Pharmacogenomic Testing Might Aid Antidepressant Treatment, Researchers Say

By Will Boggs MD

NEW YORK (Reuters Health) - Pharmacogenomics testing might help to identify less effective medications for patients with major depressive disorder, according to results from the GUIDED trial.

Pharmacogenomic testing has been proposed as a way of identifying metabolic variants that could influence the effectiveness of particular medications, but evidence supporting this approach remains limited and inconsistent.

Dr. John F. Greden of the University of Michigan Comprehensive Depression Center and National Network of Depression Centers in Ann Arbor and colleagues compared active treatment guided by pharmacogenomic testing against unguided active treatment as usual in their study of patients with major depressive disorder who had failed at least one antidepressant trial (mean, 3.51 failed medications).

Patients and raters were blinded to study arm, but clinicians could not be blinded to study arm, as the pharmacogenomic test results had to be consulted to select potential medications for the guided-care arm.

Unblinding may have occurred prior to week 12, but data collected through week 8 of the 24-week trial were considered blinded. The protocol did not mandate adherence to the test results.

Overall, 1,541 patients were included in the final intent-to-treat group; the per-protocol group included 1,398 patients (681 in the guided-care arm and 717 in the treatment-as-usual (TAU) arm); 1,167 per-protocol patients completed the study through the blinded week-8 endpoint.

At week 8, the improvement in HAM-D17 scores, the primary endpoint, did not differ significantly between the guided-care arm and the TAU arm, the researchers report in the Journal of Psychiatric Research, January 4.

In contrast, among secondary outcomes, the response rate was significantly higher in the guided-care arm (26.0%) than in the TAU arm (19.9%), as was the remission rate (15.3% vs. 10.1%).

Response was defined as at least a 50% decrease at week 8 in HAM-D17, Quick Inventory of Depression Symptomatology (QIDS-C16), or Patient Health Questionnaire (PHQ-9). Remission was defined as having a score of 7 or less for HAM-D17, 5 or less for QIDS-C16 and less than 5 for PHQ-9.

The proportion of patients who were prescribed medications congruent with the pharmacogenomic test report increased from 79.4% (456/574) to 91.2% (508/557) in the guided-care arm but remained relatively unchanged from the baseline 77.5% (476/614) in the TAU arm.

The magnitude of improvements in symptoms, response rates, and remission rates was significantly greater for patients on incongruent medications at baseline who switched to congruent medications by week 8, regardless of study arm assignment.

The number of side effects through week 8 did not differ between the groups, but patients taking incongruent medications at baseline who switched to congruent medications by week 8 had fewer side effects compared to those who remained incongruent.

The researchers conclude "that pharmacogenomic testing is effective in improving response and remission rates among those with prior treatment resistance, particularly for patients who are treated with medications that are incongruent with their genetic profile."

Dr. Roger S. McIntyre of the University of Toronto, Canada, whose recent meta-analysis provided preliminary support for improved response and remission rates in major depressive disorder with pharmacogenomics-guided treatment, disagreed. He told Reuters Health by email, "The study is a negative study. Gene testing should not be used, for it does not work on efficacy, as this study seems to prove; maybe another study will show it helps on side effects."

Dr. Chad Bousman of the University of Calgary, also in Canada, found higher rates of symptom remission with pharmacogenetic-guided treatment of major depressive disorder in a separate meta-analysis of 1,737 individuals from five randomized controlled trials.

"There is lively debate about when and for who pharmacogenetic testing should be offered, with no consensus," he told Reuters Health by email.

"The benefits of testing are dependent on the timeframe that they are examined," he said. "Pharmacogenetic test results have the potential to provide benefits for the lifetime of the patient because the genes tested have implications for drugs other than antidepressants, for example antipsychotics, analgesics, and proton-pump inhibitors. Capturing the full potential benefit of testing is not possible in a 24-week trial."

In a statement from November 1, Dr. Jeffrey Shuren, director of the U.S. Food and Drug Administration (FDA)'s Center for Devices and Radiological Health, and Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, commented on the agency's warning to consumers about genetic tests that claim to predict patients' responses to specific medications.

They wrote, "The FDA is aware of genetic tests that claim results can be used by physicians to identify which antidepressant medication would have increased effectiveness or side effects compared to other antidepressant medications. However, the relationship between DNA variations and the effectiveness of antidepressant medications has never been established. Moreover, the FDA is aware that health care providers have made changes to patients' medication based on genetic test results that claim to provide information on the personalized dosage or treatment regimens for some antidepressant medications, which could potentially lead to patient harm."

"We believe, with more scientific study, there is great potential for pharmacogenetics," they conclude. "We have so much more to learn about the use of these tests for specific medications, what the results mean, and how we can apply the information to improve a patient's health. While we are committed to supporting innovation in this area, we will also be vigilant in protecting against the potential risks."

When the FDA approved the 23andMe Personal Genome Service Pharmacogenetics Reports test, it cautioned that the test of 33 variants for multiple genes "is not intended to provide information on a patient's ability to respond to any specific medication. The test does not describe an association between the detected variants and any specific drug nor whether a person will or will not respond to a particular drug. Furthermore, health care providers should not use the test to make any treatment decisions."

"Results from this test should be confirmed with independent pharmacogenetic testing before making any medical decisions," they added.

Assurex Health, which manufactured the GeneSight test used in this study and has been acquired by Myriad Genetics Inc., sponsored the study and employed several of the authors.

Dr. Greden did not respond to a request for comments.

SOURCE: https://bit.ly/2Hl1jIN

J Psychiatr Res 2019.

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