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 January 2007 | Back to Table of Contents

Clinical and Health Affairs

Current Applications of Clinical Genetic Testing for Psychiatric Practice

By David A. Mrazek, M.D., F.R.C., Psych.

ABSTRACT
Pharmacogenetic testing allows physicians to identify patients who are likely to have adverse reactions to certain medications because they metabolize them poorly or too rapidly. Much research has focused on the gene P-450 2D6, which has been shown to affect patients’ response to various drugs including antidepressants and antipsychotics. Patients with certain genotypes may experience negative side effects from medications or may see no benefit at all. This article describes the first pharmacogenetic test to be widely used, which identifies variation in the P-450 2D6 gene, and the patient populations that would benefit from it.


Basic pharmacogenetic research over the last 30 years has set the stage for tailoring drug treatment to the patient’s genetic constitution.1 Clinical applications of that work are emerging, and it is now possible for practicing physicians to use new principles that are shaping the field of personalized medicine.

One of the genes of particular interest to psychiatrists is P-450 2D6. Variability in the structure of this gene is associated with dramatic differences in the availability of the 2D6 enzyme, which metabolizes more than 70 drugs, including atomoxetine (a selective norepinephrine reuptake inhibitor used for treating attention deficit hyperactivity disorder), antidepressants, and antipsychotics as well as commonly prescribed nonpsychiatric drugs such as codeine, dextromethorphan, and tamoxifen. For a decade, we have known that genetic variation in this gene affects metabolism of antidepressant medication.2

Genotyping of the cytochrome P-450 2D6 gene is the first pharmacogenomic test to be widely used. The test became available to practicing clinicians at Mayo Clinic in February of 2003. In April of 2004, it became available to all physicians who use the Mayo Medical Laboratories. Since then, Mayo Medical Laboratories has expanded its capabilities to include pharmacogenomic tests for the cytochrome P-450 2C19 gene, the cytochrome P-450 2C9 gene, the serotonin transporter gene (SLC6A4), and two of the serotonin receptor genes (2A and 2C). All provide information related to the response of patients to a variety of antidepressant medications.

In 2005, the Food and Drug Administration (FDA) approved a standard genotyping method developed by Roche Diagnostic Laboratories that can be easily adopted by any hospital clinical laboratory with the microarray platform for determining 2D6 and 2C19 genotypes. A small blood sample is all that is required from the patient. Although the FDA has suggested that people who are poor 2D6 metabolizers are at increased risk for adverse reactions to drugs metabolized by the 2D6 enzyme, the agency has not required that patients be tested to determine their metabolic status prior to being prescribed certain drugs. That may well change in the coming year.

Indications for 2D6 Genotyping
There are basically 2 reasons to determine the 2D6 genotype of a patient. The first is to identify individuals who are poor metabolizers and, thus, are more likely to have adverse side effects when prescribed 2D6 substrate medications. The second is to identify ultra-rapid metabolizers of these same medications. If a patient metabolizes a drug too quickly, the drug doesn’t have the intended effect. Knowing whether a patient is a poor or ultra-rapid metabolizer can help physicians determine which drugs—and which doses of those medications—will work best in certain individuals. It can also help them assess whether a patient’s symptoms are caused by certain medications or whether medications are interfering with one another.

A growing body of research supports the use of pharmacogenomic testing for psychiatric patients.3 Ongoing studies are showing that these tests may be especially valuable for certain populations. For example, about 1 in 10 Caucasians in Minnesota is a poor metabolizer of 2D6 substrate medications and only about 1 in 50 is an ultra-rapid metabolizer. However, slightly more than half of patients of Somali origin treated in Minnesota have a normal 2D6 genotype and will do well on normal doses of these medications, while approximately 3 in 10 are ultra-rapid metabolizers and will experience no therapeutic benefit of 2D6 substrate medications at standard doses. Physicians can use patients’ racial appearance or self-declaration of ethnic origin to make prescribing decisions that will increase the odds of their avoiding adverse drug reactions, but these clinical inferences are a poor proxy for genotyping.
Both psychiatrists and primary care physicians should be concerned about the potential of patients to react adversely to selective serotonin reuptake inhibitors (SSRIs). Although lethal reactions are quite rare, some tragic, avoidable deaths of patients who were poor metabolizers of 2D6 medications and were treated with high doses of those medications have been reported.4 The FDA’s black-box warning associated with prescribing such medications has highlighted the importance of monitoring suicidality during the initiation of treatment. Careful monitoring is particularly important for patients who are poor 2D6 metabolizers, as they are likely to have much higher levels of these medications in their bloodstream during the initiation of treatment. Poor 2D6 metabolizers are also believed to be at increased risk for manic or hypomanic symptoms for the same reason. Aside from these concerns, poor 2D6 metabolizers are more susceptible to sexual side effects and are at increased risk for the development of common side effects such as headaches and diarrhea. Although most of these adverse effects do not provide an immediate threat to patients, they are often associated with decreased compliance with their medication schedule, which can have a major impact on the effectiveness of the intervention.

