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Jun 15, 2010 (Vol. 30, No. 12)

Pharmacogenomics on Its Way Toward Clinic

Technology Is Proving Its Worth in Assessment of Drug Efficacy, Toxicity, and Dosing

  • Psychiatric Therapy

    Cancer is just one example of a category of disease whose treatment is affected by genetic variation. Psychiatric medications also have a great deal of variation in effect, dosing, and toxicity between individuals, and much of this difference has been linked to specific genes.

    David Mrazek, M.D., chair of the department of psychiatry and psychology at Mayo Clinic, has focused his research on antidepressant and antipsychotic medications. His team tests for five gene variants. Three are drug-metabolizing enzymes, including the cytochrome P450 2D6 gene variants. Some 2D6 variants are completely ineffective, meaning the enzyme can’t metabolize medications like Paxil and pyroxitine. Of the two copies that each individual possesses, if both are ineffective, you have no 2D6 activity and can’t metabolize pyroxitine. Other classes of drugs affected by P450 enzymes include SSRI inhibitors and many antipsychotic medications.

    A case study illustrated how genetic testing can help schizophrenics in the real world. Some individuals have a form of the gene that is highly inducible, and highly active when the person smokes, and smoking is a common habit among people with schizophrenia.

    When a person with schizophrenia is admitted to a psychiatric hospital for treatment, they are typically not allowed to smoke, and thus their enzyme returns to a basal (noninduced) level. Once the patient is stabilized on an appropriate dose of olanzipine, an antipsychotic medication, they are released from the hospital and typically begin smoking again. This causes the enzyme to be induced once more, and destabilizes the illness, because the dose that was perfect in the hospital is now no longer enough to control symptoms.

  • Future

    Increasingly, patients want to be tested and told which drugs will work for them. “We’re getting closer to that, but we’re not quite there,” Dr. Mrazek said. “We can say this is a medicine you shouldn’t take, because it’s going to be very hard to get the dose right, or this is a medicine you shouldn’t take because it might not help you, but we still don’t have enough of an indication to say we can find a medicine and it will have a 90 percent probability of working.”

    Pharmacogenomics is a branch of personalized medicine that is rapidly entering clinical use. It has tremendous potential to help patients, but only if the information is organized and managed properly. Potential pitfalls include a too-narrow focus on specific mutations of SNPs, over- and undertesting due to lack of training or fear of liability, and information overload as the genome is explored. Simulation and prediction strategies can demonstrate how this information is useful in the clinic, but ultimately it will be necessary to test real genes and drugs in real patients in large-scale prospective studies such as CPMC.

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