A U.S. Department of Veterans Affairs study has found that pharmacogenomic testing can help clinicians avoid prescribing antidepressant medications that may have undesirable outcomes. Results from the PRIME (PRecision Medicine In MEntal Health Care) Care study— which is claimed to be the largest clinical trial to date to examine a drug-gene interaction in patients with depression—indicated that patients who underwent genetic testing had more positive outcomes, compared with patients under usual care.
The study was led by principal investigator David Oslin, MD, chief of behavioral health at Corporal Michael J. Crescenz VA Medical Center (CMCVAMC), and director of the Department of Veterans Affairs Veterans Health Administration’s VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC). Oslin stated, “While the effect in the overall population was small, these findings indicate that for a key segment of patients, pharmacogenomic testing could provide an important piece of the puzzle clinicians face in developing effective, tolerable, personalized depression treatment plans.”
Karen Flaherty-Oxler, medical center director for the CMCVAMC, added, “The findings of this study will have far-reaching clinical implications for patients around the world.”
Oslin is also a professor of psychiatry in the Perelman School of Medicine at the University of Pennsylvania, and lead author of the team’s published report in JAMA, which is titled, “Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder—The PRIME Care Randomized Clinical Trial.”
Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an “imprecise practice,” and remission rates are about 30% at the initial treatment, the authors wrote. There is significant in interest in pharmacogenomic testing as a mechanism that will aid personalized medication selection. However, the team further acknowledged, “… despite the proliferation of pharmacogenomics testing, there is limited research demonstrating improved clinical outcomes.”
Most pharmacogenomics testing focuses on detecting variations in genes that code for cytochrome p450 (CYP450) enzymes, which can indicate how an individual metabolizes drugs. “In theory, pharmacogenomic testing may improve drug selection or dosing in patients with genetic variation that alters pharmacokinetics or pharmacodynamics,” the investigators continued. “Pharmacogenomic testing may be particularly helpful in the treatment of MDD where initial treatment response can be expected in 28% to 33% of patients, with the odds of remission and treatment engagement decreasing for each treatment trial.”
The PRIMECare study was designed to determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing might lead to better clinical outcomes.
A drug-gene interaction is an association between a medication and a genetic variant that may affect a patient’s response to drug treatment. Having that information helps the provider select the appropriate dosage for a specific patient. Oslin and his team focused a commercial battery of genes centered on the CYP450 system. The battery tested eight genes, six of which test for variants in liver enzymes. “The genes we tested don’t actually relate to depression,” Oslin said. “They relate to how a person metabolizes the drugs once they’re in the body. Some of these genes will cause the medications to metabolize much faster than normal. Others will cause the drugs to metabolize much slower than normal, which means you’ll end up with a lot of medication in your body.”
Oslin and his colleagues wanted to find out if genetic testing helped patients receive fewer medications with predicted drug-gene interactions and if that produced better outcomes. The study included nearly 2,000 patients from 22 VA medical centers who were randomized evenly, with half receiving pharmacogenomic testing and the other half getting usual care. The patients enrolled in the study were initiating or switching treatment with an antidepressant drug.
The patients in the control group received genetic testing, but their providers didn’t see the results. That meant those providers made medication choices for their patients that weren’t supported by pharmacogenomic tests. “That was really the crux of the study,” Oslin said. “Does the pharmacogenetic test help you choose the medicine that you want to use with this particular patient?”
The study found a marked shift in prescribing away from medications with significant drug-gene interactions or moderate drug-gene interactions. Overall, 59% of the patients in the genetic testing group received a medication with no predicted 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 would not see such a dramatic effect in predicted drug-gene interactions. He was “somewhat surprised” by the result. “There was essentially a major shift in avoiding medicines that had a predicted drug-gene interaction,” he said. The authors noted, “Among patients with MDD, provision of pharmacogenomics testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care.”
To test their DNA, the patients used a cheek swab. “Some companies do use a blood draw,” Oslin explained. “There’s no advantage or disadvantage to one versus 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 sample is then used to look at several very specific genes that are known to relate to the metabolism of antidepressants and many other drugs. But in this study, we were interested only in antidepressants.”
