Compared with usual care, genotype-guided prescribing of selective serotonin reuptake inhibitors (SSRI) in children and adults with depression didn’t improve symptoms at 3 months but was associated with higher remission rates at 6 months, results of a large randomized trial revealed.

While depression scores were similar between groups at 3 months, nearly half of the participants taking an SSRI selected after pharmacogenetic testing reported symptom remission after 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,” wrote the authors, led by Kathryn V. Blake, PharmD, Center for Pharmacogenomics and Translational Research, Nemours Children’s Health, Jacksonville, Florida.

The findings were published online on May 6 in JAMA Network Open.

Resistance to Genotype-Guided Care?

SSRI are the most prescribed pharmacotherapy for depression, but their effectiveness is often suboptimal. As variants in the cytochrome P450 enzymes CYP2D6 and CYP2C19 can significantly affect SSRI metabolism, treatment decisions informed by pharmacogenetic testing in patients with depression may improve medication efficacy.

Clinical Pharmacogenetics Implementation Consortium guidelines provide recommendations for SSRI prescribing when genotype information is available. However, most psychiatry experts and practice guidelines haven’t endorsed pharmacogenetic-informed therapy, citing insufficient evidence, the researchers wrote.

The ADOPT PGx Depression study — one of three randomized clinical trials testing whether pharmacogenetic testing improves medication response — included 1460 individuals with depression (75.1% women; 65.6% White or European American individuals; 15.8% Black or African American individuals) from nine US health systems. Nearly 85% of the cohort were adults (mean age, 40.6 years) and 15% were children (mean age, 14.6 years).

At baseline, participants had moderate depressive symptoms, with a mean Patient-Reported Outcomes Measurement Information System (PROMIS) depression T score of 61.5, and a mean Patient Health Questionnaire-8 (PHQ-8) score of 12.6.

No Effect at 3 Months

Researchers collected DNA samples at baseline to determine genetic variants in CYP2C19 and CYP2D6. Participants either received genotype-guided SSRI prescribing (intervention group) or usual care (control group). Frequencies of CYP2C19 and CYP2D6 phenotypes were evenly distributed between groups.

Investigators focused on “actionable phenotypes,” defined as those for which clinical guidelines recommend selecting an alternative medication or dose adjustment. The actionable phenotype population included 692 patients (50.7% in the intervention group and 49.3% in the control group.)

Overall, 34.5% of patients reported taking strong or moderate CYP2D6 inhibitors (or both), with no differences between groups.

About 6.3% of the genotype-guided group and 6.2% in the usual care group failed to complete the PROMIS survey or discontinued the study, leaving 649 patients as the actionable phenotype population for analysis of the primary endpoint of change in PROMIS depression T scores from baseline to 3 months after treatment initiation.

At 3 months, the mean PROMIS T scores were 57.0 in the genotype-guided group vs 57.5 in the usual care group (mean difference, -0.3; P = .67).

As for secondary outcomes, there were no significant between-group differences in the mean change in the PHQ-8 scores or the proportion of patients with a 50% or greater decrease in PHQ-8 score at 3 months.

Significant Differences in 6-Month Remission

However, the proportion of patients who experienced remission from depression (defined as a depression score of 16 or less on PROMIS) was significantly higher in the genotype-guided group at 6 months. Based on PROMIS scores, 48.3% of those in the genotype-guided group achieved symptom remission compared with 39.4% in the usual care group (P = .02).

Similarly, remission based on PHQ-8 scores was more frequent in the genotype-guided group than in the usual care group (29.9% vs 21.0%; P = .01).

“The higher remission rates observed at 6 months in this trial suggest a potential longer-term benefit that warrants further study,” the researchers wrote.

The most frequently reported moderate or severe adverse effects were sleepiness, anxiety, trouble sleeping, and fatigue, affecting 30%-50% of patients. The severity of adverse effects was similar between groups at 3 months.

As the design of the study prevented formal assessment of a major depression diagnosis, the study may have included patients with milder forms of depression. Another limitation is that patients could access their genotype results, which may have influenced their responses to study assessments.

Also, detailed data on the timing of medication changes were not collected, and there were delays in follow-up visits, especially during the COVID pandemic. This, as well as the pragmatic study design not restricting other antidepressant treatments, could have affected the power to detect between-group differences.

This study was supported by the National Institutes of Health (NIH) and by the NIH IGNITE Network Genome Medicine Knowledge Base. Disclosure information for study authors is available in the original study publication.