NEW YORK — Patients with major depressive disorder (MDD) in whom initial antidepressant therapy fails do better the next time around if their medication selection is guided by pharmacogenomic testing, according to results of the largest-ever pharmacogenomics clinical study in depression.
In the study, patients with treatment-resistant MDD were 30% more likely to respond to treatment and 50% more likely to achieve remission when their medication selection was guided by the GeneSight (Myriad Genetics) psychotropic genetic test.
The study was presented here at the American Psychiatric Association (APA) 2018 Annual Meeting.
Precision Prescribing
Currently, trial-and-error prescribing of antidepressants for MDD is a contributing factor in treatment failure, and it increases costs. Combinatorial pharmacogenomics may improve outcomes by identifying medications that, for genetic reasons, will be less effective, that may lead to more adverse events, and that may require being switched, principal investigator John Greden, MD, told Medscape Medical News.
The GeneSight test combines personal genetic data with medication information to shorten the road to recovery. The information involves 12 genes and 56 medications. DNA samples are taken with cheek swabs, which are sent to a laboratory. Results are returned in 36 hours in the form of a color-coded chart listing drugs with significant gene-drug interactions (red), those with moderate gene-drug interactions (yellow), and those that are not associated with any known genetic problems (green) for the patient.
This test can help spare the physician and patient from “riding through weeks” of an antidepressant trial only to fail, said Greden, executive director of the University of Michigan’s Comprehensive Depression Center, Ann Arbor.
“We’ve been using the test in our depression center, as have a number of centers, especially in patients who have failed a trial of antidepressants. In my case, I use it routinely for anyone who I am seeing for the first visit for the simple reason that I get referrals that are more difficult to treat and I want to know why they have failed other medications, so this is valuable information,” added Greden.
The study included 1167 outpatients with moderate to very severe treatment-resistant depression for whom at least one antidepressant medication had failed. Most patients had experienced at least three treatment failures. The mean age of the patients was 47.5 years, 71% were women, and most were white (81%). At screening and baseline, the patients had a score of 11 or higher on the 16-item Quick Inventory of Depressive Symptomatology.
The patients were divided into two groups. In one group, clinicians used GeneSight test results to guide treatment decisions (guided-care arm, n = 560). In the other group, clinicians prescribed medication as they normally would without the benefit of genetic testing (treatment-as-usual arm, n = 607). The primary assessment was the Hamilton Depression scale (HAM-D17). Patients were assessed at baseline and at 4, 8, 12, and 24 weeks.
At 8 weeks, symptom improvement (reduction in HAM-D17 score) was seen in the GeneSight guided-care arm relative to the TAU arm, but was not significant. Improvements in rates of response (50% decrease in HAM-D17 from baseline) and remission (HAM-D17 score <7) were significantly greater in the GeneSight guided-care arm.
Table 1. Outcomes at 8 Weeks by Treatment Arm
| Outcome | TAU | Guided-Care | P-Value |
|---|---|---|---|
| Symptom improvement | 24.4% | 27.2% | .11 |
| Response | 19.9% | 26.0% | .01 |
| Remission | 10.1% | 15.3% | .007 |
Response and remission rates continued to improve in the GeneSight-guided care arm through week 24, as did symptom improvement, demonstrating the long-term durability of the results, the researchers report.
The greatest potential utility of the test is for patients taking genetically incongruent medications. In this study, among the 213 patients taking incongruent medications at baseline, all outcomes were significantly improved among those who changed to congruent medications at week 8 compared to those who kept taking incongruent medications, as shown in Table 2.
Table 2. Outcomes at Week 8, Congruent vs Incongruent Medications
| Outcome | Incongruent | Congruent | P Value |
|---|---|---|---|
| Symptom improvement | 21.1% | 33.5% | .002 |
| Response | 16.7% | 28.5% | .04 |
| Remission | 8.5% | 21.5% | .007 |
“Achieving response and remission are the ultimate goals of treating patients with depression,” Greden said in a news release. “These results demonstrate promise for a pharmacogenomics approach to help improve short- and long-term response and remission rates in depressed adults compared to clinicians’ usual approaches to medication selection.”
Exciting Advance
Commenting on the findings for Medscape Medical News, James Murrough, MD, director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai in New York City, said the findings are “exciting.”
“The use of genetic testing to help determine antidepressant treatment for patients is something that the field has been working towards for a long time. It is not considered standard of care currently, so this study really adds significantly to the field and may make a real impact on clinical care,” said Murrough.
This study really adds significantly to the field and may make a real impact on clinical care.
“This is the first large-scale study I’ve seen testing whether treatment that was guided by pharmacogenetic testing actually produced superior outcomes compared with treatment as usual, so it’s an important study,” he said.
“Right now, there is overwhelming evidence of efficacy for drugs that are in the SSRI [selective serotonin reuptake inhibitor] or SNRI [serotonin-norepinephrine reuptake inhibitor] class, and these are considered first-line drugs for major depression, and approximately 50% of patients will respond to that first treatment,” Murrough noted.
“For the other 50% that don’t respond to the most effective medicines or the most highly recommended first-line treatments we have, the doctor says, ‘Now what can I do?’ That’s the time they are going to start looking for a biomarker or genetic test to help guide decision making,” he said.
“After someone doesn’t respond to a first-line SSRI or SNRI, there isn’t a lot of information to guide the clinician in the next step. That is where the need is, so that’s where I could imagine this technology starting to be utilized,” said Murrough.
According to the company, 30,000 physicians in the United States are currently using the GeneSight test. It has been used in the treatment of more than 700,000 patients.
The study was funded by Myriad Genetics. Dr Greden is an unpaid consultant to Assurex Health, a subsidiary of Myriad Genetics. Dr Murrough has disclosed no relevant financial relationships.
American Psychiatric Association (APA) 2018. Poster P5-110, presented May 7, 2018.
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