Genotype‐guided SSRI prescribing might have long‐term benefit

Abstract

Although it is believed that pharmacogenetic testing could successfully inform medication choice for patients with depression, limited research evidence to this point has discouraged formal recommendation of the practice in clinical guidelines. Investigators conducted a randomized trial to compare the effects of genotype-guided prescribing of selective serotonin reuptake inhibitors (SSRIs) and usual care in children and adults with depression. The Adopt PGx Depression trial enrolled individuals aged 8 and older with a diagnosis of depression and evidence of experiencing at least three months of depressive symptoms. Participants had no psychiatric or neurologic conditions likely to affect study outcomes. DNA samples were collected for all participants, with pharmacogenetic phenotype determined by genetic variants in the SSRI-metabolizing enzymes CYP2C19 and CYP2D6. For participants in the genotype-guided prescribing group, clinical decision support information was delivered through the electronic health record to guide medication selection. The primary outcome was change in depression scores as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) from baseline to 3 months following the return of genetic testing results to the clinician in the genotype-guided group (and an equivalent time frame in the usual-care group). A total of 1,460 participants were randomized; nearly 85% were adults with a mean age of 40.6 years. At 3 months, both the genotype-guided and usual-care groups experienced a reduction in PROMIS depression T scores, with no significant between-group difference. At 6 months, however, depression remission rates were significantly higher in the genotype-guided group, as measured by both the PROMIS and the Patient Health Questionnaire-8. There was a significant downward trend in depressive symptoms among individuals with an actionable phenotype. Adverse effect severity at 3 months was similar between the two groups. “These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on evaluating the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms,” the study's authors wrote. [Blake, K., et al. (2026). JAMA Network Open. https://doi.org/10.1001/jamanetworkopen.2026.10609]