TCPR: You mentioned the genome-wide association study (GWAS) analysis. What is GWAS?
Dr. Hamilton: GWAS allows US to look not at just a few genes, but tens of thousands of genes and millions of genetic polymorphisms simultaneously. GWAS asks whether variations from numerous genes across the genome, each of which might contribute only a small amount individually, might together influence a phenotype. Also, the question can be asked whether combinations of variants from a multitude of genes influence medication response. In a recent article, we combined all the data from large European and American studies and it was still insufficient to see anything of strong statistical significance. The individual contribution to antidepressant response by variation from numerous genes is of such low amplitude that we can’t detect it with the numbers of samples that we have (GENDEP Investigators, MARS Investigators, STAR*D Investigators, AmJPsychiatry 2013;170(2):207- 217). In the case of schizophrenia, a recent study suggested that there are over 100 variants that influence risk for this disorder. But it took tens of thousands of samples to find them. It is one thing to find someone with a particular disease phenotype, but to find someone who has gone through a clinical trial with a well-delineated treatment response phenotype–is much more difficult. SO for our meta-analysis we only had several thousand individuals, which is probably insufficient to find the pattern of variation that would help in what you are describing for personalizing medication choice.
There have never been any consistent correlations between clinical response to medications and any of these particular genotypes.
~ Steven Hamilton, MD, PhD
TCPR: Can you describe what pharmacogenetic tests are currently available to psychiatrists?
Dr. Hamilton: A great resource is a website called GeneTests.org. It is a compendium of genetic tests, not only for rare genetic disorders, but also more common tests as well. You can search for a genetic test and it will actually give you a list of all the different providers of this test. An alternative website, where practitioners can get information about genetic tests, their costs, and comparisons, is Nextgxdx.com. There are several commercial operations that sell tests for psychiatric applications. I am not recommending any of them, in any way, by mentioning them. They include Genomind, Pathway Genomics, Genelex, and Assurex Health.
TCPR: In addition to 2D6 and 2C19, there are other pharmacokinetic genes, as well as a number of pharmacodynamics genes, such as the serotonin transporter (SLC6A4), DRD2, and MTHFR, offered as a part of commercial tests. Do these also help to guide treatment options?
Dr. Hamilton: To put it simply, no. In my work studying all of these genes, as well as the work of many others, there have never been any consistent correlations between clinical response to medication and any of these particular genotypes. They are very appealing because they get at presumptive mechanisms for these drugs, but when you actually look at large samples for which there is statistical power to detect an association, the findings are either inconsistent or just don’t exist. The evidence just does not support any of them at this time.
TCPR: These tests have a reputation for being expensive. How much do they cost?
Dr. Hamilton: The prices for a relatively focused gene panel such as 2D6 and 2C19, in general, run in the hundreds of dollars. I am not aware of a strong push to get insurance companies to pay for these.
TCPR: Can you speak to the applications of commercial genome tests such as the one offered by 23andMe? Could a commercial test such as that give me the same information as these pharmacogenetic tests?
Dr. Hamilton: 23andMe offers an inexpensive genome test—about $99. I think it gives data on about a million genetic variants, including functional variants in 2C19. The information provided depends on the variant. For instance, the 2D6 region is so extremely complicated at the structural level that many of these commercial genome-wide tests such as 23andMe do not really test that gene very well, if at all. On the other hand, the information about 2C19 is in there, along with several other variants. Right now, the FDA does not allow 23andMe to give you any advice relating to the variant.
TCPR: Are you aware of any pharmaceutical developments capitalizing on specific pharmacodynamic polymorphisms?
Dr. Hamilton: There are examples from the cancer literature where specific drugs are targeted to particular mutations in tumors, but we are not there yet for psychotropics.
TCPR: Thank you, Dr. Hamilton.