A large trial of genotype-guided antidepressant prescribing finds no early benefit but higher remission later

A randomized clinical trial found that using genetic test results to guide the prescription of selective serotonin reuptake inhibitors (SSRIs) for depression did not improve symptoms after 3 months compared with usual care. However, among patients whose genetic profiles called for a different medication or dose, 48% of those in the genotype-guided group reached remission at 6 months, compared with 39% of those receiving usual care. The paper was published in JAMA Network Open.

Depression is a common mental health disorder marked by persistent low mood, loss of interest or pleasure, and other symptoms that can substantially disrupt everyday life. Its prevalence has risen over the past decade among adults, adolescents, and school-aged children. Uncontrolled depression is closely linked to suicide, which is now the second leading cause of death among adolescents and young adults.

One of the most widely used treatments for depression is a class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs. These medications increase the availability of the neurotransmitter serotonin in the brain by reducing its reuptake into nerve cells. Although SSRIs are commonly prescribed, they do not work equally well for everyone. They can also take six weeks or longer to produce a response, and can cause adverse effects that lead some patients to stop treatment.

Part of this variability may be related to genetic differences in the liver enzymes that break down SSRIs, particularly CYP2D6 and CYP2C19. Variants in the genes for these enzymes can make a person a poor, intermediate, normal, rapid, or ultrarapid metabolizer, changing how much of an SSRI remains in the body. Some other medications can also slow CYP2D6 activity, producing a similar effect. Genotype-guided prescribing uses genetic test results to help clinicians choose a medication or dose suited to how a person processes it.

The Clinical Pharmacogenetics Implementation Consortium has published guidelines for adjusting SSRI prescriptions based on these genes, but most psychiatry experts and practice guidelines have not endorsed routine genetic testing, citing insufficient evidence. Earlier trials have been criticized for relying on proprietary commercial algorithms, using small samples, or failing to meet their main goals.

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Study author Kathryn V. Blake of Nemours Children’s Health in Jacksonville, Florida, and her colleagues conducted a large randomized clinical trial to test whether genotype-guided SSRI prescribing improves depression in routine clinical care. The trial focused on CYP2D6 and CYP2C19 and used publicly available guidelines rather than a commercial algorithm to generate recommendations.

Study participants were 1,460 people with depression treated at primary care, psychiatry, and family medicine clinics in nine U.S. health systems between 2021 and 2024. Participants were aged 8 years or older, had experienced depression for 3 months or longer, and were about to start or adjust SSRI treatment. They included 1,239 adults, with an average age of 41, and 221 children and adolescents, with an average age of 15; 75% were female.

Participants were randomly assigned either to a genotype-guided group or to usual care. All provided DNA samples, which were analyzed for variants in the genes for CYP2D6 and CYP2C19, but only the genotype-guided group’s results were returned during the study; the usual care group’s samples were analyzed after it ended.

For the genotype-guided group, clinicians received recommendations about which SSRI to prescribe and at what dose through electronic health record alerts, consult notes, or pharmacist consultations, based on established guidelines and drug labels. The recommendations also accounted for other medications that can slow CYP2D6 activity. Clinicians were not required to follow the recommendations. The SSRIs covered were sertraline, escitalopram, citalopram, fluvoxamine, and paroxetine.

The main analyses focused on the 692 participants (about 47%) whose genetic results were “actionable,” meaning guidelines recommended a different medication or dose for them. Depression symptoms were measured with Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires for adults and children, and with the Patient Health Questionnaire-8 as a secondary measure.

At 3 months, depression symptoms had decreased modestly in both groups, but the decrease was nearly identical, and side effects were similar as well. At 6 months, however, 48% of patients in the genotype-guided group had reached remission on the PROMIS measure, compared with 39% in the usual care group. Using the second questionnaire, remission rates were 30% and 21%, respectively.

The genetic guidance did change prescribing: at 3 months, 85% of patients in the genotype-guided group were taking a medication and dose consistent with their genetic profile, compared with 74% in the usual care group. Among patients whose results did not call for any change, the two groups did not differ.

“In this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms,” study authors concluded.

The study contributes to the development of new ways to treat depression. However, the trial did not meet its primary goal of improving symptoms at 3 months, and the 6-month remission rates were secondary outcomes. Clinicians and patients also knew which group they were in, and patients could see their genetic results in their health records, which may have influenced how they reported their symptoms.

The authors also note that the study design did not include a formal diagnosis of major depression, so the sample may have included patients with milder forms of depression. About 15% of patients in the genotype-guided group with actionable results were still not receiving a gene-matched prescription at 3 months, and delays in treatment changes, which were not tracked, may help explain why differences did not appear until later.

The paper, “Genotype-Guided Antidepressant Prescribing for Patients With Depression: A Randomized Clinical Trial,” was authored by Kathryn V. Blake, Lindsay J. Hines, Michelle Liu, Rachel A. Myers, Jordan F. Baye, Kerri L. Cavanaugh, Benjamin Q. Duong, Leslie A. Hulvershorn, Carol A. Mathews, James W. Murrough, Lori A. Orlando, Natasha J. Petry, Emma M. Tillman, Azita Sadeghpour, Deepak Voora, Sara L. Block, Emily J. Cicali, Sabrina Clermont, Erica N. Elwood, Elizabeth C. Harris, Khoa A. Nguyen, Michelle A. Ramos, Marc B. Rosenman, Nandini Shroff, Saskia Shuman, Christina Wyatt, Carol R. Horowitz, Simona Volpi, Rajbir Singh, Renee A. Rider, Hrishikesh Chakraborty, Paul R. Dexter, Julie A. Johnson, Todd C. Skaar, Larisa H. Cavallari, and Josh F. Peterson.