Genetic tests are marketed with a bold claim: that a handful of genes can predict medication response. AssureRx’s GeneSight is the most popular of these tests, and in 2015 we reviewed the evidence behind its panel. In short, it was lacking, but the company has just released new data that may move it a little closer to the mainstream.
What’s in the test
GeneSight looks at two areas where genetics can influence medication response:
1. Pharmacokinetics. Around 20%–30% of people have genetic variations in their metabolic enzymes that can lead to levels of many psychiatric medications that are abnormally high (ie, slow metabolizers) or abnormally low (ie, fast metabolizers).
2. Pharmacodynamics. While pharmacokinetics is about serum levels, pharmacodynamics is about the brain’s response to medications, which may be shaped by genetics.
GeneSight uses this information to create a stoplight with three categories of recommendations: Green (no worries—go ahead and prescribe this medication), Yellow (proceed with caution), and Red (best to avoid). Other companies present their results in a similar style, but each company’s results are driven by different, proprietary algorithms, which limits the ability of independent investigators to evaluate their validity. In other words, we’re stuck with industry-supported trials, and so far GeneSight has the largest number of them.
What we know so far
Before this new study was released, GeneSight’s clinical data had run into a brick wall. The positive studies were poorly designed, while the well-designed studies were negative. Two open-label, non-randomized studies with a total of 209 subjects suggested that GeneSight improved outcomes in depression. However, a randomized, double-blind trial failed to replicate that benefit (Zeier Z et al, Am J Psychiatry 2018;175(9):873–886). That negative study was small, involving 49 subjects, so the company undertook a larger study to see if they could demonstrate the value of their test.
A new study
GeneSight’s latest study is the largest to date, involving 1,167 subjects with moderate to severe treatment-resistant depression. They were randomized to receive antidepressant therapy that was guided either by GeneSight or by the clinician’s usual care. Most patients had failed at least 3 antidepressants, although only 1 failure was required for study inclusion. After 8 weeks, there were no significant differences between the two groups on the primary outcome measure, which was improvement on the Hamilton Depression Rating Scale (HAM-D). Although the study failed on the primary measure, results were marginally positive on secondary outcomes of response (≥ 50% improvement on the HAM-D, achieved by 26% in the GeneSight group vs 20% in the controls) and remission (final HAM-D ≤ 7, achieved by 15% in the GeneSight group vs 10% in the controls) (Greden JF et al, J Psychiatr Res 2019;111:59–67).
How impressive are these results?
A glance at GeneSight’s new brochure would have you believe the results are quite impressive. The secondary outcomes are on the cover, magnified to accentuate a small difference. In reality, you’d need to test 20 patients with treatment-resistant depression to bring 1 patient to remission. The results look a little better when limited to those patients who were switched from medications that were poorly matched with their genes to those that, according to the test, were a better fit. In this group, you’d need to test 8 patients to bring 1 to remission. That’s still fairly modest, and keep in mind that only 1 in 5 patients entered the study on medications that did not match their genes.