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Pharmacogenomic Testing May Curb Drug Interactions in MDD

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A new study shows that pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize drugs, reduces adverse interactions between drugs and genes.

In a randomized clinical trial that included nearly 2,000 adults with MDD, patients in the pharmacogenomic control group were more likely to receive an antidepressant that had no potential drug-gene interaction than patients who received conventional treatment.

In addition, among the intervention group, the remission rate at 24 weeks was significantly higher.

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Dr. David Oslin

“These tests may help rethink antidepressant choice, but clinicians should not expect them to be beneficial for every patient,” researcher David W. Oslin, MD, Corporal Michael J. Crescenza, Virginia Medical Center and professor of psychiatry at Perelman School. This is reported by Medscape Medical News from the University of Pennsylvania in Philadelphia.

The results were published online July 12 in JAMA.

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Less trial and error

Pharmacogenomic testing can provide information for drug selection or dosing for patients with genetic variations that alter pharmacokinetics or pharmacodynamics. The researchers note that such testing may be particularly helpful for patients with MDD, as less than 40% of these patients achieve clinical remission after initial antidepressant treatment.

“To get a treatment that works for a person, it’s not unusual to try two, three, or four antidepressants,” Oslin said. “If we could reduce that variance a bit with a test like this, that would be a huge advance from a public health standpoint.”

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The study included 676 physicians and 1,944 adults with MDD (mean age 48 years; 24% women) treated at 22 Department of Veterans Affairs medical centers. Eligible patients were assigned to new antidepressant monotherapy and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to obtain test results when they were available (PG control group) or after 24 weeks (usual care group). In the first group, clinicians were asked to begin treatment when test results were available, usually within 2–3 days. In the latter group, they were asked to start treatment on the day of randomization.

The scores included a 9-item patient health questionnaire (PHQ-9) with scores ranging from 0 to 27, with higher scores indicating worsening symptoms.

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Of the total patient population, 79% completed the 24-week evaluation.

The researchers characterized antidepressants based on drug-gene interaction categories: unknown interactions, moderate interactions, and significant interactions.

Additional primary outcomes were initiation of treatment within 30 days, defined on the basis of drug-gene interaction categories, and remission of depressive symptoms, defined as a PHQ-9 score ≤5.

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The evaluators, who were not aware of the clinical care and randomization of the study, evaluated the results at 4, 8, 12, 18, and 24 weeks.

Significant impact?

The results showed that the pharmacogenomic control group was more likely to receive an antidepressant that had no potential drug interaction with the gene, as opposed to the moderate/significant interaction group (odds ratio [OR], 4.32; 95% CI, 3.47–5.39; P < 0.001).

The usual care group was more likely to receive a drug with a potential mild drug–gene interaction (no/moderate interaction versus significant interaction: OR, 2.08; 95% CI, 1.52–2.84; P = 0.005).

For the intervention group, the estimated rates of antidepressant use without, moderate, and significant drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual care group, the estimates were 25.7%, 54.6%, and 19.7%.

The fact that 1 in 5 patients who received conventional care initially received a drug for which there was a significant interaction between drugs and genes means this is “not a rare event,” Oslin said. “If we can influence 20% of the people we prescribe, that’s actually quite a lot.”

The remission rate was higher in the group receiving pharmacogenomic control for 24 weeks (OR 1.28; 95% CI 1.05–1.57; P = 0.02; absolute risk difference 2.8%; 95% CI 0. 6–5.1%). .

Secondary treatment response outcomes, defined as a reduction in PHQ-9 score of at least 50%, also favored the pharmacogenomic control group. This was also the case for the secondary outcome of reduced symptom severity on the PHQ-9 scale.

Oslin noted that some physicians are skeptical of pharmacogenomic testing, but the study provides further evidence of its usefulness.

“While I don’t think testing should become standard practice, I also don’t think we should create barriers to testing until we can better understand how to target testing” to those who will benefit the most, he added.

The tests are available at a commercial price of around $1,000, Oslin said, which may not be that expensive if the testing has a significant impact on a patient’s life.

Important research, but with some limitations

In an accompanying editorial, Dan V. Iosifescu, MD, Associate Professor of Psychiatry at New York University School of Medicine and Director of Clinical Research at the Nathan Kline Institute for Psychiatric Research, called this study an important addition to the literature on pharmacogenomic testing in patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials, and is one of the few studies not funded by a pharmacogenomic test manufacturer, writes Iosifescu, who was not involved in the study.

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However, he notes that no antidepressant was prescribed within 30 days of randomization in 25% of the intervention group and 31% of the usual care group, which was “puzzling”. “Because these rates were comparable across the two groups, this cannot be explained primarily by the delay in pharmacogenomic test results in the intervention group,” he writes.

In addition, as a co-primary outcome in symptom remission rates, the difference in clinical improvement in favor of pharmacogenomically targeted treatment was only “moderate” – an increase of less than 2% in Iosifescu’s proportion of patients achieving remission. adds.

He adds that this is “probably not very clinically significant, even though this difference reaches statistical significance in this large study sample.”

Other potential limitations of the study that he cites include the lack of blinding of patients when prescribing treatment, and the lack of clarity as to why MDD response and remission rates over time were relatively low in both treatment groups.

A possible approach to optimizing antidepressant choice could involve integrating pharmacogenomic data into larger predictive models that include clinical and demographic variables, Iosifescu notes.

“Developing such complex models is challenging, but it is now possible given significant recent advances in computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), the Health Research and Development Service, and the Mental Health Research, Education, and Clinical Center at Corporal Michael J. Crescenz Medical Center, Virginia. Oslin says he received grants from Virginia Research and Development and Janssen Pharmaceuticals, as well as non-financial support from Myriad Genetics during the study. He also co-chaired the VA/Department of Defines Clinical Practice Practice Guidelines for Major Depressive Disorder at the time of the study. Iosifescu says he has received personal honoraria from Alkermes, Allergan, Axsome, Biogen, Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion, as well as grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire. .

JAMA. Posted online July 12, 2022 Editorial abstract

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