05. 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

Text version

Are you using genetic testing to guide your choice of antidepressants? Perhaps you’ve thought, “It doesn’t cost much, so if it improves outcomes even a little bit, of course.” But then your impression of efficacy is subject to multiple cognitive biases, right? So, we really need a randomized trial of pharmacogenomic testing that was not deeply sponsored by the lab tests manufacturer. And finally, we have one. At the start of the trial, imagine 2,000 people with a PHQ-9 of 10 or higher. The finish line remission is a PHQ-9 of 5 or less. Half the participants have genomic test results when their antidepressant decision is made, and half do not. That control group gets their results 6 months later. And they’re off! Will the genomic testing push more people over the remission finish line? Answer: It depends on when you look. Four weeks? No. At 8 weeks, the results-now group is edging ahead of the results-later group. At 12 weeks, the results-now group is statistically significantly ahead in terms of achieving remission. And then as the race continues, at 18 weeks the difference is shrinking. And at 24 weeks, it’s gone. Was it worth it?

Well, wait a minute. Remember the old “It was statistically significant, but was it clinically significant” question? Let’s look at that 12 weeks’ advantage, the largest one. In the results-now group, the remission rate was 16%. Yeah, this is a tough crowd—veterans, 60% with PTSD and other reasons for treatment resistance. In the control group, who were tested but whose results would only become available after 6 months, the remission rate at 12 weeks was 11%. Sixteen percent vs 11% at 12 weeks, less of a difference before and after that. Well, that’s a big percentage difference but maybe a relatively small absolute difference? We’ll compare the reductions in PHQ-9 scores. At 12 weeks, the results-now group had dropped their scores by 5.3 points; the results-later group by 4.4 points. The genetic testing improved outcomes by 1 point on the PHQ-9 at maximum. By 24 weeks, it was one-third of a point.

Well, you can tell I’m not a convert to genetic testing, so take the following 3 quibbles with a grain of salt before we turn to conclusions. First, note that the results-now group got what they were hoping for, which was genetic testing, and the results-later group got disappointed. Second, the results-now group was instructed to call in if they’d not been started on an antidepressant in 10 days, and that group was slightly more likely to actually receive an antidepressant—75% vs 69% of the control group. And third, the genetic test was explained in brochures, a website, and a video and all of these were immediately relevant and presumably reinforcing of hope but, again, only for the results-now group. Similarly, the test manufacturer made available a call center for questions and they knew the veteran’s name from the test result code for personalized support.

But the test is not all that expensive, right? That depends. According to a National Public Radio story, the test costs about $2,000 in the United States. Some insurances will cover that. Some leave the patient with as much as $330 out of pocket. One way or another, in the United States, we’re paying the manufacturer over $100 million a year for this. I must sound like one of those old doctors who thinks a stethoscope is a perfectly good way to diagnose pneumonia, so who needs an x-ray, let alone a CT scan. Well, these pharmacogenomic tests will get better. For now, how much shall we all pay to help 5 more patients per 100 achieve remission at 12 weeks and land a point lower on the PHQ-9 when treatment as usual will get them outcomes equal to the testing group 3 months later? If we could divert and direct that money, would we spend the $20,000 those 100 tests actually cost to do something else?

There’s more in this paper, which is linked here at the Psychopharmacology Institute, including data on how many patients got metabolically appropriate antidepressants. Unfortunately, no data on side effects, which would really matter in that respect, although these may be forthcoming data in another publication because they were assessed. Take note that this paper was published in the Journal of the American Medical Association (JAMA), not JAMA Psychiatry. So, this is a milestone publication regardless of what you make of the results.

Abstract

Effect of Pharmacogenomic Testing for Drug–Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trials

David W Oslin, Kevin G Lynch, Mei-Chiung Shih, Erin P Ingram, Laura O Wray, Sara R Chapman, Henry R Kranzler, Joel Gelernter, Jeffrey M Pyne, Annjanette Stone, Scott L DuVall, Lisa Soleymani Lehmann, Michael E Thase; PRIME Care Research Group; Muhammad Aslam, Steven L Batki, James M Bjork, Frederic C Blow, Lisa A Brenner, Peijun Chen , Shivan Desai , Eric W Dieperink , Scott C Fears , Matthew A Fuller , Courtney S Goodman , David P Graham , Gretchen L Haas , Mark B Hamner , Amy W Helstrom , Robin A Hurley , Michael S Icardi , George J Jurjus , Amy M Kilbourne , Julie Kreyenbuhl , Daniel J Lache Steven P Lieske Julie A Lynch Laurence J Meyer Cristina Montalvo Sumitra Muralidhar Michael J Ostacher Gayla Y Paschall Paul N Pfeiffer Susana Prieto Ronald M Przygodzki Mohini Ranganathan Mercedes M Rodriguez-Suarez Hannah Roggenkamp Steven A Schichman John S Schneeweis Joseph A Simonetti Stuart R Steinhauer Trisha Suppes Maria A Umbert Jason L Vassy Deepak Voora Ilse R Wiechers Amanda E Wood

IMPORTANCE

Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment.

OBJECTIVE

To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS

A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications.

INTERVENTIONS

Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978).

MAIN OUTCOMES AND MEASURES

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). Remission was analyzed as a repeated measure across 24 weeks by blinded raters.

RESULTS

Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. 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% 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 < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). 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 = .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 = .45).

CONCLUSIONS AND RELEVANCE

Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.

Reference

Oslin, D. W., Lynch, K. G., Shih, M. C., Ingram, E. P., Wray, L. O., Chapman, S. R., … & PRIME Care Research Group. (2022). 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, 328(2), 151-161.