Genotype-guided prescribing missed its primary endpoint, even when the study was not blinded.
STUDY: Blake KV et al, JAMA Netw Open 2026;9(5)
STUDY TYPE: Randomized unblinded clinical trial
FUNDING: National Institutes of Health (National Human Genome Research Institute)
Background
Pharmacogenetic tests make sense in depression, but it’s not clear that they make a difference for the average patient. Early, unblinded trials were encouraging, but when put to the more rigorous test of blinding, the benefits disappeared. That suggests hopeful expectations are guided the recoveries here, whether conveyed by the unblinded clinician who is more confident in their prescriptions or the patient who get this high-tech test.
This study looks impressive. Large and randomized, and focused on the two CYP tests that matter most. There are some positive secondary outcomes, but a big caveat.
The Study
- 1,460 patients aged 8 and older with depression at primary care and psychiatry clinics in US
- Randomized to genotype-guided SSRI prescribing or usual care for 6 months
- The intervention used genetic variants in two liver enzymes — CYP2C19 and CYP2D6 — to flag patients whose metabolism would make standard SSRI doses likely to underperform or cause side effects.
- Only those with an “actionable” phenotype (about 47% of the group) were expected to benefit from the guidance; the primary analysis focused on these 692 patients.
Genotype results were returned to the treating clinician within 7 to 10 days, along with clinical decision support built into the electronic health record. Clinicians could act on the recommendations or ignore them.
At 3 months (the primary outcome), symptoms improved in both groups, but the difference was not statistically significant (mean change in PROMIS T score: -4.3 with genotype guidance vs. -4.0 with usual care; p = .68). Side effect burden was similar.
At 6 months, however, remission rates were meaningfully higher in the genotype-guided group: 48% vs. 39% (p = .02).
Limitations: This study was not blinded, which allows a strong placebo effect to sneak in, but wait. Why didn’t we see that boost early on?
The delayed benefit has more credibility to it, as by this time the excitement of the test is likely to wear off.
Practice Implications
- Consider this hypothesis generating. Maybe future blinded trials will see a long-term difference with genetic testing, even if they fail to change outcomes in the short term.
- Why the failure? Antidepressants have a wide therapeutic window, and outside of the tricyclics they don’t work better at higher doses. That’s why we don’t check serum levels on them, and likely why pharmacokinetic CYP tests fail (also, 30-40% of the CYP metabolic rate is driven by non-genetic factors).
- As for the pharmacodynamic tests, which weren’t included here (like SERT), the brain is too complicated for single-genes to predict much.
- Learn more about which genetic tests make a difference in Prescribing Psychotropics.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