The researchers interviewed the patients about their depression outcomes. All three outcomes, depression remission, depression response, and symptom improvement, favored the group that received the genetic tests. They were all statistically significant over the course of 24 weeks, with a peak effect at 12 weeks. Depression outcomes were not statistically significant between the groups at 24 weeks. As the authors reported in their published paper, “Overall, there were small positive effects on symptom remission over the 24 weeks with peak differences early in the trial and no significant difference in remission at 24 weeks. The secondary outcomes of response and symptom reduction followed similar patterns.”
Oslin further noted, “We were not powered to look specifically at 24 weeks. That wasn’t part of our primary hypothesis. Our primary hypothesis was an overall effect. And we showed an overall effect in all three of the ways that we measured outcomes. So, it’s a glass half full, glass half empty kind of thing. Another way to think about the results is the group that had the pharmacogenetic test results had a faster response. That also was not something that we tested. But clearly if you look at 12 weeks in all three outcomes, the group that got the genetic test showed a better improvement in remission, response, and symptom improvement.
It’s important to realize that the test is not telling you whether the patient is going to respond to the treatment or not, Oslin pointed out. “It’s telling you something about how the patient metabolizes the medication. So it’s not telling me that this is a good medicine for the patient. It’s telling me not to prescribe this medicine, or perhaps to adjust the dosing, because the patient doesn’t metabolize it well.”
Most patients do not have a significant known antidepressant-gene interaction, Oslin stated. “ … however for the roughly 1-in-5 who do have affected genes, having test results that identify this will only serve to help clinicians tailor antidepressant medications that could reduce some of the uncertainty and trial-and-error involved in finding the right medication and dose for an individual patient. Moreover, as test results are applicable to many different medications and not just antidepressants, there is possibly a broader gain for patients when they get tested.” He noted that “from a VA policy perspective, I don’t think that we would say the study is robust enough that we recommend testing everybody.”
Moreover, stated Oslin, who is also a psychiatrist at the CMCVAMC in Philadelphia, “The results were not a slam dunk, and in fact, an important outcome of the study is that only about 15% to 20% of the patients had genes that would significantly interfere with the prescribed medication. But I think the results favoring a positive effect on treatment, although small, will encourage providers to test patients and get this genetic information. Future research should explore if there are subgroups of patients who would benefit more from testing.”
In recent years, pharmacogenomic testing has received greater attention as a tool to personalize medication selection and is often used for patients with health conditions such as cancer and heart disease. Many in the medical community hope the testing can also be helpful in treating people with major depressive disorder. Research has been limited, however, on demonstrating improved clinical outcomes.
In supplemental material, the researchers noted that the presence of PTSD in patients had a profound negative impact on remission from depression. Basically, the patients with PTSD responded poorly to antidepressants. “We know from the literature that PTSD doesn’t respond well to antidepressants,” Oslin said. The main psychotherapies for patients with PTSD, he points out, are cognitive processing therapy and prolonged exposure—both widely used in VA.
Investigators also found that Caucasians had the highest remission rates, African Americans were in the middle, and other races had the lowest remission rates. Race did not change the effects of the intervention and additionally, gender and age were not associated with a response. The authors wrote, “While the sample comprised only patients receiving care at VA medical centers with a higher proportion of males than a community sample, racial minority representation was higher than in typical clinical trials. Remission rates were significantly affected by subgroups.”
“One of the special ways that we did this study is as a pragmatic study in frontline clinical practices,” Oslin said. “We used clinicians and their patients. The providers all had to say that the patients were being treated for depression. But they could have had comorbidities, and many of them had comorbid PTSD, which had a big influence on treatment outcomes in a negative way.”
For providers who would like to do pharmacogenomic testing in the future, the burden is low across the board, Oslin noted. There’s no risk to patients in getting the test. “The costs actually are very low because the results can be used over the patient’s lifetime. So you’re not talking about a test that has a shelf life of only five minutes. And there’s really no risk to getting the test. You’re just getting the cheek swab or a blood test. Cost is low, risk is low, and the population benefits are probably low. But overall, this test likely benefits some patients substantially.”
