Kathryn Blake, Lindsay J. Hines, Michelle Liu, Rachel A. Myers, Jordan Baye, Kerri L. Cavanaugh, Benjamin Q. Duong, Leslie A. Hulvershorn, Carol A. Mathews, James W. Murrough, Lori A. Orlando, Natasha Petry, Emma M. Tillman, Azita Sadeghpour, Deepak Voora, Sara Block, Emily J. Cicali, Sabrina Clermont, Erica N. Elwood, Elizabeth Harris, Khoa A. Nguyen, Michelle A. Ramos, Marc B. Rosenman, Nandini Shroff, Saskia Shuman, Christina Wyatt, Carol R. Horowitz, Simona Volpi, Rajbir Singh, Renee Rider, Hrishikesh Chakraborty, Paul Dexter, Julie A. Johnson, Todd C. Skaar, Larisa H. Cavallari, Josh F. Peterson, IGNITE Pragmatic Trials Network, Neil Calman, Kerri Cavanaugh, Geoff Ginsburg, Kady-Ann Steen-Burrell, Bhargav Adagarla, Sarah George, Phyllis Kennel, Kristen Linney, Rania Metry, Wanda Parker, Gayle Passmore, Carol Pereira, Teji Rakhra-Burris, Jaclyn Holland, Yashika Johnson, Ryanne Wu, Ruth Lehan, Tyffany Locklear, Sabrina Clermont, BART FERKET, Kenneth Fifer, Diane Hauser, Joseph Kannry, James Murrough, Janet Seo, Tatiana Sabin, Nandini Shroff, Saskia Shuman, Abi Colwell, Amy M. Breman, Zeru Desta, Cathy Fulton, Jennelle C. Hodge, Sheryl Lynch, Jonathan Oliver, Victoria M. Pratt, Ross Robinson, Elizabeth Rowe, Jennifer Stuart, Ashley Vetor, Kelsey Cook, Karam Diaby, Julio Duarte, Ben Duong, Karla Giron, Elizabeth Eddy, Julia Krutov, Carol Mathews, Haesuk Park, Robyn Nelson, Ryan Rhoden, Caroline Schlierle, Taylor Sullivan, Almut Winterstein, Kristen Wiisanen, Sara Van Driest, Sara Block, Michelle Benck, Chantel Bender, Sylvia Eluhu, Colette Free, Shane Gonnelly, Sarah Hedeen
Importance: The effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation. Objective: To determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression. Design, Setting, and Participants: The ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer. Intervention: Patients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment. Main Outcomes and Measures: The primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months. Results: This study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P = .13). However, at 6 months, the PROMIS depression T-score remission rate (score ≤16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial).