P450 (CYP) 2D6 locus, which resulted in poor fluoxetine metabolism. In another case, a woman spent 10 years trying different treatments for her depression, but with each new antidepressant, she experienced excruciating headaches or other intolerable adverse effects until she was switched to a drug that did not need the CYP 2D6 enzyme to function (Lerner, 2004).
Psychiatrists and other physicians have long known that patients vary considerably in their responses to psychotropic medications, with some requiring much higher or lower doses than average and others failing to respond at all. Many factors, including diet, drug-drug interactions, gender, age, overall health, hepatic disease and genetic variations, can affect the availability of a drug in the body. Now, technology, clinical research and government policy are converging to create what has been called "personalized medicine." Advances in DNA testing combined with clinical studies are helping clinicians identify the best drug or dosing strategy for a particular patient.
Recently, the U.S. Food and Drug Administration cleared for marketing the first laboratory test system that allows physicians to consider unique genetic information from patients in selecting medications and doses for psychiatric disorders, among other medical conditions. The new test, the AmpliChip Cytochrome P450 Genotyping Test made by Roche Molecular Systems, Inc., was cleared for use with the Affymetrix GeneChip Microarray Instrumentation System, manufactured by Affymetrix, Inc. A microarray is similar to a computer microchip, but instead of tiny circuits, the chip contains millions of tiny DNA molecules. The test is performed using DNA extracted from a patient's blood. A person's DNA sequence is determined based on the sequence of the probe molecule to which the DNA is most similar.
Last December, the FDA cleared the AmpliChip CYP450 Test for CYP 2D6 and two weeks later cleared the test for CYP 2C19. The complete test kit and instrument system, a company spokesperson told Psychiatric Times, are being made available to reference laboratories and high complexity labs. The AmpliChip CYP450 Test was launched in Europe in fall 2004.
The test checks for the 31 polymorphisms (naturally occurring variations in DNA sequence) and mutations, including gene deletions and duplications, on a single chip (29 polymorphisms and mutations for the 2D6 gene and two polymorphisms for the 2C19 gene). The CYP 2D6 and CYP 2C19 enzymes play a role in the metabolism of about 25% of all prescription drugs. The polymorphisms influence how an individual metabolizes antidepressants, antipsychotics and other psychotropic medications. For example, by recognizing common DNA polymorphisms in the CYP 2D6 or CYP 2C19 genes, DNA chips can determine if an individual is a poor metabolizer who would be at increased risk for experiencing adverse drug reactions or toxicities or an ultrarapid metabolizer who would be at increase risk of being a nonresponder (Table).
