But Results Weren’t Conclusive Enough for Widespread VHA Use
David Oslin, MD, director of VA’S VISN 4 Mental Illness, Research, Education and Clinical Center (MIRECC), said that pharmacogenomic testing can be helpful for prescribing antidepressant medications. VA photo by Jonathan Hodges
PHILADELPHIA — Pharmacogenomic testing can help clinicians avoid prescribing antidepressant medications that might have undesirable outcomes. In fact, a recent VA study found that patients who underwent genetic testing had more positive outcomes, compared with patients in usual care.
The report in JAMA noted that, over 24 weeks of treatment, the veterans with major depressive disorder (MDD) who received genetic testing had a decline in depression symptoms with a peak effect at 12 weeks.1
But VA clinicians shouldn’t expect a dramatic change in practice as a result of the study. Researchers advised that, while pharmacogenomic testing for drug-gene interactions in MDD reduced prescription of medications with predicted drug-gene interactions, it had only a small and nonpersistent effect on symptom remission.
The study was led by David Oslin, MD, director of VA’s VISN 4 Mental Illness, Research, Education and Clinical Center (MIRECC). He suggested the results might encourage providers to consider using pharmacogenomic testing, with patient consent, to help improve treatment decisions.
“From a VA policy perspective, I don’t think that we would say the study is robust enough that we recommend testing everybody,” explained Oslin, who is also a psychiatrist at the Corporal Michael J. Crescenz VAMC 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.”
Background information in the article pointed out that choosing effective antidepressants for the treatment of MDD can be imprecise and has remission rates of about 30% at the initial treatment.
Oslin’s study team sought to determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.
Researchers conducted a pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs. usual care. Participants included 676 clinicians and 1,944 patients who were enrolled from 22 VAMCs from July 2017 through February 2021, with follow-up ending November 2021. Patients were eligible if they were diagnosed with MDD and were initiating or switching treatment with a single antidepressant. Veterans with active substance use disorder, mania, psychosis or concurrent treatment with a specified list of medications were excluded.
In the pharmacogenomic-guided group, involving 966 patients, clinicians were provided with results from a commercial pharmacogenomic test. At the same time, the comparison group of 978 veterans received usual care and access to pharmacogenomic results after 24 weeks.
‘Crux of the Study’
“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?”
Defined as the co–primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire–9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5).
The 24-week assessment was completed by 79% of the patients, who had a mean age of 48 and were 25% women.
Results indicated that the estimated risks for receiving an antidepressant with none, moderate and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0% and 10.7%, respectively, compared with 25.7%, 54.6%, and 19.7% in the usual care group.
“The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < 0.001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = 0.005) (P < 0.001 for overall comparison),” the researchers explained. “Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = 0.02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = 0.45).”
The authors concluded that, among patients with MDD, pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care, adding, “Provision of test results had small nonpersistent effects on symptom remission.”
Oslin explained that most of the pharmacogenomic testing focuses on a variant in the genes that encode hepatic CYP450 enzymes, a pathway that metabolizes drugs in the liver, adding, “The genes we tested don’t actually relate to depression. 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.”
That fewer patients received medications with significant drug-gene interactions or moderate drug-gene interactions was called “statistically significant and clinically meaningful” in the study. Overall, 59% of the patients in the genetic testing group received therapies with no predicted drug-gene interaction, compared with 26% in the control group.
Oslin said he was “somewhat surprised” by the result. “There was essentially a major shift in avoiding medicines that had a predicted drug-gene interaction.”
Essentially, results were statistically significant over 12 weeks, according to Oslin, who advised, “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.”
For providers who opt to do pharmacogenomic testing in the future, Oslin pointed out that the burden is low, with no risk to patients getting tested.
“The costs actually are very low, because the results can be used over the patient’s lifetime,” Oslin noted. “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.”
- Oslin DW, Lynch KG, Shih M, et al. 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. JAMA. 2022;328(2):151–161. doi:10.1001/jama.2022.9805
