Pharmacogenomic testing could help providers avoid prescribing antidepressant medications that have undesirable outcomes, suggests a new US Department of Veterans Affairs study.
Pharmacogenomics is the study of how genes influence the body’s response to drugs. The results of this new study appear in the Journal of the American Medical Association. The researchers found that patients who underwent genetic testing had more positive outcomes compared to patients receiving usual care. At 24 weeks of treatment, the group with genetic testing had a reduction in depressive symptoms – with a peak effect at 12 weeks.
Every patient in the study had major depressive disorder. Symptoms of that health condition include insomnia, loss of appetite, feelings of sadness and depression, and thoughts of dying by suicide. The study was led by Dr. David Oslin, director of the VA’s VISN 4 Mental Illness, Research, Education and Clinical Center (MIRECC). He hopes the results will encourage providers to consider using pharmacogenomic testing with patient consent to help drive treatment decisions.
“From a VA policy standpoint, I don’t think we can say it’s a solid enough study to recommend that everyone get tested,” said Oslin, who is also a psychiatrist at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia.
“The results aren’t a slam dunk. In fact, the most important result of the study is that only 15% to 20% of patients have genes that significantly interfere with the prescribed medication. But even if the results are small, I think that the positive impact on treatment will encourage providers to test patients and get this genetic information. Future research should explore if there are subgroups of patients who may benefit more from testing.”
In recent years, pharmacogenomic testing has received increasing attention as a tool to personalize drug selection and is often used to treat patients with health conditions such as cancer and heart disease. Many in the medical community hope the test will also be helpful in treating people with major depressive disorder. Research is limited in demonstrating improved clinical outcomes. Currently, most pharmacogenomic tests focus on variation in genes encoding hepatic CYP450 enzymes, the pathway that metabolizes drugs in the liver.
Oslin and his team used a commercial battery of genes focusing on the CYP450 system. The battery tested eight genes, six of which tested for variations in liver enzymes. What do genes have to do with antidepressants?
“The genes we tested were not actually associated with depression,” Oslin said. “They have to do with how a person metabolizes drugs after they enter the body. Some of these genes cause drugs to metabolize much faster than normal. Others cause drugs to metabolize much slower than normal, meaning you end up with a lot of drugs in your body.
Patients enrolled in the study were starting or changing treatment with an antidepressant drug. The study involved nearly 2,000 patients from 22 VA medical centers who were randomized, with half receiving pharmacogenomic testing and the other half receiving usual care.
Oslin and his colleagues aimed to determine whether genetic testing could help patients receive fewer medications with drug-gene interactions and whether that would lead to better outcomes. A drug-gene interaction is an association between a drug and a gene variant that affects a patient’s response to drug therapy. Having that information helps the provider select the appropriate dose for a particular patient.
Patients in the control group received genetic testing, but their providers did not see the results. That means those providers made drug choices for their patients that were not supported by pharmacogenomic testing.
“That’s really the crux of the study,” Oslin said.
“Will the pharmacogenetic test help you choose the drug you want to use with this particular patient?” The study found a significant shift in prescribing away from drugs with significant drug-gene interactions or moderate drug-gene interactions. Overall, 59% of patients in the gene test group received drugs without drug-gene interaction, compared with 26% in the control group. The researchers defined that difference as “statistically significant and clinically meaningful.”
Oslin said he went into the study thinking the research team wouldn’t see such a dramatic effect in hypothetical drug-gene interactions. He was “somewhat surprised” by the result. “There is a significant shift toward avoiding drugs that predict drug-gene interactions,” he says.
To test their DNA, patients used a cheek swab. “Some companies use a blood draw,” Oslin explained.
“There is no advantage or disadvantage to one over the other. It really has to do with how the company processes the sample. Cheek swabs and blood samples are the most common sources of DNA. The model is then used to look at several specific genes involved in the metabolism of antidepressants and many other drugs. But in this study, we are only interested in antidepressants.
Researchers interviewed patients about their depression outcomes. All three outcomes—depression remission, depression response, and symptom improvement—favored the group that received genetic testing. They were all statistically significant at 24 weeks, with a peak effect at 12 weeks. Depression results were not statistically significant between groups at 24 weeks.
“We didn’t have the energy to look specifically at 24 weeks,” Oslin explains. “That’s not part of our primary hypothesis. Our primary hypothesis is the total effect. And we looked at the total effect in the three ways we measured the results. So, it’s a glass half full, glass half empty. Another way to think about the results is that we have pharmacogenetic test results. group has a faster response. That’s also not what we tested. But clearly, if you look at 12 weeks out of the three outcomes, the group that got the genetic test showed the greatest improvement in remission, response and symptom improvement. “It’s important to realize that the test doesn’t tell you whether or not the patient is going to respond to treatment, He said.
“It tells you about how the patient metabolizes the drug. So I am not saying that this is a good drug for the patient. It tells me not to prescribe this drug, or to adjust the dose because the patient does not metabolize it well. In supplemental material, the researchers noted that the presence of PTSD in patients had a profoundly negative effect on relief from depression. Basically, patients with PTSD respond poorly to antidepressants.
“We know from the literature that PTSD does not respond well to antidepressants,” Oslin said. He points out that the main psychological treatments for patients with PTSD, cognitive processing therapy and prolonged exposure—are both widely used at the VA. “One of the unique ways we did this study was as a practical study in frontline clinical practices,” Oslin said.
“We used physicians and their patients. The providers all had to say that the patients were being treated for depression. But they might have comorbidities, and many of them had comorbid PTSD, which could have a big impact on treatment outcomes in a negative way.
For providers looking to perform pharmacogenomic testing in the future, Oslin said, the burden will be lower across the board. There is no risk to the patients from undergoing the test. “The costs are actually very low because the results are used over the lifetime of the patient,” Oslin said.
“So you’re not just talking about a test that has a five-minute shelf life. And there is really no danger in getting tested. You are getting a cheek swab or blood test. The cost is low, the risk is low, and the population benefits may be small. But overall, this test can significantly benefit some patients.
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