Children are more vulnerable to the side effects of medications than adults because their complaints are often taken less seriously. Few adults will continue taking an SSRI if they experience intense headaches or other side effects, but children have less autonomy. By testing children to determine whether they are poor or ultra-rapid metabolizers of 2D6 medications, physicians can help them avoid adverse reactions and help their parents understand the possible reason behind complaints of side effects. Pharmacogenomic testing is particularly indicated for children whose mother or father has been shown to be either a poor or ultra-rapid 2D6 metabolizer.

Older patients also may benefit from pharmacogenetic testing. They may not remember which medications they have taken, whether they suffered side effects from those medications, or whether they responded well to them. Geriatric patients often take many medications for a variety of medical problems and may be at risk for drug interactions. For patients who are poor metabolizers, these interactions can be particularly dangerous.

Patients who require pain medication may be candidates for pharmacogenetic testing as well. Ideally, physicians should determine whether the patient has sufficient 2D6 enzyme to metabolize the pro-drug codeine to its active metabolite, morphine. A previous history of nonresponse would strongly indicate that the patient is a poor metabolizer. Alternatively, ultra-rapid metabolizers often experience a sudden euphoria, which can be unsettling. They may also experience less efficient pain relief as the gradual onset of increasingly severe pain develops before the patient anticipates a need for the next dose. Fortunately, most patients who experience these reactions quickly learn to avoid taking pain medications that include codeine.

Patients who take cold medications and are poor metabolizers of 2D6 can develop a high serum level of dextrometh-orphan after only a few doses. In extreme cases, this can lead to transient psychotic symptoms. Ultra-rapid metabolizers benefit very little from using this medication because of its rapid clearance.

One of the most important stories of 2006 in the area of genomics was the discovery that women who are poor metabolizers of 2D6 do not benefit fully from treatment with tamoxifen. Goetz et al. demonstrated this problem, which has been confirmed by other investigators.5 Furthermore, women who are receiving strong 2D6 inhibitors such as paroxetine and fluoxetine for depression or hot flashes do not appear to respond as well to tamoxifen as those who do not receive these inhibitors, even if they have a genotype that indicates adequate production of the 2D6 enzyme.

Genotyping in the Future
The only significant concern related to pharmacogenomic 2D6 genotyping is the cost of the test. The 2D6 test varies in price from less than $300 in some settings to more than $1,000 in others. However, the price is certain to drop with new technological advances and growing demand. Currently, many insurance companies pay for pharmacogenomic testing; but given that this is a relatively new procedure, there is some variability in how these tests are billed and reimbursed.

As the test becomes more widely used, knowing a patient’s genotype will be much like knowing their blood type. Within the next decade, pediatricians will probably gather this information by ordering a standard panel of pharmacogenomically relevant genes during the initial medical evaluation of a healthy infant. Other physicians will simply need to consult the medical records of their patients to clarify their drug metabolic status. However, for the time being, if a patient does not already know his or her 2D6 genotype, it is wise to test them in order to avoid easily detected adverse drug reactions. Clearly, the ancient admonition of Hippocrates that physicians should do no harm has already shifted the practice of many psychiatrists who are scrupulous about trying to minimize the side effects associated with psychotropic medications.

With the increased use of pharmacogenomic testing, both improved response to medications and a decrease in adverse reactions should be expected. These are the goals of personalized psychiatric care and ultimately will be an expectation of medical care provided by all specialties. MM

David Mrazek is chair of the department of psychiatry and psychology at Mayo Clinic.
 
References
1. Weinshilboum R. Inheritance and drug response. N Engl J Med. 2003;348;6:529-37.
2. Dalen P, Dahl ML, Bernal Ruiz ML, Nordin J, Bertilsson L. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.
Clin Pharmacol Ther. 1998 Apr;63(4):444-52.
3. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmoller J. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004 May;9(5):442-73. 4. Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic efficiency. J Child and Adolesc Psychopharmacol. 2000;10(1):27-34.
5. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of Tamoxifen Biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005;23(36):9312-8.
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